**5. Combined radiation and chemotherapy regimen**

#### **5.1. Chemotherapy regimens**

Concurrent radiation with chemotherapy has come to age relatively recently, with cisplatinbased chemotherapy rising at the dawn of the twenty-first century.

Before this era, numerous institutional trials had been published with various chemotherapy regimens selections.

Among previously suggested regimens, hydroxyurea was used in the 1960s, perceived as being a radiosensitizer. Hydroxyurea induces a block on the G1-S phase of the cell cycle, hence enhancing cell kill by radiation; prevention of sub-lethal damage repair has also been proven.

A Gynecological Oncology Group (GOG 56) study confirmed the benefit of added hydroxyurea to radiation therapy, with a higher Progression Free interval, though no significant survival benefit was found [8]. This study was controversial in its setting and the recommendations were not applied widely. Hydroxyurea involves a high risk of myelosuppression, and prospects of considering it as a viable combination therapy to radiation were abandoned overtime.

5-Fluorouracil has also been considered as an alternative chemotherapy regimen for combination therapy. However, the few published studies failed to prove local disease control and survival benefit with an added 5-Fluorouracil regimen [9].

Based on a five-study analysis, cisplatin added to radiation therapy was confirmed to have a superior survival when compared to radiation alone.

A large systematic review of 18 trials combining radiation and chemotherapy for locally advanced cervical carcinoma proved the survival benefit of adding chemotherapy. Platinum based chemotherapy was not seen to be significantly different from non-platinum based chemotherapy (HR: 0.84 vs. 0.76, *p* = 0.48). Platinum-based regimens were also found to have a non-significant increased toxicity trend. However, single agent platinum offered an important alternative with regards to local disease control, adherence to treatment and ease of administration.

Historically, the GOG 120 compared different chemo-radiation regimens, combined with a brachytherapy boost. The arms had a cisplatin alone, a hydroxyurea alone and a cisplatin/5- Fluorouracil/Hydroxyurea components. The arms containing cisplatin had improved survival and disease down-staging was achieved. Subsequent studies removed hydroxyurea and compared upfront radiation therapy with concurrent cisplatin (with or without 5-Fluorouracil) with radiation therapy, which established the standard of care of adding chemotherapy to radiation therapy, as it was shown to increase survival and decrease recurrence risks.

The rationale behind adding cisplatin to radiation is that it acts as a radiosensitizer, by preventing the Non-Homologous End Joining pathway, which is paramount in the Double Strand Breaks repair. Double Strand Breaks in DNA are induced by high energy radiation therapy.

Cisplatin is given on a weekly basis, a few hours before radiation therapy, and care needs to be taken for its administration. As a nephrotoxic agent, adequate hydration is to be ensured, before and after cisplatin infusion. Together with knowing prior the renal status of the patient, dosing can be altered to prevent toxicity. Carboