**Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index**

Chi Lin, Shifeng Chen and Michael J. Baine *University of Nebraska Medical Center, USA* 

#### **1. Introduction**

Approximately 44,000 patients will develop new pancreatic cancers in the US in 2011 and 38,000 patients will die from the disease (ACS). Prognosis is directly related to the extent of tumor. The median survivals for these patients range from 11-18 months for those with localized disease, 10-12 months for those with locally advanced disease, and 5-7 months for those with metastatic disease, respectively (Evans DBAJ 2011). Although surgical resection is the only treatment associated with long-term survival, patients with resectable diseases usually account for only 20-25% of cases at diagnosis.

Despite resection, local regional recurrence and distant metastases occur in up to 50% of patients and two-year survival rates range from 20-40% with surgery alone. In 1974, the Gastrointestinal Tumor Study Group prospectively randomized patients after curative resection of pancreatic adenocarcinoma to adjuvant chemoradiation versus observation. The results of this study indicated a doubling of median and quadrupling of long-term survival with adjuvant chemoradiation (median, 20 vs. 11 months; 5-year survival, 19% vs. 5%). A US Intergroup study compared gemcitabine vs. infusional 5-FU chemotherapy for one month prior to and three months after chemoradiation, consisting of continuous infusional 5-FU, as adjuvant therapy after pancreatic cancer resection; outcome in those with tumor located in the pancreatic head was the primary study endpoint (Regine et al. 2008). The gemcitabine plus chemoradiation arm was superior to the 5-FU plus chemoradiation arm, with a median survival of 20.6 months vs. 16.9 months and survival at 3-years of 32% vs. 21%. This survival advantage came at a cost of appreciable toxicity, with grade 3-4 hematologic and nonhematologic toxicities occurring in 58% and 58% of subjects, respectively. Oettle et al compared gemcitabine given at 1000 mg/m² weekly for 3 of 4 weeks x 6 cycles to no additional therapy in 368 patients with resected pancreatic cancer (Oettle et al. 2007). Adjuvant gemcitabine was associated with a significant improvement in disease-free survival (13.4 vs 6.9 months), and a trend towards improvement in overall survival (median 22.1 vs 20.2 months); 34% of those receiving gemcitabine were alive at 3 yr vs. 20.5% with

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

radiation in larger fractions over a shorter time.

5 Gy x 5.

**2. Methods 2.1 Patients** 

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 5

Where *n* is the # of fractions and *d* is the dose/fraction. The "alpha-beta ratio" characterizes the radiation response of a particular tissue; a higher value is indicative of a tissue that responds acutely to the effects of radiation. Due to their highly proliferative nature, most tumors fall into this category. Because prolonging the treatment time introduces a sparing (repair) effect in acutely responding tissues, there is significant motivation to deliver

As the duodenum is in closest proximity to the majority of the pancreatic head tumors, it is impossible to avoid treating this structure to a relatively high radiation dose. Koong et al's data suggests that it is possible to irradiate a small volume of duodenum to a dose of 22.5 Gy in one fraction with acceptable toxicity. While the dose-fractionation scheme employed by Koong et al resulted in no significant morbidity, we proposed a phase I study of hypofractionated stereotactic body radiotherapy as part of a neoadjuvant regimen in patients with locally advanced pancreatic cancer using a more conservative starting dose of

The types of geometric uncertainties that should be considered in stereotactic body radiotherapy include tumor motion and patient position (setup error). Discrepancies between the actual and planned positions of targets and organs-at-risk during stereotactic body radiotherapy can lead to reduced doses to the tumor and/or increased doses to normal tissues than planned, potentially reducing the local control probability and/or increasing toxicity. Therefore, accurate and precise target localization is critical for hypofractionated stereotactic body radiotherapy. Studies found that the bony anatomy is a poor surrogate for intraabdominal (Herfarth et al. 2000) and intrathoracic (Guckenberger et al. 2006; Sonke, Lebesque, and van Herk 2008) targets. Therefore, direct tumor localization is important. Unfortunately, soft tissues are not seen on Exac-Trac (BrainLAB, Heimstetten, Germany) Xray images. Thus, fiducial markers for the pancreatic cancer are required. The purpose of the current study is to assess daily set-up error using the Exac-Trac system and implanted pancreatic fiducial markers during stereotactic body radiotherapy for patients with locally advanced pancreatic adenocarcinoma in the current ongoing institutional phase I study and

Included in this study are adult patients (≥ 19 years old) who had a Karnofsky performance status of ≥ 60 and underwent stereotactic body radiotherapy planning and treatment between October 2008 and February 2011 as part of an institutional research ethics boardapproved study of neoadjuvant hypofractionated stereotactic body radiotherapy following chemotherapy in patients with borderline resectable or unresectable pancreatic adenocarcinoma. Daily isocenter positioning correction was investigated in 26 patients treated with 5 fractions of SBRT for locally advanced pancreatic cancer. Two fiducial markers were implanted into the pancreatic head approximately two centimeters apart. With daily Exac-Trac images, 3 dimensional couch shifts were made by matching corresponding fiducial markers to the digitally reconstructed radiograph from a simulation CT scan. BMI was calculated by Weight (kg)/Height2 (m2) and categorized into normal

to evaluate the effect of body mass index (BMI) on set-up error correction.

weight 18.5 -25 (kg/m2) and overweight/obese >25 (kg/m2).

surgery alone. Grade 3-4 hematologic and non-hematologic toxicities occurred in fewer than 5% of subjects receiving gemcitabine.

While these studies indicate improvement with adjuvant therapy, there is still need to improve upon these results. A disadvantage of adjuvant therapy is that as many as 25% of patients have their treatment either delayed or forgone due to post-operative complications (Yeo CJ 1997; Spitz et al. 1997; Klinkenbijl et al. 1999). In an effort to increase the number of patients receiving adjuvant therapy, chemotherapy and radiation therapy can be administered pre-operatively (neoadjuvantly) to potential surgical candidates. Additional potential benefits of pre-operative therapy include the delivery of therapy to welloxygenated tissues, the potential to downstage tumors (particularly when the lesion is borderline resectable or unresectable because of regional factors such as tumor involvement of the superior mesenteric vein or portal vein, or tumor abutment/encasement of the superior mesenteric artery or celiac trunk or gastroduodenal artery up to hepatic artery), and the opportunity to observe patients for the development of metastatic disease during therapy. After maximal tumor shrinkage and no interval development of metastatic disease, surgery can be considered.

The current standard neoadjuvant regimen includes several months of chemotherapy followed by 5 – 6 weeks of radiation therapy concurrent with radiation sensitizing chemotherapy, followed by a 4 - 6 week therapy break prior to surgery. This chemoradiation regimen is fairly debilitating. ECOG (Pisters et al. 2000) conducted a phase II trial of preoperative conventional (50.4 Gy, 1.8 Gy/fraction) chemoradiation, showing that 51% of patients had toxicity-related hospital admissions. Treatment-related toxicities were found to be proportional to the irradiated volume and radiation dose. At M.D. Anderson, an accelerated radiotherapy schedule using 30 Gy in 10 fractions appeared to be more tolerable and equally effective (Breslin et al. 2001; Pisters et al. 1998). A recent randomized trial (Bujko et al. 2006) has compared preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. The results showed no difference in actuarial 4-year overall survival (67.2% in the short-course group vs. 66.2% in the chemoradiation group, P = 0.960), disease-free survival (58.4% vs. 55.6%, P = 0.820), and crude incidence of local recurrence (9.0% vs. 14.2%, P = 0.170). The study also reported similar late toxicity (10.1% vs. 7.1%, P = 0.360) and higher early radiation toxicity in the chemoradiation group (18.2% vs. 3.2%, P < 0.001). These data suggest the equivalence in efficacy between short course and long course neoadjuvant therapy. Koong et al. (Koong et al. 2004) has conducted a phase I study of stereotactic radiosurgery in patients with unresectable pancreatic cancer. Fifteen patients were treated at 3 dose levels (3 patients received 15 Gy in 1 fraction, 5 patients received 20 Gy in 1 fraction, and 7 patients received 25 Gy in 1 fraction). No Grade 3 or higher acute GI toxicity was observed. In the 6 evaluable patients who received 25 Gy, the median survival was 8 months. All patients in the study had local control until death or progressed systemically as the site of first progression. This study suggests the feasibility of stereotactic radiosurgery in pancreatic cancer.

Following the methodology of Koong et al, one can apply the linear-quadratic formulism for radiation cell killing to "equate" schemes that vary the dose/fraction and number of fractions. This concept of biologically equivalent dose says that the total effect is given by:

$$(nd)\left\{1+d\left\langle \frac{\alpha}{\beta} \right\rangle\right\}$$

Where *n* is the # of fractions and *d* is the dose/fraction. The "alpha-beta ratio" characterizes the radiation response of a particular tissue; a higher value is indicative of a tissue that responds acutely to the effects of radiation. Due to their highly proliferative nature, most tumors fall into this category. Because prolonging the treatment time introduces a sparing (repair) effect in acutely responding tissues, there is significant motivation to deliver radiation in larger fractions over a shorter time.

As the duodenum is in closest proximity to the majority of the pancreatic head tumors, it is impossible to avoid treating this structure to a relatively high radiation dose. Koong et al's data suggests that it is possible to irradiate a small volume of duodenum to a dose of 22.5 Gy in one fraction with acceptable toxicity. While the dose-fractionation scheme employed by Koong et al resulted in no significant morbidity, we proposed a phase I study of hypofractionated stereotactic body radiotherapy as part of a neoadjuvant regimen in patients with locally advanced pancreatic cancer using a more conservative starting dose of 5 Gy x 5.

The types of geometric uncertainties that should be considered in stereotactic body radiotherapy include tumor motion and patient position (setup error). Discrepancies between the actual and planned positions of targets and organs-at-risk during stereotactic body radiotherapy can lead to reduced doses to the tumor and/or increased doses to normal tissues than planned, potentially reducing the local control probability and/or increasing toxicity. Therefore, accurate and precise target localization is critical for hypofractionated stereotactic body radiotherapy. Studies found that the bony anatomy is a poor surrogate for intraabdominal (Herfarth et al. 2000) and intrathoracic (Guckenberger et al. 2006; Sonke, Lebesque, and van Herk 2008) targets. Therefore, direct tumor localization is important. Unfortunately, soft tissues are not seen on Exac-Trac (BrainLAB, Heimstetten, Germany) Xray images. Thus, fiducial markers for the pancreatic cancer are required. The purpose of the current study is to assess daily set-up error using the Exac-Trac system and implanted pancreatic fiducial markers during stereotactic body radiotherapy for patients with locally advanced pancreatic adenocarcinoma in the current ongoing institutional phase I study and to evaluate the effect of body mass index (BMI) on set-up error correction.

### **2. Methods**

4 Modern Practices in Radiation Therapy

surgery alone. Grade 3-4 hematologic and non-hematologic toxicities occurred in fewer than

While these studies indicate improvement with adjuvant therapy, there is still need to improve upon these results. A disadvantage of adjuvant therapy is that as many as 25% of patients have their treatment either delayed or forgone due to post-operative complications (Yeo CJ 1997; Spitz et al. 1997; Klinkenbijl et al. 1999). In an effort to increase the number of patients receiving adjuvant therapy, chemotherapy and radiation therapy can be administered pre-operatively (neoadjuvantly) to potential surgical candidates. Additional potential benefits of pre-operative therapy include the delivery of therapy to welloxygenated tissues, the potential to downstage tumors (particularly when the lesion is borderline resectable or unresectable because of regional factors such as tumor involvement of the superior mesenteric vein or portal vein, or tumor abutment/encasement of the superior mesenteric artery or celiac trunk or gastroduodenal artery up to hepatic artery), and the opportunity to observe patients for the development of metastatic disease during therapy. After maximal tumor shrinkage and no interval development of metastatic disease,

The current standard neoadjuvant regimen includes several months of chemotherapy followed by 5 – 6 weeks of radiation therapy concurrent with radiation sensitizing chemotherapy, followed by a 4 - 6 week therapy break prior to surgery. This chemoradiation regimen is fairly debilitating. ECOG (Pisters et al. 2000) conducted a phase II trial of preoperative conventional (50.4 Gy, 1.8 Gy/fraction) chemoradiation, showing that 51% of patients had toxicity-related hospital admissions. Treatment-related toxicities were found to be proportional to the irradiated volume and radiation dose. At M.D. Anderson, an accelerated radiotherapy schedule using 30 Gy in 10 fractions appeared to be more tolerable and equally effective (Breslin et al. 2001; Pisters et al. 1998). A recent randomized trial (Bujko et al. 2006) has compared preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. The results showed no difference in actuarial 4-year overall survival (67.2% in the short-course group vs. 66.2% in the chemoradiation group, P = 0.960), disease-free survival (58.4% vs. 55.6%, P = 0.820), and crude incidence of local recurrence (9.0% vs. 14.2%, P = 0.170). The study also reported similar late toxicity (10.1% vs. 7.1%, P = 0.360) and higher early radiation toxicity in the chemoradiation group (18.2% vs. 3.2%, P < 0.001). These data suggest the equivalence in efficacy between short course and long course neoadjuvant therapy. Koong et al. (Koong et al. 2004) has conducted a phase I study of stereotactic radiosurgery in patients with unresectable pancreatic cancer. Fifteen patients were treated at 3 dose levels (3 patients received 15 Gy in 1 fraction, 5 patients received 20 Gy in 1 fraction, and 7 patients received 25 Gy in 1 fraction). No Grade 3 or higher acute GI toxicity was observed. In the 6 evaluable patients who received 25 Gy, the median survival was 8 months. All patients in the study had local control until death or progressed systemically as the site of first progression. This

study suggests the feasibility of stereotactic radiosurgery in pancreatic cancer.

Following the methodology of Koong et al, one can apply the linear-quadratic formulism for radiation cell killing to "equate" schemes that vary the dose/fraction and number of fractions. This concept of biologically equivalent dose says that the total effect is given by:

> +

1)( *dnd*

 

β

α

5% of subjects receiving gemcitabine.

surgery can be considered.

#### **2.1 Patients**

Included in this study are adult patients (≥ 19 years old) who had a Karnofsky performance status of ≥ 60 and underwent stereotactic body radiotherapy planning and treatment between October 2008 and February 2011 as part of an institutional research ethics boardapproved study of neoadjuvant hypofractionated stereotactic body radiotherapy following chemotherapy in patients with borderline resectable or unresectable pancreatic adenocarcinoma. Daily isocenter positioning correction was investigated in 26 patients treated with 5 fractions of SBRT for locally advanced pancreatic cancer. Two fiducial markers were implanted into the pancreatic head approximately two centimeters apart. With daily Exac-Trac images, 3 dimensional couch shifts were made by matching corresponding fiducial markers to the digitally reconstructed radiograph from a simulation CT scan. BMI was calculated by Weight (kg)/Height2 (m2) and categorized into normal weight 18.5 -25 (kg/m2) and overweight/obese >25 (kg/m2).

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

maintain treatment accuracy.

**2.2.5 Dose computation** 

dose to normal tissues.

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 7

silicon flat panel detectors mounted to the ceiling. Each x-ray tube/detector pair is configured to image through the linac isocenter with a coronal field of view of approximately 18 cm in both the superior-inferior and left-right directions at isocenter. For soft tissue targets, the system is designed to be used with radio-opaque platinum markers implanted near the target. Two markers, 2 cm away from each other and placed close enough to the target anatomy so that they could be observed within the field of view of the x-ray localization system at the time of treatment, were implanted prior to CT imaging and treatment planning,. Specific patient breathing characteristics were determined during 4D CT. If the breathing pattern was adequate, respiratory-gated delivery (turning the beam on only at a specified phase of respiration) was used. This method "freezes" target motion and allows reduction of beam margins, thereby reducing the amount of irradiated normal tissue. The Novalis system is well suited to gated delivery and has been evaluated extensively by Tenn et al (Tenn, Solberg, and Medin 2005). The following is a brief procedural summary from that work which is incorporated into this study: The patient is set up in the treatment room and infrared reflective markers with adhesive bases are attached to their anterior surface so that breathing motion can be monitored. A second set of infrared reflective markers is rigidly attached to the treatment couch and used as a reference against which the movement of patient markers is measured. These rigidly mounted reflectors are also used to track couch location during the patient positioning process. The 3D movement of the patient's anterior surface is tracked via the infrared markers and the anterior-posterior component of this trajectory is used to monitor breathing motion. The system plots breathing motion versus time and a reference level is specified on this breathing trace. This designates the point in the breathing trace at which the verification x-ray images will be triggered. The two images are obtained sequentially at the instant the breathing trace crosses this level during exhale phase. Because the patient is localized based on these images, the gating level is set at the same phase in the breathing cycle at which the planning CT data was obtained. Within each image the user locates the positions of the implanted markers. From these positions the system reconstructs the 3D geometry of the implanted markers and determines the shifts necessary to bring them into alignment with the planning CT. The patient is subsequently positioned according to the calculated shifts. Finally, a gating window (beam-on region) during which the linac beam will be delivered is selected about the reference level. The system can gate the beam in both inhale and exhale phases of the breathing cycle. Subsequent x-ray images verifying the location of the implanted markers are obtained at the gating level continuously during treatment. If marker positions remain within tolerance limits, the target position may also be assumed to be correctly positioned. If they are outside the limit, the newly obtained images can be used to reposition the patient and

The treatment plan used for each patient was based on an analysis of the volumetric dose, including dose volume histogram (DVH) analyses of the PTV and critical normal structures. Treatment planning was accomplished with multiple coplanar conformal beams or arcs to allow for a high degree of dose conformality. The uniformity requirement is +10%/-5% of the total dose at the prescription point within the tumor volume. The IMRT was used if it was of benefit for decreasing tissue complications. Beam's Eye View techniques were used to select the beam isocenter and direction to fully encompass the target volume while minimizing the inclusion of the critical organs in order to select the plan that minimizes the

#### **2.2 Stereotactic body radiotherapy planning and treatment**

#### **2.2.1 Patient's positioning**

The treatment position of the patient was supine, with their arms above their head. The immobilization device (Medical Intelligence blue bag) was molded into an immobilizing bed for the intended patient's entire body to make sure that the patients' position was the same during planning, simulation and treatment.

#### **2.2.2 Patient data acquisition**

A treatment planning free breathing CT scan with IV contrast was required to define tumor, clinical, and planning target volumes. A respiratory sorted treatment planning 4D CT scan was then acquired with the patient in the same position and immobilized using the same device as used for treatment. All tissues to be irradiated were included in the CT scan, with a slice thickness of 3 mm. Conventional MRI scans (T1 and T2) were included to assist in definition of target volumes. FDG PET-CT, if available, was also included in the treatment planning. The Gross Tumor Volume (GTV), Clinical Target Volume (CTV), Planning Target Volume (PTV), and organs-at-risk were outlined on all CT slices in which the structures exist.

#### **2.2.3 Volumes**

The GTV was defined as all known gross disease determined from CT, clinical information, endoscopic findings, FDG PET-CT and/or conventional MRI. The Integrated Tumor Volume based on CT/MRI/PET (GTVfusion) was defined as gross disease on the free breathing CT scan, MRI scan and FDG-PET scan. These scans were correlated via image fusion technique. The volume was delineated by the treating physician on the above scans separately. The GTVCT, GTVMRI and GTVPET (if done) were eventually fused together to generate GTVfusion. Patients who had the maximal dimension of the GTVfusion > 8 cm were not eligible for the study. The CTV was defined as the GTVs plus areas considered containing potential microscopic disease. In this study, we had no intension to treat the potential microscopic disease with stereotactic body radiotherapy, therefore the CTV was defined as GTVs (i.e. both the primary tumor and the lymph nodes containing clinical or radiographic evidence of metastases) plus areas between GTVprimary and GTVlymph nodes. The integrated CTV was created with 4D CT information to compensate for internal organ motion. The PTV provided a margin around integrated CTV to compensate for the variability of treatment set-up. Organs-at-Risk were defined as follows: the skin surface, the unspecified tissue (the tissue within the skin surface and outside all other critical normal structures and PTVs was designated as unspecified tissue), spinal cord (spinal cord contours were defined at least 5 mm larger in the radial dimension than the spinal cord itself, i.e. the cord diameter on any given slice was 10 mm larger than the cord itself), duodenum, stomach, liver, right kidney, left kidney, small bowels excluding duodenum, and spleen.

#### **2.2.4 The treatment technique**

The Novalis accelerator (BrainLAB, Heimstetten, Germany) was used to deliver stereotactic body radiotherapy. It incorporates stereotactic x-ray capabilities for verifying target position. This consists of two floor mounted x-ray tubes and two opposing amorphous silicon flat panel detectors mounted to the ceiling. Each x-ray tube/detector pair is configured to image through the linac isocenter with a coronal field of view of approximately 18 cm in both the superior-inferior and left-right directions at isocenter. For soft tissue targets, the system is designed to be used with radio-opaque platinum markers implanted near the target. Two markers, 2 cm away from each other and placed close enough to the target anatomy so that they could be observed within the field of view of the x-ray localization system at the time of treatment, were implanted prior to CT imaging and treatment planning,. Specific patient breathing characteristics were determined during 4D CT. If the breathing pattern was adequate, respiratory-gated delivery (turning the beam on only at a specified phase of respiration) was used. This method "freezes" target motion and allows reduction of beam margins, thereby reducing the amount of irradiated normal tissue. The Novalis system is well suited to gated delivery and has been evaluated extensively by Tenn et al (Tenn, Solberg, and Medin 2005). The following is a brief procedural summary from that work which is incorporated into this study: The patient is set up in the treatment room and infrared reflective markers with adhesive bases are attached to their anterior surface so that breathing motion can be monitored. A second set of infrared reflective markers is rigidly attached to the treatment couch and used as a reference against which the movement of patient markers is measured. These rigidly mounted reflectors are also used to track couch location during the patient positioning process. The 3D movement of the patient's anterior surface is tracked via the infrared markers and the anterior-posterior component of this trajectory is used to monitor breathing motion. The system plots breathing motion versus time and a reference level is specified on this breathing trace. This designates the point in the breathing trace at which the verification x-ray images will be triggered. The two images are obtained sequentially at the instant the breathing trace crosses this level during exhale phase. Because the patient is localized based on these images, the gating level is set at the same phase in the breathing cycle at which the planning CT data was obtained. Within each image the user locates the positions of the implanted markers. From these positions the system reconstructs the 3D geometry of the implanted markers and determines the shifts necessary to bring them into alignment with the planning CT. The patient is subsequently positioned according to the calculated shifts. Finally, a gating window (beam-on region) during which the linac beam will be delivered is selected about the reference level. The system can gate the beam in both inhale and exhale phases of the breathing cycle. Subsequent x-ray images verifying the location of the implanted markers are obtained at the gating level continuously during treatment. If marker positions remain within tolerance limits, the target position may also be assumed to be correctly positioned. If they are outside the limit, the newly obtained images can be used to reposition the patient and maintain treatment accuracy.

#### **2.2.5 Dose computation**

6 Modern Practices in Radiation Therapy

The treatment position of the patient was supine, with their arms above their head. The immobilization device (Medical Intelligence blue bag) was molded into an immobilizing bed for the intended patient's entire body to make sure that the patients' position was the same

A treatment planning free breathing CT scan with IV contrast was required to define tumor, clinical, and planning target volumes. A respiratory sorted treatment planning 4D CT scan was then acquired with the patient in the same position and immobilized using the same device as used for treatment. All tissues to be irradiated were included in the CT scan, with a slice thickness of 3 mm. Conventional MRI scans (T1 and T2) were included to assist in definition of target volumes. FDG PET-CT, if available, was also included in the treatment planning. The Gross Tumor Volume (GTV), Clinical Target Volume (CTV), Planning Target Volume (PTV), and organs-at-risk were outlined on all CT slices in which the structures

The GTV was defined as all known gross disease determined from CT, clinical information, endoscopic findings, FDG PET-CT and/or conventional MRI. The Integrated Tumor Volume based on CT/MRI/PET (GTVfusion) was defined as gross disease on the free breathing CT scan, MRI scan and FDG-PET scan. These scans were correlated via image fusion technique. The volume was delineated by the treating physician on the above scans separately. The GTVCT, GTVMRI and GTVPET (if done) were eventually fused together to generate GTVfusion. Patients who had the maximal dimension of the GTVfusion > 8 cm were not eligible for the study. The CTV was defined as the GTVs plus areas considered containing potential microscopic disease. In this study, we had no intension to treat the potential microscopic disease with stereotactic body radiotherapy, therefore the CTV was defined as GTVs (i.e. both the primary tumor and the lymph nodes containing clinical or radiographic evidence of metastases) plus areas between GTVprimary and GTVlymph nodes. The integrated CTV was created with 4D CT information to compensate for internal organ motion. The PTV provided a margin around integrated CTV to compensate for the variability of treatment set-up. Organs-at-Risk were defined as follows: the skin surface, the unspecified tissue (the tissue within the skin surface and outside all other critical normal structures and PTVs was designated as unspecified tissue), spinal cord (spinal cord contours were defined at least 5 mm larger in the radial dimension than the spinal cord itself, i.e. the cord diameter on any given slice was 10 mm larger than the cord itself), duodenum, stomach, liver, right kidney, left kidney, small bowels excluding duodenum, and spleen.

The Novalis accelerator (BrainLAB, Heimstetten, Germany) was used to deliver stereotactic body radiotherapy. It incorporates stereotactic x-ray capabilities for verifying target position. This consists of two floor mounted x-ray tubes and two opposing amorphous

**2.2 Stereotactic body radiotherapy planning and treatment** 

**2.2.1 Patient's positioning** 

**2.2.2 Patient data acquisition** 

**2.2.4 The treatment technique** 

exist.

**2.2.3 Volumes** 

during planning, simulation and treatment.

The treatment plan used for each patient was based on an analysis of the volumetric dose, including dose volume histogram (DVH) analyses of the PTV and critical normal structures. Treatment planning was accomplished with multiple coplanar conformal beams or arcs to allow for a high degree of dose conformality. The uniformity requirement is +10%/-5% of the total dose at the prescription point within the tumor volume. The IMRT was used if it was of benefit for decreasing tissue complications. Beam's Eye View techniques were used to select the beam isocenter and direction to fully encompass the target volume while minimizing the inclusion of the critical organs in order to select the plan that minimizes the dose to normal tissues.

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

Fig. 1A. Longitudinal vs. Lateral couch shifts

Fig. 1B. Vertical vs. Longitudinal couch shifts

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 9

**Random Error Mean (mm) ± SD** **P (X2)** 

**Systematic Error Mean (mm) ± SD** 

**Lateral shift -0.3 ± 3.6 4.1 ± 2.8 <0.0001 Longitudinal shift -1.1 ± 4.1 5.5 ± 3.2 <0.0001 Vertical shift -0.1 ± 3.1 3.5 ± 2.0 <0.0001** Table 1. The averages of systematic and random daily couch shifts three-dimensionally

#### **2.2.6 Dose specification**

A 5-fraction dose was prescribed. The prescription dose was the isodose which encompasses at least 95% of PTV. DVHs were generated for all critical organs-at-risk. The dose to the kidneys was carefully monitored and kidney volumes were defined on simulation fields. The percent of total kidney volume (defined as the sum of the left and right kidney volumes) receiving 15 Gy (3 Gy per fraction) was required to be less than 35% of the total kidney volume. The maximum dose to any point within the spinal cord was not allowed to exceed 15 Gy (3 Gy per fraction). At least 700 ml or 35% of normal liver was required to receive a total dose less than 15 Gy (3 Gy per fraction). The maximum point dose to the stomach or small bowel except duodenum could not exceed 60% of prescription dose. An isodose distribution of the treatment at the central axis view indicating the position of kidneys, liver and spinal cord was required. Dose homogeneity was defined as follows: No more than 20% of PTV receive >110% of its prescribed dose; No more than 1% of PTV receive <93% of its prescribed dose; No more than 1% or 1 cc of the tissue outside the PTV receive >110% of the dose prescribed to the PTV.

#### **2.2.7 Daily target verification**

The locations of the implanted markers were verified on daily Exac-Trac X-Rays prior to the delivery of stereotactic body radiation therapy.

#### **2.3 Statistical analysis**

For each patient, the mean and standard deviation of daily 3-dimensional position shifts (lateral, longitudinal and vertical) were measured. The systematic error (the mean of all patients' means) and the random error (the standard deviation around the systemic error) were calculated for daily patient position shifts. The amplitude changes and variability in amplitude changes were also measured. Multivariate logistic regression was used to analyze the effect of patients' BMI on patient position changes. All statistical calculations were performed using SAS 9.2 (SAS Institute Inc., Cary, North Carolina, USA).

#### **3. Results**

#### **3.1 Systematic and random daily couch shifts**

A total of 127 treatments from 26 patients were studied. Table 1 provides a summary of the systematic and random couch shifts using implanted internal markers. The entire group mean (systematic) and standard deviation (random) of the couch shifts from the body surface markers are -0.4 ± 5.6 mm, -1.3 ± 6.6 mm and -0.3 ± 4.7 mm in lateral (left-right), longitudinal (superior-inferior) and vertical (anterior-posterior) directions, respectively. The mean systematic couch shifts > 0 occur in (13/26) 50%, (12/26) 46% and (10/26) 38% in the left-right, superior-inferior and anterior-posterior directions, respectively. The mean random couch shifts > 5mm occur in (7/26) 27%, (12/26) 46% and (5/26) 19% in the left-right, superior-inferior and anterior-posterior directions, respectively. The mean systematic couch shifts are significantly smaller than the mean random couch shifts in left-right (-0.3 ± 3.6 mm vs. 4.1 ± 2.8 mm, p < 0.0001), superior-inferior (-1.1 ± 4.1 mm vs. 5.5 ± 3.2 mm, p < 0.0001) and anterior-posterior (-0.1 ± 3.1 mm vs. 3.5 ± 2.0 mm, p < 0.0001) directions, respectively. The couch shifts for the majority of fractions are within ± 10 mm (Figure 1A-1C)


Table 1. The averages of systematic and random daily couch shifts three-dimensionally

Fig. 1A. Longitudinal vs. Lateral couch shifts

8 Modern Practices in Radiation Therapy

A 5-fraction dose was prescribed. The prescription dose was the isodose which encompasses at least 95% of PTV. DVHs were generated for all critical organs-at-risk. The dose to the kidneys was carefully monitored and kidney volumes were defined on simulation fields. The percent of total kidney volume (defined as the sum of the left and right kidney volumes) receiving 15 Gy (3 Gy per fraction) was required to be less than 35% of the total kidney volume. The maximum dose to any point within the spinal cord was not allowed to exceed 15 Gy (3 Gy per fraction). At least 700 ml or 35% of normal liver was required to receive a total dose less than 15 Gy (3 Gy per fraction). The maximum point dose to the stomach or small bowel except duodenum could not exceed 60% of prescription dose. An isodose distribution of the treatment at the central axis view indicating the position of kidneys, liver and spinal cord was required. Dose homogeneity was defined as follows: No more than 20% of PTV receive >110% of its prescribed dose; No more than 1% of PTV receive <93% of its prescribed dose; No more than 1% or 1 cc of the tissue outside the PTV

The locations of the implanted markers were verified on daily Exac-Trac X-Rays prior to the

For each patient, the mean and standard deviation of daily 3-dimensional position shifts (lateral, longitudinal and vertical) were measured. The systematic error (the mean of all patients' means) and the random error (the standard deviation around the systemic error) were calculated for daily patient position shifts. The amplitude changes and variability in amplitude changes were also measured. Multivariate logistic regression was used to analyze the effect of patients' BMI on patient position changes. All statistical calculations were

A total of 127 treatments from 26 patients were studied. Table 1 provides a summary of the systematic and random couch shifts using implanted internal markers. The entire group mean (systematic) and standard deviation (random) of the couch shifts from the body surface markers are -0.4 ± 5.6 mm, -1.3 ± 6.6 mm and -0.3 ± 4.7 mm in lateral (left-right), longitudinal (superior-inferior) and vertical (anterior-posterior) directions, respectively. The mean systematic couch shifts > 0 occur in (13/26) 50%, (12/26) 46% and (10/26) 38% in the left-right, superior-inferior and anterior-posterior directions, respectively. The mean random couch shifts > 5mm occur in (7/26) 27%, (12/26) 46% and (5/26) 19% in the left-right, superior-inferior and anterior-posterior directions, respectively. The mean systematic couch shifts are significantly smaller than the mean random couch shifts in left-right (-0.3 ± 3.6 mm vs. 4.1 ± 2.8 mm, p < 0.0001), superior-inferior (-1.1 ± 4.1 mm vs. 5.5 ± 3.2 mm, p < 0.0001) and anterior-posterior (-0.1 ± 3.1 mm vs. 3.5 ± 2.0 mm, p < 0.0001) directions, respectively.

performed using SAS 9.2 (SAS Institute Inc., Cary, North Carolina, USA).

The couch shifts for the majority of fractions are within ± 10 mm (Figure 1A-1C)

**2.2.6 Dose specification** 

receive >110% of the dose prescribed to the PTV.

delivery of stereotactic body radiation therapy.

**3.1 Systematic and random daily couch shifts** 

**2.2.7 Daily target verification** 

**2.3 Statistical analysis** 

**3. Results** 

Fig. 1B. Vertical vs. Longitudinal couch shifts

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

Fig. 2B. Cumulative distribution of absolute vertical couch shifts

Fig. 2C. Distribution of absolute longitudinal couch shifts

Fig. 2D. Cumulative distribution of absolute longitudinal couch shifts

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 11

Fig. 1C. Vertical vs. Lateral couch shifts

#### **3.2 Absolute systematic and random daily couch shifts**

The amplitudes of the systemic and random daily couch shifts are summarized in table 2. The mean amplitudes of systematic couch shifts are significantly larger than the mean amplitude of random couch shift in left-right (4.1 ± 2.9 mm vs. 2.5 ± 1.3 mm, p = 0.015), superior-inferior (5.2 ± 3.1 mm vs. 3.2 ± 1.6 mm, p = 0.007) and anterior-posterior (3.6 ± 1.5 mm vs. 2.5 ± 1.6 mm, p = 0.016) directions, respectively. The amplitudes of couch shifts in the superior-inferior direction are significantly larger than those in the left-right (p = 0.045) or anterior-posterior directions (p = 0.001). The absolute couch shifts ≤ 3 mm, ≤ 5 mm and ≤ 10 mm occur in (51%, 71% and 93%), (37%, 60% and 87%) and (51%, 73% and 98%) in the left-right, superior-inferior and anterior-posterior directions, respectively (Figure 2A-2F). There is no correlation among 3 dimensional couch shifts (Figure 3A-3C).

Fig. 2A. Distribution of absolute vertical couch shifts

Fig. 2B. Cumulative distribution of absolute vertical couch shifts

The amplitudes of the systemic and random daily couch shifts are summarized in table 2. The mean amplitudes of systematic couch shifts are significantly larger than the mean amplitude of random couch shift in left-right (4.1 ± 2.9 mm vs. 2.5 ± 1.3 mm, p = 0.015), superior-inferior (5.2 ± 3.1 mm vs. 3.2 ± 1.6 mm, p = 0.007) and anterior-posterior (3.6 ± 1.5 mm vs. 2.5 ± 1.6 mm, p = 0.016) directions, respectively. The amplitudes of couch shifts in the superior-inferior direction are significantly larger than those in the left-right (p = 0.045) or anterior-posterior directions (p = 0.001). The absolute couch shifts ≤ 3 mm, ≤ 5 mm and ≤ 10 mm occur in (51%, 71% and 93%), (37%, 60% and 87%) and (51%, 73% and 98%) in the left-right, superior-inferior and anterior-posterior directions, respectively (Figure 2A-2F).

Fig. 1C. Vertical vs. Lateral couch shifts

**3.2 Absolute systematic and random daily couch shifts** 

Fig. 2A. Distribution of absolute vertical couch shifts

There is no correlation among 3 dimensional couch shifts (Figure 3A-3C).

Fig. 2C. Distribution of absolute longitudinal couch shifts

Fig. 2D. Cumulative distribution of absolute longitudinal couch shifts

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

Fig. 3A. Absolute longitudinal vs. absolute lateral couch shifts

Fig. 3B. Absolute vertical vs. absolute lateral couch shifts

Fig. 3C. Absolute vertical vs. absolute longitudinal couch shifts

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 13

Fig. 2E. Distribution of absolute lateral couch shifts

Fig. 2F. Cumulative distribution of absolute lateral couch shifts


Table 2. The averages of absolute systematic and random daily couch shifts threedimensionally

Fig. 3A. Absolute longitudinal vs. absolute lateral couch shifts

Fig. 2E. Distribution of absolute lateral couch shifts

Fig. 2F. Cumulative distribution of absolute lateral couch shifts

Systematic Error Mean (mm) ± SD

Lateral shift 4.1 ± 2.9 2.5 ± 1.3 0.015 Longitudinal shift 5.2 ± 3.1 3.2 ± 1.6 0.007 Vertical shift 3.6 ± 1.6 2.5 ± 1.6 0.016

Table 2. The averages of absolute systematic and random daily couch shifts three-

Random Error Mean (mm) ± SD P (X2)

Absolute Value (Amplitude)

dimensionally

Fig. 3B. Absolute vertical vs. absolute lateral couch shifts

Fig. 3C. Absolute vertical vs. absolute longitudinal couch shifts

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

**3.4 The effect of body mass index on daily couch shifts** 

distribution between these two groups based on BMIs of > 25 or ≤ 25.

**≤ 0 5 (62.5) 8 (44.4) > 0 3 (37.5) 10 (55.6)**

**≤ 0 4 (50) 10 (55.6) > 0 4 (50) 8 (44.4)**

**≤ 0 7 (87.5) 9 (50) > 0 1 (12.5) 9 (50)**

**≤ 5 mm 5 (62.5) 14 (77.8) > 5 mm 3 (37.5) 4 (22.2)**

**≤ 5 mm 5 (62.5) 9 (50) > 5 mm 3 (37.5) 9 (50)**

**≤ 5 mm 7 (87.5) 14 (77.8) > 5 mm 1 (12.5) 4 (22.2)**

direction

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 15

Fig. 4C. Relationship between amplitude of respiration and setup correction in the vertical

The median age for this group of patients is 60 years old (range: 34 -79). Slightly more than half of the patients (14/26) are males. The BMIs for this group of patients range between 20 and 46 with a median value of 27 (kg/m2). There are 8 patients with BMIs of 20-25 and 18 patients with the BMIs of 26-46. Table 3 shows that there is no difference in daily couch shift

> **BMI 20-25 N (%)**

**Lateral systematic shift 0.395**

**Longitudinal systematic shift 0.793**

**Vertical systematic shift 0.070**

**Lateral random shift 0.418**

**Longitudinal random shift 0.555**

**Vertical random shift 0.562**

Table 3. Distributions of daily couch shifts in patients with body mass indexes of > 25 and ≤ 25

**BMI 26-46 N (%)**

**P (X2)**

#### **3.3 The magnitude of the pancreatic tumor motion vs. the amplitude of setup correction**

Inter-fraction variability in the position of pancreatic tumors is generally considered to be resultant from pancreatic breathing motion and patient positioning. We examined the association of the magnitude of the changes in the pancreatic tumor breathing motion in 50% and 80% inhale and exhale with the amplitude of daily setup error correction and found no correlation between them (R2≤0.012). (Figure 4A-4C)

Fig. 4A. Relationship between amplitude of respiration and setup correction in the longitudinal direction

Fig. 4B. Relationship between amplitude of respiration and setup correction in the lateral direction

Fig. 4C. Relationship between amplitude of respiration and setup correction in the vertical direction

#### **3.4 The effect of body mass index on daily couch shifts**

14 Modern Practices in Radiation Therapy

Inter-fraction variability in the position of pancreatic tumors is generally considered to be resultant from pancreatic breathing motion and patient positioning. We examined the association of the magnitude of the changes in the pancreatic tumor breathing motion in 50% and 80% inhale and exhale with the amplitude of daily setup error correction and

**3.3 The magnitude of the pancreatic tumor motion vs. the amplitude of setup** 

Fig. 4A. Relationship between amplitude of respiration and setup correction in the

Fig. 4B. Relationship between amplitude of respiration and setup correction in the lateral

found no correlation between them (R2≤0.012). (Figure 4A-4C)

**correction** 

longitudinal direction

direction

The median age for this group of patients is 60 years old (range: 34 -79). Slightly more than half of the patients (14/26) are males. The BMIs for this group of patients range between 20 and 46 with a median value of 27 (kg/m2). There are 8 patients with BMIs of 20-25 and 18 patients with the BMIs of 26-46. Table 3 shows that there is no difference in daily couch shift distribution between these two groups based on BMIs of > 25 or ≤ 25.


Table 3. Distributions of daily couch shifts in patients with body mass indexes of > 25 and ≤ 25

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

**Maximum (mm)** 

3.0 18.9 65/127

4.2 26.2 47/127

3.0 20.5 65/127

correction.

(Table 5)

Left-Right

Superior-Inferior

Anterior-Posterior

mm, 5 mm and 10 mm.

is not used (Feng et al. 2009).

**Shifts Median** 

**(mm)** 

Error Correction Using Internal Markers and Its Association with the Patient's Body Mass Index 17

patients for daily setup correction. We acquired treatment planning CT scans at least 1 week after two fiducial markers were implanted to allow time for inflammation or edema to subside. The positions of these markers were then used to guide the daily patient setup

In this study, inter-fractional shifts of > 5 mm are observed in 29%, 27% and 40% of fractions in left-right, anterior-posterior and superior-inferior directions. When we examined the percentage of fractions with the inter-fractional shifts of > 10 mm, we observed only 7% and 2% in the directions of left-right and anterior-posterior but 13% in the direction of superiorinferior. The median and maximum couch shifts are 4.2 and 26.2 mm, 3.0 and 20.5 mm and 3.0 and 18.9 mm in superior-inferior, anterior-posterior and left-right directions, respectively. The couch shift in the superior-inferior direction is significantly larger than that in the anterior-posterior (p = 0.001) and left-right (p = 0.045) directions. There is no difference in couch shifts between anterior-posterior and left-right directions (p = 0.22).

> **≤ 3 mm N (%)**

(51)

(37)

(51)

Table 5. Comparison of the amplitudes of three-dimensional shifts in median, maximum, 3

There is no correlation in either the direction or the amplitude of couch shifts among all three directions. In contrast to our findings, Jayachandran et al. reported that the maximum shifts needed in the anterior-posterior, left-right, and superior-inferior directions were 9 mm, 13 mm, and 19 mm, respectively when fiducial markers were used which are smaller than what we found in the current study (Jayachandran et al. 2010). On the other hand, some earlier studies have shown much larger inter-fractional pancreatic motions of up to 40 mm (Booth and Zavgorodni 1999; Horst et al. 2002). Allen et al. reported a maximum of 17.7 mm inter-fractional setup error in pancreatic cancer using daily on line CT scan images (Li et al. 2007). Feng et al. characterized pancreatic tumor motion using CINE MRI and found that tumor borders moved much more than expected. They indicated that to provide 99% geometric coverage, margins of 20mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mm posteriorly are required if respiratory gating

**≤ 5 mm N (%)** 

90/127 (71)

76/127 (60)

93/127 (73)

**≤ 10 mm N (%)** 

118/127 (93)

111/127 (87)

124/127 (98)

**T-test** 

SI vs. LR p=0.001

SI vs. AP p=0.045

LR vs. AP p=0.216

**4.1 The magnitude of the inter-fractional setup correction for pancreatic cancer** 

Table 4 shows the results of multivariate regression analysis, revealing that patients with a BMI ≤ 25 are less likely to have an anterior vertical couch shift from the initial positioning (OR: 0.35, 95% CI: 0.16-0.77, p = 0.009) than those with a BMI > 25 after adjusting for age and gender, suggesting less correction is needed due to less body relaxation and skin movement in patients with a BMI ≤ 25 (kg/m2) than those with a BMI > 25. BMI has no effect on the left-right or superior-inferior couch shifts.


Table 4. The effect of body mass index on daily couch shifts by multivariate logistic regression analysis

Factors included in the regression models are age, gender and BMI.

#### **4. Discussion**

Accurate and precise patient positioning at the time of delivering stereotactic body radiotherapy is crucial. Image-guided respiratory-gated radiation therapy has been a major advancement in minimizing inter- and intra- fractional target variations. To minimize and correct for setup uncertainties and inter-fractional motion of extracranial tumors, various immobilization and localization techniques have been clinically implemented, including transabdominal ultrasonography (Lattanzi et al. 1999; Chandra et al. 2003; Langen et al. 2003), megavoltage imaging (Schiffner et al. 2007; Serago et al. 2006), kilovoltage imaging (Jaffray et al. 1999; Kupelian et al. 2008), use of an in-room computed tomography (CT)– linear accelerator system (Court et al. 2003; Wong et al. 2005), cone-beam CT (Jaffray et al. 1999; Kupelian et al. 2008), and placement of internal fiducials (Kupelian et al. 2008; Chen et al. 2007; Chung et al. 2004). Pancreatic tumor targets usually exhibit inter-fractional motion relative to the bony anatomy because of daily variation in stomach and duodenal filling and respiratory patterns. The bony anatomy can be imaged and aligned using in-room kilovoltage X-rays; however, with this approach, the position of the pancreatic tumor with respect to the bony anatomy is uncertain. Jayachandran et al. has compared the interfractional variation in pancreatic tumor position using bony anatomy to implanted fiducial markers and observed substantial residual uncertainty after alignment to bony anatomy when irradiating pancreatic tumors using respiratory gating (Jayachandran et al. 2010). They reported that bony anatomy matched tumor position in only 20% of the radiation treatments. This study evaluates the use of implanted platinum markers in pancreatic cancer

Table 4 shows the results of multivariate regression analysis, revealing that patients with a BMI ≤ 25 are less likely to have an anterior vertical couch shift from the initial positioning (OR: 0.35, 95% CI: 0.16-0.77, p = 0.009) than those with a BMI > 25 after adjusting for age and gender, suggesting less correction is needed due to less body relaxation and skin movement in patients with a BMI ≤ 25 (kg/m2) than those with a BMI > 25. BMI has no effect on the

BMI 20-25 vs. BMI 26-46 Odd Ratio (95% CI) P (X2)

Lateral systematic shift 0.787 (0.371-1.671) 0.533

Longitudinal systematic shift 1.384 (0.657-2.914) 0.393

Vertical systematic shift 0.351 (0.160-1.773) 0.009

Lateral random shift 2.087 (0.333-13.077) 0.432

Longitudinal random shift 0.606 (0.105-3.513) 0.577

Vertical random shift 0.501 (0.043-5.838) 0.581

Factors included in the regression models are age, gender and BMI.

Table 4. The effect of body mass index on daily couch shifts by multivariate logistic

Accurate and precise patient positioning at the time of delivering stereotactic body radiotherapy is crucial. Image-guided respiratory-gated radiation therapy has been a major advancement in minimizing inter- and intra- fractional target variations. To minimize and correct for setup uncertainties and inter-fractional motion of extracranial tumors, various immobilization and localization techniques have been clinically implemented, including transabdominal ultrasonography (Lattanzi et al. 1999; Chandra et al. 2003; Langen et al. 2003), megavoltage imaging (Schiffner et al. 2007; Serago et al. 2006), kilovoltage imaging (Jaffray et al. 1999; Kupelian et al. 2008), use of an in-room computed tomography (CT)– linear accelerator system (Court et al. 2003; Wong et al. 2005), cone-beam CT (Jaffray et al. 1999; Kupelian et al. 2008), and placement of internal fiducials (Kupelian et al. 2008; Chen et al. 2007; Chung et al. 2004). Pancreatic tumor targets usually exhibit inter-fractional motion relative to the bony anatomy because of daily variation in stomach and duodenal filling and respiratory patterns. The bony anatomy can be imaged and aligned using in-room kilovoltage X-rays; however, with this approach, the position of the pancreatic tumor with respect to the bony anatomy is uncertain. Jayachandran et al. has compared the interfractional variation in pancreatic tumor position using bony anatomy to implanted fiducial markers and observed substantial residual uncertainty after alignment to bony anatomy when irradiating pancreatic tumors using respiratory gating (Jayachandran et al. 2010). They reported that bony anatomy matched tumor position in only 20% of the radiation treatments. This study evaluates the use of implanted platinum markers in pancreatic cancer

left-right or superior-inferior couch shifts.

regression analysis

**4. Discussion** 

patients for daily setup correction. We acquired treatment planning CT scans at least 1 week after two fiducial markers were implanted to allow time for inflammation or edema to subside. The positions of these markers were then used to guide the daily patient setup correction.

#### **4.1 The magnitude of the inter-fractional setup correction for pancreatic cancer**

In this study, inter-fractional shifts of > 5 mm are observed in 29%, 27% and 40% of fractions in left-right, anterior-posterior and superior-inferior directions. When we examined the percentage of fractions with the inter-fractional shifts of > 10 mm, we observed only 7% and 2% in the directions of left-right and anterior-posterior but 13% in the direction of superiorinferior. The median and maximum couch shifts are 4.2 and 26.2 mm, 3.0 and 20.5 mm and 3.0 and 18.9 mm in superior-inferior, anterior-posterior and left-right directions, respectively. The couch shift in the superior-inferior direction is significantly larger than that in the anterior-posterior (p = 0.001) and left-right (p = 0.045) directions. There is no difference in couch shifts between anterior-posterior and left-right directions (p = 0.22). (Table 5)


Table 5. Comparison of the amplitudes of three-dimensional shifts in median, maximum, 3 mm, 5 mm and 10 mm.

There is no correlation in either the direction or the amplitude of couch shifts among all three directions. In contrast to our findings, Jayachandran et al. reported that the maximum shifts needed in the anterior-posterior, left-right, and superior-inferior directions were 9 mm, 13 mm, and 19 mm, respectively when fiducial markers were used which are smaller than what we found in the current study (Jayachandran et al. 2010). On the other hand, some earlier studies have shown much larger inter-fractional pancreatic motions of up to 40 mm (Booth and Zavgorodni 1999; Horst et al. 2002). Allen et al. reported a maximum of 17.7 mm inter-fractional setup error in pancreatic cancer using daily on line CT scan images (Li et al. 2007). Feng et al. characterized pancreatic tumor motion using CINE MRI and found that tumor borders moved much more than expected. They indicated that to provide 99% geometric coverage, margins of 20mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mm posteriorly are required if respiratory gating is not used (Feng et al. 2009).

Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

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#### **4.2 Relationship between setup correction and amplitude of pancreatic tumor breathing motion**

To our knowledge, this is the first study to evaluate the correlation of the amplitude of respiration to patient position displacement in pancreatic cancer. We did not find any association between the magnitude of the changes in the pancreatic tumor breathing motion and the amplitude of daily setup error correction. This is consistent with the results reported by Case et al. for liver tumors (Case et al. 2009).

#### **4.3 Effect of body mass index on setup correction**

This is the first study to examine the influence of BMI on setup correction for pancreatic cancer. We observed that patients with a BMI of > 25 have a greater possibility of needing vertical setup correction than those with a BMI of ≤ 25. On the other hand, BMI has no effect on the setup corrections in superior-inferior and left-right directions. Worm et al reported that intrafractional errors for liver and lung cancer were independent of patient's BMI (Worm et al.). A study on generic planning target margin for rectal cancer treatment setup variation did show that BMI was significantly associated with systemic superior-inferior (p<0.05) and anterior-posterior (p<0.01) variation and random left-right variation (p<0.05) (Robertson, Campbell, and Yan 2009).

#### **5. Conclusion**

Daily alignment using fiducial markers is an effective method of localizing pancreas displacement. It provides the option of reducing margins, thus limiting normal tissue toxicity and allowing the possibility of dose escalation for better long-term control. For those patients without daily image guided set-up correction, margins of |mean| + 2|standard deviation| (11.6 mm, 14.5 mm, and 9.7 mm in left-right, superior-inferior, and anteriorposterior directions, respectively) should be added to the planning target volume. Patients with BMI >25 (kg/m2) may need a larger anterior-posterior margin for planning target volume than those with BMI ≤ 25 (kg/m2).

#### **6. Abbreviations**

US: United States ACS: American Cancer Society 5-FU: 5-Fluorouracil ECOG: The Eastern Cooperative Oncology Group CT: computed tomography 4D CT: 4 dimensional computed tomography MRI: Magnetic resonance imaging FDG PET: fluorodeoxyglucose Positron emission tomography GTV: Gross tumor volume CTV: Clinical target volume PTV: Planning target volume DVH: Dose volume histogram IMRT: Intensity modulated radiation therapy SD: Standard deviation BMI: Body mass index

#### **7. References**

18 Modern Practices in Radiation Therapy

To our knowledge, this is the first study to evaluate the correlation of the amplitude of respiration to patient position displacement in pancreatic cancer. We did not find any association between the magnitude of the changes in the pancreatic tumor breathing motion and the amplitude of daily setup error correction. This is consistent with the results reported

This is the first study to examine the influence of BMI on setup correction for pancreatic cancer. We observed that patients with a BMI of > 25 have a greater possibility of needing vertical setup correction than those with a BMI of ≤ 25. On the other hand, BMI has no effect on the setup corrections in superior-inferior and left-right directions. Worm et al reported that intrafractional errors for liver and lung cancer were independent of patient's BMI (Worm et al.). A study on generic planning target margin for rectal cancer treatment setup variation did show that BMI was significantly associated with systemic superior-inferior (p<0.05) and anterior-posterior (p<0.01) variation and random left-right variation (p<0.05)

Daily alignment using fiducial markers is an effective method of localizing pancreas displacement. It provides the option of reducing margins, thus limiting normal tissue toxicity and allowing the possibility of dose escalation for better long-term control. For those patients without daily image guided set-up correction, margins of |mean| + 2|standard deviation| (11.6 mm, 14.5 mm, and 9.7 mm in left-right, superior-inferior, and anteriorposterior directions, respectively) should be added to the planning target volume. Patients with BMI >25 (kg/m2) may need a larger anterior-posterior margin for planning target

**4.2 Relationship between setup correction and amplitude of pancreatic tumor** 

**breathing motion** 

**5. Conclusion** 

**6. Abbreviations**  US: United States

5-FU: 5-Fluorouracil

ACS: American Cancer Society

MRI: Magnetic resonance imaging

CT: computed tomography

GTV: Gross tumor volume CTV: Clinical target volume PTV: Planning target volume DVH: Dose volume histogram

SD: Standard deviation BMI: Body mass index

by Case et al. for liver tumors (Case et al. 2009).

(Robertson, Campbell, and Yan 2009).

volume than those with BMI ≤ 25 (kg/m2).

ECOG: The Eastern Cooperative Oncology Group

FDG PET: fluorodeoxyglucose Positron emission tomography

4D CT: 4 dimensional computed tomography

IMRT: Intensity modulated radiation therapy

**4.3 Effect of body mass index on setup correction** 

ACS. 2011, Cancer Facts& Figures,

 http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/docume nts/document/acspc-029771.pdf.


Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Set-Up

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Serago, C. F., S. J. Buskirk, T. C. Igel, A. A. Gale, N. E. Serago, and J. D. Earle. 2006.

Sonke, J. J., J. Lebesque, and M. van Herk. 2008. "Variability of four-dimensional computed tomography patient models." Int J Radiat Oncol Biol Phys no. 70 (2):590-8. Spitz, F. R., J. L. Abbruzzese, J. E. Lee, P. W. Pisters, A. M. Lowy, C. J. Fenoglio, K. R. Cleary,

Tenn, S. E., T. D. Solberg, and P. M. Medin. 2005. "Targeting accuracy of an image guided

Wong, J. R., L. Grimm, M. Uematsu, R. Oren, C. W. Cheng, S. Merrick, and P. Schiff. 2005.

Worm, E. S., A. T. Hansen, J. B. Petersen, L. P. Muren, L. H. Praestegaard, and M. Hoyer.

prostatectomy." Int J Radiat Oncol Biol Phys no. 67 (2):610-9.

fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma." J Clin

Crane, R. Lenzi, R. A. Wolff, J. L. Abbruzzese, and D. B. Evans. 2000. "Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents." J

Benson, J. S. Macdonald, M. R. Kudrimoti, M. L. Fromm, M. G. Haddock, P. Schaefer, C. G. Willett, and T. A. Rich. 2008. "Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial." Jama no.

rectal cancer treatment setup variation." Int J Radiat Oncol Biol Phys no. 74

Shinohara, and M. Roach, 3rd. 2007. "Daily electronic portal imaging of implanted gold seed fiducials in patients undergoing radiotherapy after radical

"Comparison of daily megavoltage electronic portal imaging or kilovoltage imaging with marker seeds to ultrasound imaging or skin marks for prostate localization and treatment positioning in patients with prostate cancer." Int J Radiat

N. A. Janjan, M. S. Goswitz, T. A. Rich, and D. B. Evans. 1997. "Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas." J Clin Oncol no. 15

gating system for stereotactic body radiotherapy." Phys Med Biol no. 50 (23):5443-

"Image-guided radiotherapy for prostate cancer by CT-linear accelerator combination: prostate movements and dosimetric considerations." Int J Radiat

"Inter- and intrafractional localisation errors in cone-beam CT guided stereotactic radiation therapy of tumours in the liver and lung." Acta Oncol no. 49 (7):1177-

of patients treated for liver metastases." Int J Radiat Oncol Biol Phys no. 46 (2):329- 35.


Horst, E., O. Micke, C. Moustakis, A. Schuck, U. Schafer, and N. A. Willich. 2002.

Jaffray, D. A., D. G. Drake, M. Moreau, A. A. Martinez, and J. W. Wong. 1999. "A

Jayachandran, P., A. Y. Minn, J. Van Dam, J. A. Norton, A. C. Koong, and D. T. Chang. 2010.

Klinkenbijl, J. H., J. Jeekel, T. Sahmoud, R. van Pel, M. L. Couvreur, C. H. Veenhof, J. P.

Koong, A. C., Q. T. Le, A. Ho, B. Fong, G. Fisher, C. Cho, J. Ford, J. Poen, I. C. Gibbs, V. K.

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Lattanzi, J., S. McNeeley, W. Pinover, E. Horwitz, I. Das, T. E. Schultheiss, and G. E. Hanks.

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Oettle, H., S. Post, P. Neuhaus, K. Gellert, J. Langrehr, K. Ridwelski, H. Schramm, J. Fahlke,

Pisters, P. W., J. L. Abbruzzese, N. A. Janjan, K. R. Cleary, C. Charnsangavej, M. S. Goswitz,

localized prostate cancer." Int J Radiat Oncol Biol Phys no. 70 (4):1151-7. Langen, K. M., J. Pouliot, C. Anezinos, M. Aubin, A. R. Gottschalk, I. C. Hsu, D. Lowther, Y.

radiotherapy." Int J Radiat Oncol Biol Phys no. 57 (3):635-44.

prostate cancer." Int J Radiat Oncol Biol Phys no. 43 (4):719-25.

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Phys no. 68 (2):581-91.

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Radiat Oncol Biol Phys no. 58 (4):1017-21.

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Arnaud, D. G. Gonzalez, L. T. de Wit, A. Hennipman, and J. Wils. 1999. "Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer

Mehta, S. Kee, W. Trueblood, G. Yang, and J. A. Bastidas. 2004. "Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer." Int J

L. Meeks. 2008. "Evaluation of image-guidance strategies in the treatment of

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C. Zuelke, C. Burkart, K. Gutberlet, E. Kettner, H. Schmalenberg, K. Weigang-Koehler, W. O. Bechstein, M. Niedergethmann, I. Schmidt-Wolf, L. Roll, B. Doerken, and H. Riess. 2007. "Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a

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fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma." J Clin Oncol no. 16 (12):3843-50.


**2** 

*USA* 

**STAT RAD: A Potential Real-Time** 

**1. Introduction** 

**1.1 Epidemiology and cost of metastatic disease** 

not well palliated with pharmacologic treatment (Halperin et al., 2008).

spinal instability (Coleman, 2006).

The American Cancer Society estimates that approximately 1.5 million people in the United States will be diagnosed with cancer, and 560,000 will die of cancer in 2010 (Jemal et al., 2010). These numbers are projected to increase rapidly in the near future due to national demographics with a large number of Americans reaching retirement age over the next 15-20 years, resulting in a doubling of projected new cancer diagnoses in 2050 to 3 million (Hayat et al., 2007). Most cancer deaths involve extensive locoregional tumors or metastatic disease to brain, lung, liver, or bone causing pain, disability, and decreased quality of life. As treatments for cancer improve, patients are living longer with advanced cancer than ever before, and the management of metastatic disease is becoming increasingly more multi-disciplinary and complex with patients treated simultaneously with systemic therapy, surgery, and radiation. It is well documented that cancer-related pain is often inadequately controlled in the palliative care setting, and both the pain and opioid medication interfere with patient function and quality of life (Bruera & Kim, 2003; Cleeland et al., 1994; McGuire, 2004). Radiotherapy is an important treatment for the alleviation of pain and suffering for cancer patients. It prevents pathologic bone fractures, and palliates tumor-induced obstruction, bleeding, and pain that is

The skeleton is one of the most common sites of metastatic disease and is often the first site affected by metastases and the most common origin of cancer-related pain (Schulman & Kohles, 2007; Coleman, 2006). It was estimated that in 2004, 250,000 cancer patients were afflicted with metastatic bone disease (Schulman & Kohles, 2007). Bone metastases are most common in patients with multiple myeloma, of whom 90% develop bone metastases (Lipton, 2010). Approximately 70% of patients dying of breast and prostate cancer have evidence of metastatic bone disease, and bone metastases are also common in thyroid, kidney, and lung cancers, occurring in 30-40% of these cancers (Coleman, 2006). Metastatic bone disease causes considerable morbidity in patients with cancer, resulting in pain, hypercalcemia, pathologic fractures, compression of the spinal cord or cauda equina, and

 **Radiation Therapy Workflow** 

David Wilson, Ke Sheng, Wensha Yang, Ryan Jones, Neal Dunlap and Paul Read

*University of Virginia,* 

Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, Hruban RH, Ord SE, Sauter PK, Coleman J, Zahurak ML, Grochow LB, Abrams RA. 1997. "Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes." Ann Surg no. 226:248-257.

## **STAT RAD: A Potential Real-Time Radiation Therapy Workflow**

David Wilson, Ke Sheng, Wensha Yang, Ryan Jones, Neal Dunlap and Paul Read *University of Virginia, USA* 

#### **1. Introduction**

22 Modern Practices in Radiation Therapy

Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, Hruban RH, Ord SE,

complications, and outcomes." Ann Surg no. 226:248-257.

Sauter PK, Coleman J, Zahurak ML, Grochow LB, Abrams RA. 1997. "Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology,

#### **1.1 Epidemiology and cost of metastatic disease**

The American Cancer Society estimates that approximately 1.5 million people in the United States will be diagnosed with cancer, and 560,000 will die of cancer in 2010 (Jemal et al., 2010). These numbers are projected to increase rapidly in the near future due to national demographics with a large number of Americans reaching retirement age over the next 15-20 years, resulting in a doubling of projected new cancer diagnoses in 2050 to 3 million (Hayat et al., 2007). Most cancer deaths involve extensive locoregional tumors or metastatic disease to brain, lung, liver, or bone causing pain, disability, and decreased quality of life. As treatments for cancer improve, patients are living longer with advanced cancer than ever before, and the management of metastatic disease is becoming increasingly more multi-disciplinary and complex with patients treated simultaneously with systemic therapy, surgery, and radiation. It is well documented that cancer-related pain is often inadequately controlled in the palliative care setting, and both the pain and opioid medication interfere with patient function and quality of life (Bruera & Kim, 2003; Cleeland et al., 1994; McGuire, 2004). Radiotherapy is an important treatment for the alleviation of pain and suffering for cancer patients. It prevents pathologic bone fractures, and palliates tumor-induced obstruction, bleeding, and pain that is not well palliated with pharmacologic treatment (Halperin et al., 2008).

The skeleton is one of the most common sites of metastatic disease and is often the first site affected by metastases and the most common origin of cancer-related pain (Schulman & Kohles, 2007; Coleman, 2006). It was estimated that in 2004, 250,000 cancer patients were afflicted with metastatic bone disease (Schulman & Kohles, 2007). Bone metastases are most common in patients with multiple myeloma, of whom 90% develop bone metastases (Lipton, 2010). Approximately 70% of patients dying of breast and prostate cancer have evidence of metastatic bone disease, and bone metastases are also common in thyroid, kidney, and lung cancers, occurring in 30-40% of these cancers (Coleman, 2006). Metastatic bone disease causes considerable morbidity in patients with cancer, resulting in pain, hypercalcemia, pathologic fractures, compression of the spinal cord or cauda equina, and spinal instability (Coleman, 2006).

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 25

Although fractionation schedules in Europe are trending toward hypofractionation (fewer treatments), the most common palliative dose fractionation schedules in the United States vary between 20 and 30 gray (Gy) in 5 -10 fractions delivered over 1 -2 weeks (Fairchild et al., 2009). Adding the one week pre-treatment work process to the 1-2 weeks of treatment delivery results in an overall duration of 2-3 weeks for completion of palliative treatment. Conventional radiotherapy, regardless of fractionation schedule, has been found to be modestly effective in treatment of bone metastases, resulting in an improvement in pain in only about 60% of patients (Wu et al., 2003; Chow et al., 2007). In a retrospective study of end stage cancer patients receiving palliative radiotherapy, Gripp et al found that half of the patients received treatment for >60% of their final days of life (Gripp et al., 2010). Thus, these often modestly effective treatments subject the patients to repeated visits to the treatment center and consume precious time and energy for ill patients and their families. Clearly it is important that we design more effective palliative treatments that are more efficient to plan and deliver,

Traditional emergent radiation therapy workflows referred to as "mark and start" protocols were developed to rapidly treat patients with severe pain, spinal cord compression, superior vena cava syndrome, and life-threatening obstruction of major organs. They generally rely on a good understanding of surface anatomy to direct placement of square or rectangular treatment fields on the patient with the patient on the treatment couch. A port film is obtained to confirm that the target is being treated and to document the treatment volume. The treatment field is then marked on the patient and documentation photos are obtained. Following anatomic volume determination and verification, the prescription dose is converted to treatment unit monitor units which are calculated using the field size, treatment distance, treatment depth, and machine-specific output factors for a given photon energy. The best quality assurance practices are to have two people calculate the monitor units independently and to have at least one person perform the calculation by hand if a computer calculation program is used. Once the monitor units are calculated, the patient can be treated. Emergent treatments generally use one or two parallel opposed beams to deliver non-conformal dose with large volumes of non-target tissue being irradiated to the

Since most patients treated with radiation therapy on an emergent basis are symptomatic with pain, bleeding, or obstruction, it can be difficult for them to lie still on a flat treatment table for prolonged periods of time. Therefore, the faster the clinical workflow, the better the patient will tolerate the process. Most new linear accelerators (LINACs) are equipped with kilovoltage imaging capabilities on the treatment unit which can make the initial field placement easier by functioning similar to a CT or fluoroscopic simulator. This can increase the efficiency of the process since accurate field placement is the most time consuming part of the "mark and start" workflow. Once the field is accurately marked, the monitor unit

Clearly, for emergency situations, a simple treatment option is highly desirable for any treatment system, especially for a system in a one-unit radiation oncology clinic. Some

calculations take only a few minutes, and the patient can rapidly be treated.

**2.3 Inconvenient, modestly effective treatments** 

minimize acute toxicity, and require fewer total treatments and time.

**2.4 Mark-and-start radiation therapy workflows** 

prescribed dose.

The treatment of metastatic bone disease is financially costly. Schulman and Kohles estimated that the mean per patient direct cost for cancer patients after diagnoses with metastatic bone disease was \$75,329 compared to \$31,455 for cancer-matched controls without metastatic bone disease (Schulman & Kohles, 2007). Using this data, the authors estimated that the national cost burden for patients with metastatic bone disease was \$12.6 billion in 2004, which was 17% of the NIH-reported \$74 billion direct medical costs for cancer (Schulman & Kohles, 2007). These costs will clearly increase with our aging population and associated increase in cancer prevalence (Hayat et al., 2007). From a societal standpoint, looming Medicare financial constraints will likely result in reduced reimbursement for palliative services, driving the economic incentive to develop the next generation of more clinically efficient palliative radiotherapy workflows.

#### **2. Standard palliative radiotherapy techniques**

#### **2.1 Lack of dose conformality**

For 30-40 years, standard palliative radiotherapy treatment techniques have utilized simple opposed beam arrangements such as treating a patient with parallel opposed anterior and posterior beams. Although simple to plan and deliver, such techniques provide poor conformality, and large volumes of organs at risk (OARs) may receive the full prescribed dose depending on the area treated. See Figure 1. Radiation to these OARs (skin, lung, esophagus, trachea, stomach, small bowel, rectum, bladder, or genitals) may result in cough, dysphagia, odynophagia, nausea, vomiting, weight loss, fatigue, diarrhea, dysuria, erythema, and pruritus of the skin and genitals (Gaze et al., 1997; Langendijk et al., 2000). Despite being planned and delivered on sophisticated systems, these treatments are frequently only moderately effective, and cause significant toxicity to an already ill patient population with a limited life expectancy (Gaze et al., 1997).

#### **2.2 Slow treatment planning and quality assurance workflow**

Conventional simulation and treatment planning is performed over a several day process prior to the first delivered treatment. The patient is first seen in consultation and scheduled for a CT simulation on a subsequent day. During the CT simulation the patient is placed in the position in which they will ultimately be treated on a treatment unit, and immobilization and support devices are fabricated, after which they undergo a CT scan in the treatment position. He or she must then wait, sometimes several days, for the contouring of the CT simulation images, a process by which the radiation oncologist specifies the planning target volume (PTV) of the tumor to be treated and the regional OARs or adjacent tissues that may receive radiation resulting in toxicity. Following the contouring of the CT images, radiation treatment planning is performed, during which time medical dosimetrists and physicians determine the beam angles and treatment techniques to deliver the prescribed dose to the PTV while attempting to minimize dose to OARs if possible. Following treatment planning, quality assurance calculations and/or measurements are performed by medical physicists before delivery of the first treatment to ensure accuracy of delivering the planned dose and ensure patient safety. Finally, the first treatment is then delivered 3-7 working days after the initial consultation.

#### **2.3 Inconvenient, modestly effective treatments**

24 Modern Practices in Radiation Therapy

The treatment of metastatic bone disease is financially costly. Schulman and Kohles estimated that the mean per patient direct cost for cancer patients after diagnoses with metastatic bone disease was \$75,329 compared to \$31,455 for cancer-matched controls without metastatic bone disease (Schulman & Kohles, 2007). Using this data, the authors estimated that the national cost burden for patients with metastatic bone disease was \$12.6 billion in 2004, which was 17% of the NIH-reported \$74 billion direct medical costs for cancer (Schulman & Kohles, 2007). These costs will clearly increase with our aging population and associated increase in cancer prevalence (Hayat et al., 2007). From a societal standpoint, looming Medicare financial constraints will likely result in reduced reimbursement for palliative services, driving the economic incentive to develop the next

For 30-40 years, standard palliative radiotherapy treatment techniques have utilized simple opposed beam arrangements such as treating a patient with parallel opposed anterior and posterior beams. Although simple to plan and deliver, such techniques provide poor conformality, and large volumes of organs at risk (OARs) may receive the full prescribed dose depending on the area treated. See Figure 1. Radiation to these OARs (skin, lung, esophagus, trachea, stomach, small bowel, rectum, bladder, or genitals) may result in cough, dysphagia, odynophagia, nausea, vomiting, weight loss, fatigue, diarrhea, dysuria, erythema, and pruritus of the skin and genitals (Gaze et al., 1997; Langendijk et al., 2000). Despite being planned and delivered on sophisticated systems, these treatments are frequently only moderately effective, and cause significant toxicity to an already ill patient

Conventional simulation and treatment planning is performed over a several day process prior to the first delivered treatment. The patient is first seen in consultation and scheduled for a CT simulation on a subsequent day. During the CT simulation the patient is placed in the position in which they will ultimately be treated on a treatment unit, and immobilization and support devices are fabricated, after which they undergo a CT scan in the treatment position. He or she must then wait, sometimes several days, for the contouring of the CT simulation images, a process by which the radiation oncologist specifies the planning target volume (PTV) of the tumor to be treated and the regional OARs or adjacent tissues that may receive radiation resulting in toxicity. Following the contouring of the CT images, radiation treatment planning is performed, during which time medical dosimetrists and physicians determine the beam angles and treatment techniques to deliver the prescribed dose to the PTV while attempting to minimize dose to OARs if possible. Following treatment planning, quality assurance calculations and/or measurements are performed by medical physicists before delivery of the first treatment to ensure accuracy of delivering the planned dose and ensure patient safety. Finally, the first treatment is then delivered 3-7 working days after the

generation of more clinically efficient palliative radiotherapy workflows.

**2. Standard palliative radiotherapy techniques** 

population with a limited life expectancy (Gaze et al., 1997).

**2.2 Slow treatment planning and quality assurance workflow** 

**2.1 Lack of dose conformality** 

initial consultation.

Although fractionation schedules in Europe are trending toward hypofractionation (fewer treatments), the most common palliative dose fractionation schedules in the United States vary between 20 and 30 gray (Gy) in 5 -10 fractions delivered over 1 -2 weeks (Fairchild et al., 2009). Adding the one week pre-treatment work process to the 1-2 weeks of treatment delivery results in an overall duration of 2-3 weeks for completion of palliative treatment. Conventional radiotherapy, regardless of fractionation schedule, has been found to be modestly effective in treatment of bone metastases, resulting in an improvement in pain in only about 60% of patients (Wu et al., 2003; Chow et al., 2007). In a retrospective study of end stage cancer patients receiving palliative radiotherapy, Gripp et al found that half of the patients received treatment for >60% of their final days of life (Gripp et al., 2010). Thus, these often modestly effective treatments subject the patients to repeated visits to the treatment center and consume precious time and energy for ill patients and their families. Clearly it is important that we design more effective palliative treatments that are more efficient to plan and deliver, minimize acute toxicity, and require fewer total treatments and time.

#### **2.4 Mark-and-start radiation therapy workflows**

Traditional emergent radiation therapy workflows referred to as "mark and start" protocols were developed to rapidly treat patients with severe pain, spinal cord compression, superior vena cava syndrome, and life-threatening obstruction of major organs. They generally rely on a good understanding of surface anatomy to direct placement of square or rectangular treatment fields on the patient with the patient on the treatment couch. A port film is obtained to confirm that the target is being treated and to document the treatment volume. The treatment field is then marked on the patient and documentation photos are obtained. Following anatomic volume determination and verification, the prescription dose is converted to treatment unit monitor units which are calculated using the field size, treatment distance, treatment depth, and machine-specific output factors for a given photon energy. The best quality assurance practices are to have two people calculate the monitor units independently and to have at least one person perform the calculation by hand if a computer calculation program is used. Once the monitor units are calculated, the patient can be treated. Emergent treatments generally use one or two parallel opposed beams to deliver non-conformal dose with large volumes of non-target tissue being irradiated to the prescribed dose.

Since most patients treated with radiation therapy on an emergent basis are symptomatic with pain, bleeding, or obstruction, it can be difficult for them to lie still on a flat treatment table for prolonged periods of time. Therefore, the faster the clinical workflow, the better the patient will tolerate the process. Most new linear accelerators (LINACs) are equipped with kilovoltage imaging capabilities on the treatment unit which can make the initial field placement easier by functioning similar to a CT or fluoroscopic simulator. This can increase the efficiency of the process since accurate field placement is the most time consuming part of the "mark and start" workflow. Once the field is accurately marked, the monitor unit calculations take only a few minutes, and the patient can rapidly be treated.

Clearly, for emergency situations, a simple treatment option is highly desirable for any treatment system, especially for a system in a one-unit radiation oncology clinic. Some

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 27

average 3 to 6 months of palliation with conventional therapy (Gaze et al., 1997; Foro Arnalot et al., 2008). Additionally, spinal SBRT treatments have been effective in achieving local control in tumors typically resistant to radiotherapy, such as renal cell carcinoma and melanoma, reportedly due in part to radiation injury to the tumor vasculature (Gerszten et

Though great success is seen in high dose, hypofractionated therapy, care must be taken to avoid incorrectly delivering the high dose radiation to normal tissue. Prevention of damage to normal tissue is ensured through careful patient immobilization, co-registration of multiple diagnostic imaging modalities (MRI, PET CT, contrast enhanced CT) to the kVCT simulation to accurately define the target and OARs, inverse treatment planning with the use of intensity modulated radiation therapy, patient-specific quality assurance, and CT image guidance at the time of treatment delivery. Nevertheless, common side effects of radiotherapy can occur with SBRT. However, the advantage of conformal radiation is that it spares high radiation dose to normal tissue with the relatively small target volumes employed in this technique compared to parallel opposed techniques in which prescription doses are delivered to all tissues, target and OARs, in the beam path through the patient. This advantage of SBRT has been demonstrated in many trials by reports of little to no toxicity (Gerszten et al., 2007; Gagnon et al., 2009), and is reinforced by the findings of McIntosh et al, who compared conformal TomoTherapy to conventional 3D conformal treatment techniques on an anthropomorphic phantom and showed that TomoTherapy plans significantly improved conformality and reduced dose to regional critical structures

Most significant adverse events in spinal SBRT have occurred with treatments that used extremely high-doses (>20 Gy) in a single fraction. Gomez et al reported odynophagia and dysphagia in 1 patient who had received 22 Gy to the esophagus in a single dose, and another patient developed an esophageal ulcer and necrosis after receiving 24 Gy to his esophagus in one fraction (Gomez et al., 2009). Another patient developed bronchial stenosis after receiving 11 Gy to a bronchus in a single fraction. In another study with similarly high dose fractionation schedules, 39% of patients treated with 18 to 24 Gy in a single dose developed new or progressive vertebral fractures (Rose et al., 2009). However, their patient selection did not utilize a scoring system to identify patients at high risk for pathologic fracture, such as the Mirels scoring system (Cumming et al., 2009). In contrast, Gagnon et al, using mean doses of 26 Gy in 3 fractions in 200 patients, only had 2 patients (1%) develop vertebral fractures (Gagnon et al., 2009). Sahgal et al reported 5 cases of radiation myelopathy and concluded that for single fraction SBRT, up to 10 Gy to a maximum point to

**3.2 Extrapolation of spinal SBRT-like dose distributions to non-spine metastases** 

Given the advances in radiation delivery with SBRT and its success in palliation of spine metastases, it is logical to apply these advancements in technology to extra-axial bone metastases; however, no trials have been published to date. This is due to the fact that SBRT is only reimbursed for limited indications such as spinal metastases. It is fair to hypothesize that the extrapolation of SBRT-like dose distributions to extra-axial bone metastases will

al., 2007; Gibbs et al., 2007; Ryu et al., 2008; Gagnon et al., 2009).

**3.1 Adverse events with SBRT: Minimal toxicity** 

(McIntosh et al., 2010).

the thecal sac is safe (Sahgal et al., 2010).

complex treatment systems have no easy methodology or workflow to treat patients emergently with simple fields if the patient has not undergone a separate CT simulation. This is due to the fact that they have no way to calculate a treatment plan without a contoured CT image dataset. In addition, some intensity modulated radiation therapy (IMRT) dedicated systems with their own CT treatment planning algorithms do not have an easy way to perform an independent calculation to verify the accuracy of the planned dose calculation. Due to these limitations, the treatment of the emergency patient on these systems generally requires performance of the standard workflow of CT simulation, CT contouring, dose calculation, dose verification with unit measurements, and then image guided treatment delivery to the patient. The development of novel and greatly expedited workflows for these systems that utilize conformal dose delivery would provide an improved method to treat emergency patients that could also be used to treat non-emergent palliative patients more rapidly. In this chapter, we propose the development of one potential rapid clinic workflow utilizing the TomoTherapy system called STAT RAD.

#### **3. Stereotactic Body Radiotherapy (SBRT): A more effective, highly conformal hypofractionated palliative radiation technique**

In the search for more effective and less toxic radiotherapy techniques, much attention has been focused on stereotactic body radiotherapy (SBRT). SBRT utilizes hypofractionated, highly conformal, high dose radiation delivery that has been modeled after intracranial stereotactic radiosurgery (SRS). Like SRS, SBRT uses multiple beams that converge on the target volume. This minimizes the volume of tissue receiving high dose to where the beams intersect, reducing dose to normal tissue. This allows for the delivery of ablative doses of radiation in a few fractions with acceptable toxicity (Read, 2007; Timmerman et al., 2010). SBRT is a proven method for treating lung cancer, yielding excellent rates of local control for non-small-cell lung cancer and resulting in 5-year survival rates potentially comparable to that of surgery (Timmerman et al., 2010; Onishi et al., 2010). In addition, the treatment of liver metastases with SBRT has yielded promising results, achieving local control rates at 2 years of approximately 70–90% (Dawood, Mahadevan, & Goodman 2009; Rusthoven et al., 2009).

SBRT has also been used in the palliative treatment of bone metastases to the spine with remarkable success. Multiple studies have used SBRT to safely deliver high doses of radiation to spinal metastases while significantly limiting dose to the spinal cord and achieving local control rates of >80% at one year (Gerszten et al., 2007; Nelson et al., 2009; Gibbs et al., 2007). Fractionations in these studies have ranged from 1 to 5 fractions delivering 4 – 24 Gy per individual fraction, with total doses between 10 to 30 Gy (Gerszten et al., 2007; Nelson et al., 2009; Gibbs et al., 2007). In the largest prospective study of spine SBRT by Gerszten, 336 cases were treated primarily to relieve pain, and they achieved significant pain improvement in 290 patients (86%). Nelson, Gibbs, and Ryu, have also reported pain reduction in greater than 80% of patients in their studies (Gerszten et al. 2007; Nelson et al., 2009; Gibbs et al., 2007; Ryu et al., 2008), much improved over the 60% in conventional radiotherapy (Wu et al., 2003; Chow et al., 2007). Not only do more people experience pain relief with SBRT, but the pain relief is reported to be more durable. Gagnon demonstrated statistically significant improvement in pain scores lasting throughout 4 years of follow-up (Gagnon et al., 2009). Ryu found the median duration of pain relief to be 13.6 months with SBRT (Ryu et al., 2008), which is a dramatic improvement compared to the

complex treatment systems have no easy methodology or workflow to treat patients emergently with simple fields if the patient has not undergone a separate CT simulation. This is due to the fact that they have no way to calculate a treatment plan without a contoured CT image dataset. In addition, some intensity modulated radiation therapy (IMRT) dedicated systems with their own CT treatment planning algorithms do not have an easy way to perform an independent calculation to verify the accuracy of the planned dose calculation. Due to these limitations, the treatment of the emergency patient on these systems generally requires performance of the standard workflow of CT simulation, CT contouring, dose calculation, dose verification with unit measurements, and then image guided treatment delivery to the patient. The development of novel and greatly expedited workflows for these systems that utilize conformal dose delivery would provide an improved method to treat emergency patients that could also be used to treat non-emergent palliative patients more rapidly. In this chapter, we propose the development of one potential rapid clinic workflow utilizing the TomoTherapy system called STAT RAD.

**3. Stereotactic Body Radiotherapy (SBRT): A more effective, highly** 

In the search for more effective and less toxic radiotherapy techniques, much attention has been focused on stereotactic body radiotherapy (SBRT). SBRT utilizes hypofractionated, highly conformal, high dose radiation delivery that has been modeled after intracranial stereotactic radiosurgery (SRS). Like SRS, SBRT uses multiple beams that converge on the target volume. This minimizes the volume of tissue receiving high dose to where the beams intersect, reducing dose to normal tissue. This allows for the delivery of ablative doses of radiation in a few fractions with acceptable toxicity (Read, 2007; Timmerman et al., 2010). SBRT is a proven method for treating lung cancer, yielding excellent rates of local control for non-small-cell lung cancer and resulting in 5-year survival rates potentially comparable to that of surgery (Timmerman et al., 2010; Onishi et al., 2010). In addition, the treatment of liver metastases with SBRT has yielded promising results, achieving local control rates at 2 years of approximately

SBRT has also been used in the palliative treatment of bone metastases to the spine with remarkable success. Multiple studies have used SBRT to safely deliver high doses of radiation to spinal metastases while significantly limiting dose to the spinal cord and achieving local control rates of >80% at one year (Gerszten et al., 2007; Nelson et al., 2009; Gibbs et al., 2007). Fractionations in these studies have ranged from 1 to 5 fractions delivering 4 – 24 Gy per individual fraction, with total doses between 10 to 30 Gy (Gerszten et al., 2007; Nelson et al., 2009; Gibbs et al., 2007). In the largest prospective study of spine SBRT by Gerszten, 336 cases were treated primarily to relieve pain, and they achieved significant pain improvement in 290 patients (86%). Nelson, Gibbs, and Ryu, have also reported pain reduction in greater than 80% of patients in their studies (Gerszten et al. 2007; Nelson et al., 2009; Gibbs et al., 2007; Ryu et al., 2008), much improved over the 60% in conventional radiotherapy (Wu et al., 2003; Chow et al., 2007). Not only do more people experience pain relief with SBRT, but the pain relief is reported to be more durable. Gagnon demonstrated statistically significant improvement in pain scores lasting throughout 4 years of follow-up (Gagnon et al., 2009). Ryu found the median duration of pain relief to be 13.6 months with SBRT (Ryu et al., 2008), which is a dramatic improvement compared to the

**conformal hypofractionated palliative radiation technique** 

70–90% (Dawood, Mahadevan, & Goodman 2009; Rusthoven et al., 2009).

average 3 to 6 months of palliation with conventional therapy (Gaze et al., 1997; Foro Arnalot et al., 2008). Additionally, spinal SBRT treatments have been effective in achieving local control in tumors typically resistant to radiotherapy, such as renal cell carcinoma and melanoma, reportedly due in part to radiation injury to the tumor vasculature (Gerszten et al., 2007; Gibbs et al., 2007; Ryu et al., 2008; Gagnon et al., 2009).

#### **3.1 Adverse events with SBRT: Minimal toxicity**

Though great success is seen in high dose, hypofractionated therapy, care must be taken to avoid incorrectly delivering the high dose radiation to normal tissue. Prevention of damage to normal tissue is ensured through careful patient immobilization, co-registration of multiple diagnostic imaging modalities (MRI, PET CT, contrast enhanced CT) to the kVCT simulation to accurately define the target and OARs, inverse treatment planning with the use of intensity modulated radiation therapy, patient-specific quality assurance, and CT image guidance at the time of treatment delivery. Nevertheless, common side effects of radiotherapy can occur with SBRT. However, the advantage of conformal radiation is that it spares high radiation dose to normal tissue with the relatively small target volumes employed in this technique compared to parallel opposed techniques in which prescription doses are delivered to all tissues, target and OARs, in the beam path through the patient. This advantage of SBRT has been demonstrated in many trials by reports of little to no toxicity (Gerszten et al., 2007; Gagnon et al., 2009), and is reinforced by the findings of McIntosh et al, who compared conformal TomoTherapy to conventional 3D conformal treatment techniques on an anthropomorphic phantom and showed that TomoTherapy plans significantly improved conformality and reduced dose to regional critical structures (McIntosh et al., 2010).

Most significant adverse events in spinal SBRT have occurred with treatments that used extremely high-doses (>20 Gy) in a single fraction. Gomez et al reported odynophagia and dysphagia in 1 patient who had received 22 Gy to the esophagus in a single dose, and another patient developed an esophageal ulcer and necrosis after receiving 24 Gy to his esophagus in one fraction (Gomez et al., 2009). Another patient developed bronchial stenosis after receiving 11 Gy to a bronchus in a single fraction. In another study with similarly high dose fractionation schedules, 39% of patients treated with 18 to 24 Gy in a single dose developed new or progressive vertebral fractures (Rose et al., 2009). However, their patient selection did not utilize a scoring system to identify patients at high risk for pathologic fracture, such as the Mirels scoring system (Cumming et al., 2009). In contrast, Gagnon et al, using mean doses of 26 Gy in 3 fractions in 200 patients, only had 2 patients (1%) develop vertebral fractures (Gagnon et al., 2009). Sahgal et al reported 5 cases of radiation myelopathy and concluded that for single fraction SBRT, up to 10 Gy to a maximum point to the thecal sac is safe (Sahgal et al., 2010).

#### **3.2 Extrapolation of spinal SBRT-like dose distributions to non-spine metastases**

Given the advances in radiation delivery with SBRT and its success in palliation of spine metastases, it is logical to apply these advancements in technology to extra-axial bone metastases; however, no trials have been published to date. This is due to the fact that SBRT is only reimbursed for limited indications such as spinal metastases. It is fair to hypothesize that the extrapolation of SBRT-like dose distributions to extra-axial bone metastases will

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 29

As seen in Table 1, when compared with conventional fractionation schedules for palliative osseous metastases, such as 30 Gy in 10 fractions or 20 Gy in 5 fractions, high dose per fraction regimens deliver very similar BED to early responding tissues and slightly higher BED to late responding tissues. We believe that for reasonable rates of symptom relief and duration of palliation that palliative regimens should deliver a minimum BED of 25 Gy to most treatment targets. Twenty-four Gy in 3 fractions (8 Gy x 3 fractions) is an attractive palliative regimen that balances a high radiobiologic dose with the convenience of a highly hypofractioned regimen. This daily dose can generally be delivered in 10 minutes or less depending on target size and modulation allowing patients in pain to tolerate the treatment without moving. Finally, doses of 8 Gy or higher may be more effective against tumor histologies thought to be more radioresistant such as melanoma or renal cell carcinoma due to cytotoxic effects to the tumor vasculature. However, the dose per treatment, number of treatments, and total dose will depend on the patient's overall condition and tumor-specific factors including histology, location, proximity to critical OARs, and size. Relative BED provides a method to compare different dose fractionation schedules that can be used to

(Gy) Alpha/beta BED

30 10 3 10 39 20 5 4 10 28 24 3 8 10 43

30 10 3 3 60 20 5 4 3 47 24 3 8 3 88

correlate the treatment with patient outcomes.

Early Responding Tissues

Late Responding Tissues

Total dose # of fractions Dose per fraction

Table 1. Comparison of BED in Different Palliative Fractionation Schedules

cancer burden and health care costs due to the aging baby-boom population.

**4. STAT RAD: A rapid palliative radiotherapy workflow in clinic development**  Clearly a faster, more efficient workflow to treat metastatic disease is needed. Patients with widespread metastases frequently have short life expectancies and need treatments that minimize their time in clinic while providing rapid and durable pain relief for the remainder of their lives. Additionally, this need for efficiency will further rise with the increasing

Thus, at the University of Virginia we are piloting a new workflow called "STAT RAD" to rapidly deliver advanced radiotherapy to patients with metastatic disease on an internal review board approved clinical trial. This STAT RAD workflow offers same-day palliation in an approximately 6-hour time frame similar to a standard GammaKnife ® (Elekta, Stockholm, Sweden) workflow. STAT RAD is a highly coordinated conventional workflow that includes kVCT simulation, treatment planning, treatment plan quality assurance, and delivery of conformal hypofractionated radiotherapy in a single day. All treatments are planned and delivered on FDA-approved systems including the TomoTherapy treatment machine. This workflow allows patients to receive an entire course of palliative treatment from start to finish in a few days, a process that conventionally takes 2-3 weeks. Since patients are billed for each individual treatment, requiring fewer treatments reduces health care costs in addition to being more convenient. With the STAT RAD program we are now

improve pain control and that rapid institution of radiation will minimize the time patients are in pain and on high dose opioids that place them at risk for iatrogenic medical complications. By applying the concepts of spinal SBRT, highly conformal hypofractionated radiation therapy plans could be used to treat non-spinal metastases. This allows for increased dose per fraction and fewer total fractions with less toxicity compared to standard non-conformal palliative regimens. See Figures 1-2.

Fig. 1. Nonconformal Technique

Fig. 2. Conformal Technique

#### **3.3 Relative Biologic Effective Dose: A method to compare different dose fractionation schedules**

Based on the linear-quadratic equation, one can calculate the biologic effective dose (BED) to compare dose delivery of different fractionation schedules using the equation:

$$\text{BED} = \text{nd} \left[ 1 + \text{d} (\text{alpha/beta}) \right] \tag{1}$$

n = number of fractions, d = dose per fraction, alpha/beta = the ratio of intrinsic radiosensitivity to repair capacity

improve pain control and that rapid institution of radiation will minimize the time patients are in pain and on high dose opioids that place them at risk for iatrogenic medical complications. By applying the concepts of spinal SBRT, highly conformal hypofractionated radiation therapy plans could be used to treat non-spinal metastases. This allows for increased dose per fraction and fewer total fractions with less toxicity compared to standard

non-conformal palliative regimens. See Figures 1-2.

Fig. 1. Nonconformal Technique

Fig. 2. Conformal Technique

**fractionation schedules** 

radiosensitivity to repair capacity

**3.3 Relative Biologic Effective Dose: A method to compare different dose** 

compare dose delivery of different fractionation schedules using the equation:

Based on the linear-quadratic equation, one can calculate the biologic effective dose (BED) to

n = number of fractions, d = dose per fraction, alpha/beta = the ratio of intrinsic

BED = nd [1+d(alpha/beta)] (1)

As seen in Table 1, when compared with conventional fractionation schedules for palliative osseous metastases, such as 30 Gy in 10 fractions or 20 Gy in 5 fractions, high dose per fraction regimens deliver very similar BED to early responding tissues and slightly higher BED to late responding tissues. We believe that for reasonable rates of symptom relief and duration of palliation that palliative regimens should deliver a minimum BED of 25 Gy to most treatment targets. Twenty-four Gy in 3 fractions (8 Gy x 3 fractions) is an attractive palliative regimen that balances a high radiobiologic dose with the convenience of a highly hypofractioned regimen. This daily dose can generally be delivered in 10 minutes or less depending on target size and modulation allowing patients in pain to tolerate the treatment without moving. Finally, doses of 8 Gy or higher may be more effective against tumor histologies thought to be more radioresistant such as melanoma or renal cell carcinoma due to cytotoxic effects to the tumor vasculature. However, the dose per treatment, number of treatments, and total dose will depend on the patient's overall condition and tumor-specific factors including histology, location, proximity to critical OARs, and size. Relative BED provides a method to compare different dose fractionation schedules that can be used to correlate the treatment with patient outcomes.


Table 1. Comparison of BED in Different Palliative Fractionation Schedules

#### **4. STAT RAD: A rapid palliative radiotherapy workflow in clinic development**

Clearly a faster, more efficient workflow to treat metastatic disease is needed. Patients with widespread metastases frequently have short life expectancies and need treatments that minimize their time in clinic while providing rapid and durable pain relief for the remainder of their lives. Additionally, this need for efficiency will further rise with the increasing cancer burden and health care costs due to the aging baby-boom population.

Thus, at the University of Virginia we are piloting a new workflow called "STAT RAD" to rapidly deliver advanced radiotherapy to patients with metastatic disease on an internal review board approved clinical trial. This STAT RAD workflow offers same-day palliation in an approximately 6-hour time frame similar to a standard GammaKnife ® (Elekta, Stockholm, Sweden) workflow. STAT RAD is a highly coordinated conventional workflow that includes kVCT simulation, treatment planning, treatment plan quality assurance, and delivery of conformal hypofractionated radiotherapy in a single day. All treatments are planned and delivered on FDA-approved systems including the TomoTherapy treatment machine. This workflow allows patients to receive an entire course of palliative treatment from start to finish in a few days, a process that conventionally takes 2-3 weeks. Since patients are billed for each individual treatment, requiring fewer treatments reduces health care costs in addition to being more convenient. With the STAT RAD program we are now

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 31

Requirements for the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD

1. **Scan:** MVCT simulation image acquisition (10 minutes) then rigid or deformable image co-registration of existing diagnostic image sets with pre-contoured target and OAR

3. **Verify:** Real-time patient-specific quality assurance using CT detectors prior to or

4. **Treat:** Simple real-time patient motion tracking to monitor patient position real-time

In the conventional workflow, target volumes and OARs are contoured on recent diagnostic images (MRI, PET-CT, or diagnostic CT that are already available in the patient's electronic radiology chart). After the patient undergoes a kVCT simulation, the contoured diagnostic images are rigidly or deformably co-registered to the kVCT simulation images, and the contours are transferred. This allows for high resolution diagnostic images to be used for tumor and normal tissue identification, which are not always possible to differentiate on CT simulation scans due to the resolution of standard wide bore CT simulation scanners and images that are frequently obtained without intravenous contrast. Multiple commercial image processing systems are available for this image processing, and we are currently using Velocity® (Atlanta, GA) image processing software. Following treatment planning, the patient then undergoes image guided treatment delivery, a process in which a daily MVCT scan is obtained on the TomoTherapy unit and co-registered to the planning kVCT scan. Patient setup shifts can then be made to ensure accurate patient setup, and the patient

volumes to the MVCT simulation scan for contour transfer (3-5 minutes).

during the Scan-Plan-Verify-Treat process to ensure accurate delivery.

is treated. Therefore, this is a two image co-registration workflow. See Figure 3.

Fig. 3. Comparison of Image Co-Registration Workflows

2. **Plan:** Rapid inverse treatment planning (3-5 minutes).

during treatment delivery (10 minutes).

**5.1 New image co-registration workflow** 

workflow are envisioned as follows:

able to offer a unique workflow that delivers rapid, effective, and efficient palliative radiotherapy that is cost effective, less toxic, and more convenient for cancer patients and their families.

We have treated approximately 50 cancer patients with the conformal hypofractionated STAT RAD treatment regimen for a variety of palliative indications. We have treated patients with IMRT and 3D delivery using TomoHelical and TomoDirect planning modes. Retrospective review of these patients shows that the majority of these patients experienced rapid and durable palliation of symptoms with minimal toxicity (unpublished data). In general, patients are extremely satisfied with the speed at which their treatment is initiated and the convenience of the hypofractionated regimens.

In our current trial we are quantifying patient outcomes following treatment with the current STAT RAD workflow in an effort to determine its benefits and risks to patients. In addition, we are systematically evaluating and optimizing software and hardware necessary to make the STAT RAD workflow even more efficient.

#### **4.1 Technologic rationale for the choice of the TomoTherapy platform**

The TomoTherapy platform has been chosen for the STAT RAD workflow for a variety of reasons. TomoTherapy delivers highly conformal and homogenous dose distributions through modulation of dose from a bank of 64 binary 6.25-mm-wide collimator leaves capable of pneumatic opening or closing 51 times per revolution as the gantry revolves around the patient. The system can also treat patients with discreet beam angles (i.e. the radiation beam not rotating) in a mode called TomoDirect. Although all TomoTherapy treatment delivery is technically IMRT, the treatment planning can be done in either a 3D or IMRT mode allowing highly conformal treatments to be billed as 3D and thus used in the treatment of all patients with bone metastases. While the 3D planning mode limits the planning options for dose constraints on OARs, partial and complete blocking can be assigned to non-target structures. Partial blocking allows beams to exit through the structure after treating the PTV but not to enter through the structure prior to treating the PTV, and complete blocking restricts beams from entering or exiting through a structure. In addition, good preliminary data exists to support the use of the fan beam MVCT as a CT simulation image set for treatment planning and the use of CT detector-based exit dose methodology for quality assurance, making this system an excellent platform to pilot and optimize this workflow.

#### **5. Scan-plan-verify-treat STAT RAD workflow: A novel and more efficient STAT RAD workflow**

With recent advances in software and technology, we plan to further condense the STAT RAD workflow into the Scan-Plan-Verify-Treat workflow, a 30-minute process in which all steps (MVCT simulation, diagnostic image co-registration, treatment planning, and treatment delivery with real time quality assurance) are performed on the TomoTherapy unit. This advanced workflow will eliminate the need for the patients to undergo a kVCT simulation on a separate unit as well as make it unnecessary for the patient to leave the treatment table between the simulation and treatment.

able to offer a unique workflow that delivers rapid, effective, and efficient palliative radiotherapy that is cost effective, less toxic, and more convenient for cancer patients and

We have treated approximately 50 cancer patients with the conformal hypofractionated STAT RAD treatment regimen for a variety of palliative indications. We have treated patients with IMRT and 3D delivery using TomoHelical and TomoDirect planning modes. Retrospective review of these patients shows that the majority of these patients experienced rapid and durable palliation of symptoms with minimal toxicity (unpublished data). In general, patients are extremely satisfied with the speed at which their treatment is initiated

In our current trial we are quantifying patient outcomes following treatment with the current STAT RAD workflow in an effort to determine its benefits and risks to patients. In addition, we are systematically evaluating and optimizing software and hardware necessary

The TomoTherapy platform has been chosen for the STAT RAD workflow for a variety of reasons. TomoTherapy delivers highly conformal and homogenous dose distributions through modulation of dose from a bank of 64 binary 6.25-mm-wide collimator leaves capable of pneumatic opening or closing 51 times per revolution as the gantry revolves around the patient. The system can also treat patients with discreet beam angles (i.e. the radiation beam not rotating) in a mode called TomoDirect. Although all TomoTherapy treatment delivery is technically IMRT, the treatment planning can be done in either a 3D or IMRT mode allowing highly conformal treatments to be billed as 3D and thus used in the treatment of all patients with bone metastases. While the 3D planning mode limits the planning options for dose constraints on OARs, partial and complete blocking can be assigned to non-target structures. Partial blocking allows beams to exit through the structure after treating the PTV but not to enter through the structure prior to treating the PTV, and complete blocking restricts beams from entering or exiting through a structure. In addition, good preliminary data exists to support the use of the fan beam MVCT as a CT simulation image set for treatment planning and the use of CT detector-based exit dose methodology for quality assurance, making this system an excellent platform to pilot and optimize this

**5. Scan-plan-verify-treat STAT RAD workflow: A novel and more efficient** 

With recent advances in software and technology, we plan to further condense the STAT RAD workflow into the Scan-Plan-Verify-Treat workflow, a 30-minute process in which all steps (MVCT simulation, diagnostic image co-registration, treatment planning, and treatment delivery with real time quality assurance) are performed on the TomoTherapy unit. This advanced workflow will eliminate the need for the patients to undergo a kVCT simulation on a separate unit as well as make it unnecessary for the patient to leave the

and the convenience of the hypofractionated regimens.

to make the STAT RAD workflow even more efficient.

treatment table between the simulation and treatment.

**4.1 Technologic rationale for the choice of the TomoTherapy platform** 

their families.

workflow.

**STAT RAD workflow** 

Requirements for the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow are envisioned as follows:


#### **5.1 New image co-registration workflow**

In the conventional workflow, target volumes and OARs are contoured on recent diagnostic images (MRI, PET-CT, or diagnostic CT that are already available in the patient's electronic radiology chart). After the patient undergoes a kVCT simulation, the contoured diagnostic images are rigidly or deformably co-registered to the kVCT simulation images, and the contours are transferred. This allows for high resolution diagnostic images to be used for tumor and normal tissue identification, which are not always possible to differentiate on CT simulation scans due to the resolution of standard wide bore CT simulation scanners and images that are frequently obtained without intravenous contrast. Multiple commercial image processing systems are available for this image processing, and we are currently using Velocity® (Atlanta, GA) image processing software. Following treatment planning, the patient then undergoes image guided treatment delivery, a process in which a daily MVCT scan is obtained on the TomoTherapy unit and co-registered to the planning kVCT scan. Patient setup shifts can then be made to ensure accurate patient setup, and the patient is treated. Therefore, this is a two image co-registration workflow. See Figure 3.

Fig. 3. Comparison of Image Co-Registration Workflows

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 33

We have shown that accelerated treatment planning software for Helical TomoTherapy provides clinically acceptable dosimetry, with conformality and homogeneity that is superior to standard LINAC-based 3D conformal planning and is only slightly inferior to standard Helical TomoTherapy dosimetry (McIntosh et al., 2010). We have also shown that, with planning times of 2-5 minutes, this accelerated treatment planning software provides levels of dosimetric conformality, heterogeneity, and avoidance of organs at risk for simple SBRT treatments that are clinically equivalent to those generated with conventional Helical TomoTherapy treatment planning (Dunlap et al., 2010). This preliminary data supports that treatment planning speed is not likely to be rate limiting in the ultimate clinical

Current standard of care TomoTherapy quality assurance methodology requires that each patient-specific treatment plan be delivered to a cylindrical plastic phantom with ion chamber and film measurement to ensure geometric and planar dose distribution accuracy using gamma criteria of 3%/3mm. However, this method does not measure the dose that the patient is receiving during treatment or provide full 3D dose verification. It causes another delay in delivering the first treatment to the patient as it requires approximately 30 minutes to complete, and is generally done by a medical physicist after daily clinic patient treatment is finished. A methodology to monitor the patient exit dose in real time would increase patient safety through verification of daily treatment accuracy as well as expedite the treatment workflow. Clearly, a real-time quality assurance methodology that does not require moving the patient off the TomoTherapy treatment couch for phantom measurements is essential for the development of a 30-minute Scan-Plan-Verify-Treat workflow. Current dose verification methodologies measuring dose at the time of patient treatment are limited to point measurements on the patient surface (Essers & Mijnheer, 1999), which is rarely in the target volume or a critical OAR, or through expensive implanted dosimeters (Beyer et al., 2007; Scarantino et al., 2004), which are not practical for most palliative patients. Since there is no method to directly measure the three dimensional dose in the patient, alternative approaches are being developed and tested in academic clinical settings. These alternative approaches reconstruct the delivered three dimensional dose distribution based on the measurement of either entrance or exit dose and back-

projecting the measurements onto simulation or image guidance CT image sets.

2008). Investigators are currently working on methods to overcome these challenges.

The opportunity to reconstruct dose from information collected during treatment became available with the incorporation of radiation imaging detectors, such as electronic portal imaging devices (EPID) on linear-accelerators and CT detector arrays on TomoTherapy. Dose reconstruction using in-line EPID was first described by McNutt et al (McNutt, Mackie, & Paliwal 1997; McNutt et al., 1996). The EPID, when deployed during treatment, collects exit fluence from the patient and then back-projects this to X-ray fluence before entering the patient; then, the dose in the patient is re-computed using this entrance fluence and the planning CT images. However, there are many limitations to EPID-based dose verification. For example, the EPID was originally designed for semi-quantitative portal imaging; and for the purpose of dose reconstruction, it suffers from a narrow dynamic range, short life span, non-linearity in the dose response, ghost artifacts from low temporal resolution, and cross-plane scatter photon contribution to the measured fluence (Mijnheer,

implementation of the Scan-Plan-Verify-Treat STAT RAD workflow.

**5.3 Novel CT-detector-based quality assurance methodology** 

A kVCT simulation scan has historically been used for simulation in the conventional workflow for both palliative and curative radiation planning. Compared to MVCT scans, it has higher resolution and allows the possibility for administration of iodinated IV and/or GI contrast, which makes it easier to identify soft tissues and bony anatomy for treatment planning. However, contrast agents are not generally given for kVCT simulations of patients for palliative treatment of metastases since the soft tissue and bone windows are adequate. Soft tissue and bone windows of MVCT scans have quite reasonable resolution and can easily be co-registered to higher resolution diagnostic studies for contour transfer. Software has been used clinically since 2004 to automatically co-register kVCT simulation images and daily MVCT scans for image guidance on a daily basis.

Our preliminary unpublished data confirms that the MVCT scan has sufficient resolution, particularly of bone anatomy, for accurate co-registration to contoured diagnostic images and that this one step co-registration process yields comparable agreement to the conventional two step image co-registration workflow with +/- 2-3 mm differences. See Figure 3. This level of agreement is consistent with results reported from image coregistration studies performed on a multi-institutional pediatric clinical trial with coregistration data of 51 patients from 45 institutions using 11 different image software systems. They reported an inherent uncertainty of 2 mm for MRI to CT co-registration (Ulin, Urie, & Cherlow 2010). Thus, preliminary data suggests that the optimization of this one step image co-registration workflow of diagnostic image sets to a MVCT simulation scan will be clinically similar to the conventional two image co-registration workflow. MVCT image guidance scans and kVCT simulation co-registration occurs routinely in the clinic and only takes a few seconds, therefore, we do not believe that this will be a rate-limiting step in the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow. Further optimization of the image co-registration workflow will make the 30-minute Scan-Plan-Verify-Treat STAT RAD workflow feasible.

#### **5.2 Rapid inverse treatment planning on MVCT scans**

CT image sets are used for radiation treatment planning because the electron density of tissues, which is required for calculating dose, is easily determined based on the Hounsfield units. The tissue electron density determination is essentially the same for MVCT and kVCT scans. It has previously been reported that as far as the dose calculations are concerned, treatment planning on either a kVCT simulation image set or a MVCT simulation image set yields treatment plans that are within 1% of each other (Langen et al., 2005).

We have recently published that the TomoTherapy STAT RT treatment planning module can calculate SBRT plans in just a few minutes (Dunlap et al., 2010). The computing speed of radiation treatment planning systems is about to take a quantum leap forward with the incorporation of new algorithms that will take advantage of the processing power of graphics processing units (GPU) whose more rapid and parallel calculating potential can improve treatment planning speed by 10-20 times (Hissoiny, Ozell, & Despres, 2010; Hissoiny, Ozell, and Despres, 2009). Same-day inverse treatment planning of IMRT or 3D TomoTherapy plans has not been a problem for patients treated with STAT RAD to date. We are comparing planning times for current FDA-approved treatment planning systems to those of newer, in-development GPU-based algorithms. In general, highly conformal 3D or IMRT plans can be generated in 2-3 minutes with GPU-based algorithms.

A kVCT simulation scan has historically been used for simulation in the conventional workflow for both palliative and curative radiation planning. Compared to MVCT scans, it has higher resolution and allows the possibility for administration of iodinated IV and/or GI contrast, which makes it easier to identify soft tissues and bony anatomy for treatment planning. However, contrast agents are not generally given for kVCT simulations of patients for palliative treatment of metastases since the soft tissue and bone windows are adequate. Soft tissue and bone windows of MVCT scans have quite reasonable resolution and can easily be co-registered to higher resolution diagnostic studies for contour transfer. Software has been used clinically since 2004 to automatically co-register kVCT simulation images and

Our preliminary unpublished data confirms that the MVCT scan has sufficient resolution, particularly of bone anatomy, for accurate co-registration to contoured diagnostic images and that this one step co-registration process yields comparable agreement to the conventional two step image co-registration workflow with +/- 2-3 mm differences. See Figure 3. This level of agreement is consistent with results reported from image coregistration studies performed on a multi-institutional pediatric clinical trial with coregistration data of 51 patients from 45 institutions using 11 different image software systems. They reported an inherent uncertainty of 2 mm for MRI to CT co-registration (Ulin, Urie, & Cherlow 2010). Thus, preliminary data suggests that the optimization of this one step image co-registration workflow of diagnostic image sets to a MVCT simulation scan will be clinically similar to the conventional two image co-registration workflow. MVCT image guidance scans and kVCT simulation co-registration occurs routinely in the clinic and only takes a few seconds, therefore, we do not believe that this will be a rate-limiting step in the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow. Further optimization of the image co-registration workflow will make the 30-minute Scan-Plan-

CT image sets are used for radiation treatment planning because the electron density of tissues, which is required for calculating dose, is easily determined based on the Hounsfield units. The tissue electron density determination is essentially the same for MVCT and kVCT scans. It has previously been reported that as far as the dose calculations are concerned, treatment planning on either a kVCT simulation image set or a MVCT simulation image set

We have recently published that the TomoTherapy STAT RT treatment planning module can calculate SBRT plans in just a few minutes (Dunlap et al., 2010). The computing speed of radiation treatment planning systems is about to take a quantum leap forward with the incorporation of new algorithms that will take advantage of the processing power of graphics processing units (GPU) whose more rapid and parallel calculating potential can improve treatment planning speed by 10-20 times (Hissoiny, Ozell, & Despres, 2010; Hissoiny, Ozell, and Despres, 2009). Same-day inverse treatment planning of IMRT or 3D TomoTherapy plans has not been a problem for patients treated with STAT RAD to date. We are comparing planning times for current FDA-approved treatment planning systems to those of newer, in-development GPU-based algorithms. In general, highly conformal 3D or

yields treatment plans that are within 1% of each other (Langen et al., 2005).

IMRT plans can be generated in 2-3 minutes with GPU-based algorithms.

daily MVCT scans for image guidance on a daily basis.

Verify-Treat STAT RAD workflow feasible.

**5.2 Rapid inverse treatment planning on MVCT scans** 

We have shown that accelerated treatment planning software for Helical TomoTherapy provides clinically acceptable dosimetry, with conformality and homogeneity that is superior to standard LINAC-based 3D conformal planning and is only slightly inferior to standard Helical TomoTherapy dosimetry (McIntosh et al., 2010). We have also shown that, with planning times of 2-5 minutes, this accelerated treatment planning software provides levels of dosimetric conformality, heterogeneity, and avoidance of organs at risk for simple SBRT treatments that are clinically equivalent to those generated with conventional Helical TomoTherapy treatment planning (Dunlap et al., 2010). This preliminary data supports that treatment planning speed is not likely to be rate limiting in the ultimate clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow.

#### **5.3 Novel CT-detector-based quality assurance methodology**

Current standard of care TomoTherapy quality assurance methodology requires that each patient-specific treatment plan be delivered to a cylindrical plastic phantom with ion chamber and film measurement to ensure geometric and planar dose distribution accuracy using gamma criteria of 3%/3mm. However, this method does not measure the dose that the patient is receiving during treatment or provide full 3D dose verification. It causes another delay in delivering the first treatment to the patient as it requires approximately 30 minutes to complete, and is generally done by a medical physicist after daily clinic patient treatment is finished. A methodology to monitor the patient exit dose in real time would increase patient safety through verification of daily treatment accuracy as well as expedite the treatment workflow. Clearly, a real-time quality assurance methodology that does not require moving the patient off the TomoTherapy treatment couch for phantom measurements is essential for the development of a 30-minute Scan-Plan-Verify-Treat workflow. Current dose verification methodologies measuring dose at the time of patient treatment are limited to point measurements on the patient surface (Essers & Mijnheer, 1999), which is rarely in the target volume or a critical OAR, or through expensive implanted dosimeters (Beyer et al., 2007; Scarantino et al., 2004), which are not practical for most palliative patients. Since there is no method to directly measure the three dimensional dose in the patient, alternative approaches are being developed and tested in academic clinical settings. These alternative approaches reconstruct the delivered three dimensional dose distribution based on the measurement of either entrance or exit dose and backprojecting the measurements onto simulation or image guidance CT image sets.

The opportunity to reconstruct dose from information collected during treatment became available with the incorporation of radiation imaging detectors, such as electronic portal imaging devices (EPID) on linear-accelerators and CT detector arrays on TomoTherapy. Dose reconstruction using in-line EPID was first described by McNutt et al (McNutt, Mackie, & Paliwal 1997; McNutt et al., 1996). The EPID, when deployed during treatment, collects exit fluence from the patient and then back-projects this to X-ray fluence before entering the patient; then, the dose in the patient is re-computed using this entrance fluence and the planning CT images. However, there are many limitations to EPID-based dose verification. For example, the EPID was originally designed for semi-quantitative portal imaging; and for the purpose of dose reconstruction, it suffers from a narrow dynamic range, short life span, non-linearity in the dose response, ghost artifacts from low temporal resolution, and cross-plane scatter photon contribution to the measured fluence (Mijnheer, 2008). Investigators are currently working on methods to overcome these challenges.

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 35

Several advantages of this streamlined workflow are envisioned that will improve the care of patients with metastatic disease. The most obvious is that patients who live far from treatment centers can be offered palliative radiation therapy as an option. Take for example the case of a patient who lives 50 miles from a radiation oncology center. If they are seen in consultation, undergo a CT simulation on a second visit, and then are treated with 30 Gy in 10 fractions, they will have to drive 1200 miles for this treatment course. Clearly this is not practical for many ill patients in the last few months of life. If they can receive a conformal high dose palliative treatment in one day, it is much more likely that they will receive this treatment. We have been coordinating STAT RAD treatments on days that patients have appointments with other oncologists or specialists. Patients come to the radiation oncology clinic and undergo a consultation and CT simulation and then go to their other appointments while planning and quality assurance measurements are performed, and then they return to the radiation oncology clinic later that same day for treatment. Once the Scan-Plan-Verify-Treat STAT RAD workflow is available, we envision treating patients at the end of the scheduled workday on a same-day physician request basis. This service holds high utilization potential because many times physicians do not know if a patient is in significant need of palliation until they examine the patient at the

Frequently patients are admitted to the hospital for management of cancer-related symptoms such as intractable pain, spinal cord compression, profuse tumor bleeding, or tumor related acute obstruction. These patients are frequently treated with palliative radiation therapy. The STAT RAD workflow enables patients to receive high dose and conformal treatments that start faster than conventional kVCT simulation workflows and

Finally, this workflow makes the treatment of patients with oligometastatic disease more streamlined and practical because it enables SBRT-like dose distributions to be delivered to multiple lesions that currently cannot be treated with SBRT, such as nodal disease or non-

**6.2 Incorporation of translational technology development into routine clinic care for** 

Several aspects of the Scan-Plan-Verify-Treat STAT RAD clinical development can be incorporated into the routine care of patients undergoing curative radiation therapy. Specifically, CT detector-based quality assurance of all treatments could be automated and performed daily. Such quality assurance could provide a warning if the delivered dose is greater than a threshold such as +/- 5% for a patient and trigger an investigation into the cause of this deviation. Quality assurance of each fraction of treatment would be a major advancement compared to current quality assurance methods of checking each plan prior to treatment. Using daily quality assurance to monitor changes in patient status such as significant weight loss in a head and neck cancer patient could trigger re-planning that

**6. Clinical benefits and future directions of STAT RAD implementation** 

**6.1 Additional benefits to patients with metastatic disease** 

can shorten the length of hospitalization to complete treatment.

time of a scheduled appointment.

spinal bone metastases.

could be done on an adaptive basis.

**all patients** 

The TomoTherapy unit has an in-line source-patient-detector geometry with CT ion chamber detectors that are used for daily MVCT scan image guidance for accurate patient positioning that remain in place during both imaging and treatment. These CT detectors can also be used to measure the patient exit dose fluence and back-project this onto a planning CT scan for volumetric or 3D dose reconstruction. Dose verification on TomoTherapy was first studied by Kapatoes et al., who calculated the entrance fluence from the exit dose using a transfer matrix, which is calculated based on the radiological path length from the source to the detector (Kapatoes et al., 2001; Kapatoes et al., 2001). The use of a CT ion chamber array has multiple advantages over EPID for exit fluence measurement. It is more durable, and has a much longer life span. It has a wider dynamic range and doesn't limit treatment positions. Finally, it is less sensitive to the noise from cross-plane scatter photons that complicate EPID-based dose reconstruction (Siewerdsen & Jaffray 2001).

Our pre-clinical evaluation of the CT detector-based exit radiation dose verification algorithm has been retrospectively studied by Sheng et al. using in-development software (Sheng et al., 2011). We compared planned and delivered doses with the conventional phantom quality assurance measurements for 24 patients and 347 treatment fractions. The concordance of planned to delivered dose calculated by the in-development software was shown to be +/- 5% (Sheng et al., 2011). This tolerance is within the standard of care of other current clinically available quality assurance methods. Further refinements are expected to improve dose monitoring accuracy for this or other algorithms.

#### **5.4 Optical tracking methods for patient intra-fractional motion monitoring**

Consistent patient positioning during CT image acquisition and treatment is critical to ensure accurate dose delivery. Physical immobilization devices such as external body frames, aquaplast masks and other body molds, and vac-lock vacuum bags are commonly used to ensure patient positioning reproducibility. X-ray or CT image guidance prior to radiation delivery on the treatment unit is routinely employed in the clinic. Methods for optical tracking of markers on the patient surface or tracking of the patient's skin surface itself are available to ensure consistent patient positioning after image guidance and during treatment, known as intra-fractional motion (Wagner et al., 2007; Wiersma et al., 2010). This provides a method without ionizing radiation for confirming patient position that can be used real-time during treatment delivery. With this information, if the patient's position moves outside of acceptable limits in any direction, treatment could be paused. A mechanism to ensure that the patient's position doesn't change between MVCT simulation and treatment delivery would obviate the need for a repeat image guidance MVCT scan just prior to delivery in the Scan-Plan-Verify-Treat workflow.

We have recently developed an in-house optical tracking system using multiple OptiTrack FLEX:V100 cameras (Natural Point, Corvallis, OR). The camera utilizes 26 infrared lightemitting diodes and a charge coupled device to capture the reflective light from markers with special coating. By using multiple cameras, the 3D position of each reflective marker can be determined precisely. Multiple markers can be placed on a patient and monitored simultaneously. In the lab, localization precision of 0.1 mm was achieved (unpublished data). Through strategic positioning of the markers, movements of the head, neck, and extracranial locations can be closely monitored.

The TomoTherapy unit has an in-line source-patient-detector geometry with CT ion chamber detectors that are used for daily MVCT scan image guidance for accurate patient positioning that remain in place during both imaging and treatment. These CT detectors can also be used to measure the patient exit dose fluence and back-project this onto a planning CT scan for volumetric or 3D dose reconstruction. Dose verification on TomoTherapy was first studied by Kapatoes et al., who calculated the entrance fluence from the exit dose using a transfer matrix, which is calculated based on the radiological path length from the source to the detector (Kapatoes et al., 2001; Kapatoes et al., 2001). The use of a CT ion chamber array has multiple advantages over EPID for exit fluence measurement. It is more durable, and has a much longer life span. It has a wider dynamic range and doesn't limit treatment positions. Finally, it is less sensitive to the noise from cross-plane scatter photons that

Our pre-clinical evaluation of the CT detector-based exit radiation dose verification algorithm has been retrospectively studied by Sheng et al. using in-development software (Sheng et al., 2011). We compared planned and delivered doses with the conventional phantom quality assurance measurements for 24 patients and 347 treatment fractions. The concordance of planned to delivered dose calculated by the in-development software was shown to be +/- 5% (Sheng et al., 2011). This tolerance is within the standard of care of other current clinically available quality assurance methods. Further refinements are expected to

Consistent patient positioning during CT image acquisition and treatment is critical to ensure accurate dose delivery. Physical immobilization devices such as external body frames, aquaplast masks and other body molds, and vac-lock vacuum bags are commonly used to ensure patient positioning reproducibility. X-ray or CT image guidance prior to radiation delivery on the treatment unit is routinely employed in the clinic. Methods for optical tracking of markers on the patient surface or tracking of the patient's skin surface itself are available to ensure consistent patient positioning after image guidance and during treatment, known as intra-fractional motion (Wagner et al., 2007; Wiersma et al., 2010). This provides a method without ionizing radiation for confirming patient position that can be used real-time during treatment delivery. With this information, if the patient's position moves outside of acceptable limits in any direction, treatment could be paused. A mechanism to ensure that the patient's position doesn't change between MVCT simulation and treatment delivery would obviate the need for a repeat image guidance MVCT scan just

We have recently developed an in-house optical tracking system using multiple OptiTrack FLEX:V100 cameras (Natural Point, Corvallis, OR). The camera utilizes 26 infrared lightemitting diodes and a charge coupled device to capture the reflective light from markers with special coating. By using multiple cameras, the 3D position of each reflective marker can be determined precisely. Multiple markers can be placed on a patient and monitored simultaneously. In the lab, localization precision of 0.1 mm was achieved (unpublished data). Through strategic positioning of the markers, movements of the head, neck, and

complicate EPID-based dose reconstruction (Siewerdsen & Jaffray 2001).

improve dose monitoring accuracy for this or other algorithms.

prior to delivery in the Scan-Plan-Verify-Treat workflow.

extracranial locations can be closely monitored.

**5.4 Optical tracking methods for patient intra-fractional motion monitoring** 

#### **6. Clinical benefits and future directions of STAT RAD implementation**

#### **6.1 Additional benefits to patients with metastatic disease**

Several advantages of this streamlined workflow are envisioned that will improve the care of patients with metastatic disease. The most obvious is that patients who live far from treatment centers can be offered palliative radiation therapy as an option. Take for example the case of a patient who lives 50 miles from a radiation oncology center. If they are seen in consultation, undergo a CT simulation on a second visit, and then are treated with 30 Gy in 10 fractions, they will have to drive 1200 miles for this treatment course. Clearly this is not practical for many ill patients in the last few months of life. If they can receive a conformal high dose palliative treatment in one day, it is much more likely that they will receive this treatment. We have been coordinating STAT RAD treatments on days that patients have appointments with other oncologists or specialists. Patients come to the radiation oncology clinic and undergo a consultation and CT simulation and then go to their other appointments while planning and quality assurance measurements are performed, and then they return to the radiation oncology clinic later that same day for treatment. Once the Scan-Plan-Verify-Treat STAT RAD workflow is available, we envision treating patients at the end of the scheduled workday on a same-day physician request basis. This service holds high utilization potential because many times physicians do not know if a patient is in significant need of palliation until they examine the patient at the time of a scheduled appointment.

Frequently patients are admitted to the hospital for management of cancer-related symptoms such as intractable pain, spinal cord compression, profuse tumor bleeding, or tumor related acute obstruction. These patients are frequently treated with palliative radiation therapy. The STAT RAD workflow enables patients to receive high dose and conformal treatments that start faster than conventional kVCT simulation workflows and can shorten the length of hospitalization to complete treatment.

Finally, this workflow makes the treatment of patients with oligometastatic disease more streamlined and practical because it enables SBRT-like dose distributions to be delivered to multiple lesions that currently cannot be treated with SBRT, such as nodal disease or nonspinal bone metastases.

#### **6.2 Incorporation of translational technology development into routine clinic care for all patients**

Several aspects of the Scan-Plan-Verify-Treat STAT RAD clinical development can be incorporated into the routine care of patients undergoing curative radiation therapy. Specifically, CT detector-based quality assurance of all treatments could be automated and performed daily. Such quality assurance could provide a warning if the delivered dose is greater than a threshold such as +/- 5% for a patient and trigger an investigation into the cause of this deviation. Quality assurance of each fraction of treatment would be a major advancement compared to current quality assurance methods of checking each plan prior to treatment. Using daily quality assurance to monitor changes in patient status such as significant weight loss in a head and neck cancer patient could trigger re-planning that could be done on an adaptive basis.

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 37

Beyer, G. P., C. W. Scarantino, B. R. Prestidge, A. G. Sadeghi, M. S. Anscher, M. Miften, T. B.

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IV - intravenous kVCT – kilovoltage CT LINAC - linear accelerator

**9. References** 

MRI – magnetic resonance imaging

SBRT - stereotactic body radiotherapy SRS - stereotactic radiosurgery

PET CT – positron emission tomography CT

pp. 925-35, ISSN 0360-3016

STAT RAD - urgent and rapid radiation treatment

MVCT – megavoltage CT OAR - organ at risk

PTV - planning target volume

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A simple system to monitor patient motion following image guidance could reduce the risk of geometric misses due to intra-fractional patient motion. If it were determined that a specific patient had more or less intra-fractional motion than accounted for in their PTV expansion, then their treatment plan could be adaptively re-planned to mirror their specific expansion requirements.

#### **6.3 Future directions for spinal SBRT**

The Scan-Plan-Verify-Treat STAT RAD workflow could easily be incorporated into the treatment of spinal SBRT patients. We have previously reported that treatment planning algorithms currently exist that can create highly conformal spinal SBRT plans in just a few minutes (Dunlap et al., 2010) and that the CT detector-based quality assurance algorithms can measure exit dose to within +/- 5% (Sheng et al., 2011). Real-time spinal SBRT simulation, planning, and delivery would eliminate the need for patients to be accurately reset up and positioned between simulation and treatment to within two millimeters of accuracy which is the current accuracy of most co-registration-based image guided systems. In addition, differences in pitch, yaw, or roll of the patient between simulation and treatment delivery setups cannot be routinely corrected by most CT-based image guidance systems, requiring the patient to be re-positioned and re-imaged prior to treatment if they are out of tolerance. With this proposed workflow, the patient could be treated in the planning position, which could potentially eliminate these re-positioning error issues.

#### **7. Conclusion**

As the cancer burden in the population increases and heath care costs continue to rise, a faster, more efficient workflow is needed to treat patients with metastatic disease. Conformal hypofractionated treatment has demonstrated promising results for the palliation of bone metastases, and its incorporation into a workflow such as the STAT RAD workflow also improves patient convenience. In the near future, we believe the optimization of new software and hardware will enable a 30-minute Scan-Plan-Verify-Treat STAT RAD workflow to further maximize patient convenience and efficiency. This more efficient and cost effective workflow may result in more widespread incorporation of palliative radiation for cancer patients failing systemic therapy earlier in their disease process, reducing pain and functional loss and improving quality of life.

#### **8. Abbreviations**

3D - 3-dimensional BED - biologic effective dose CT – computed tomography CTV – clinical target volume EPID - electronic portal imaging device FDA – Food and Drug Administration GI - gastrointestinal GPU - graphics processing unit Gy - gray IMRT- intensity modulated radiation therapy IV - intravenous kVCT – kilovoltage CT LINAC - linear accelerator MRI – magnetic resonance imaging MVCT – megavoltage CT OAR - organ at risk PET CT – positron emission tomography CT PTV - planning target volume SBRT - stereotactic body radiotherapy SRS - stereotactic radiosurgery STAT RAD - urgent and rapid radiation treatment

#### **9. References**

36 Modern Practices in Radiation Therapy

A simple system to monitor patient motion following image guidance could reduce the risk of geometric misses due to intra-fractional patient motion. If it were determined that a specific patient had more or less intra-fractional motion than accounted for in their PTV expansion, then their treatment plan could be adaptively re-planned to mirror their specific

The Scan-Plan-Verify-Treat STAT RAD workflow could easily be incorporated into the treatment of spinal SBRT patients. We have previously reported that treatment planning algorithms currently exist that can create highly conformal spinal SBRT plans in just a few minutes (Dunlap et al., 2010) and that the CT detector-based quality assurance algorithms can measure exit dose to within +/- 5% (Sheng et al., 2011). Real-time spinal SBRT simulation, planning, and delivery would eliminate the need for patients to be accurately reset up and positioned between simulation and treatment to within two millimeters of accuracy which is the current accuracy of most co-registration-based image guided systems. In addition, differences in pitch, yaw, or roll of the patient between simulation and treatment delivery setups cannot be routinely corrected by most CT-based image guidance systems, requiring the patient to be re-positioned and re-imaged prior to treatment if they are out of tolerance. With this proposed workflow, the patient could be treated in the planning position, which could potentially eliminate these re-positioning error issues.

As the cancer burden in the population increases and heath care costs continue to rise, a faster, more efficient workflow is needed to treat patients with metastatic disease. Conformal hypofractionated treatment has demonstrated promising results for the palliation of bone metastases, and its incorporation into a workflow such as the STAT RAD workflow also improves patient convenience. In the near future, we believe the optimization of new software and hardware will enable a 30-minute Scan-Plan-Verify-Treat STAT RAD workflow to further maximize patient convenience and efficiency. This more efficient and cost effective workflow may result in more widespread incorporation of palliative radiation for cancer patients failing systemic therapy earlier in their disease process, reducing pain

expansion requirements.

**7. Conclusion** 

**8. Abbreviations**  3D - 3-dimensional

GI - gastrointestinal

Gy - gray

BED - biologic effective dose CT – computed tomography CTV – clinical target volume

GPU - graphics processing unit

EPID - electronic portal imaging device FDA – Food and Drug Administration

IMRT- intensity modulated radiation therapy

**6.3 Future directions for spinal SBRT** 

and functional loss and improving quality of life.


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**3** 

S. Zimeras

 *Greece* 

*Karlovassi Samos,* 

*University of the Aegean,* 

**Segmentation Techniques of** 

 **Anatomical Structures with Application** 

The definition of structures and the extraction of organ's shape are essential parts of medical imaging applications. These might be applications like diagnostic imaging, image guided surgery or radiation therapy. The aim of the volume definition process is to delineate a specific shape of an organ on a digital image as accurate as possible especially for 3D rendering, radiation therapy, and surgery planning. This can be done, either by manual user interaction or applying imaging processing techniques for the automatic detection of specific structures in the image using segmentation techniques. Segmentation is the process that separates an image into its important features (primitives) so that each of them can be addressed separately. This converts the planar pixel of the image into a distinguishable number of individual organs or tumour that can be clearly identified and manipulated. The segmentation process might involve complicate structures and in this case usually only an expert can perform the task of the identification manually on a slice-by-slice base. Humans can perform this task using complex analysis of shape, intensity, position, texture, and proximity to surrounding structures. In this work we present a set of tools that are implemented on several computer based medical application. Central focus of this work, are techniques used to improve time and interaction needed for a user when defining one or more structures based on segmentation techniques. These techniques involve interpolation methods for the manual volume definition and methods for the semi-automatic organ shape

The goal of radiotherapy treatment planning is to justify an effective treatment that will deliver a precise irradiation dose to the target volume without causing damage to the surrounding normal tissues. Therefore patient positioning, target volume definition and irradiation field placement are very critical steps while planning the irradiation process. Clinically a radiotherapy treatment plan is verified by Virtual Simulators (VS). (Sherouse et. al., 1987) first proposed the concept, often defined as CT-Sim to distinguish it from Sim-CT

**1. Introduction** 

extraction.

**2. Radiotherapy Treatment Planning (RTP)** 

 **in Radiotherapy Treatment Planning** 

 *Department of Statistics and Actuarial, Financial Mathematics,* 

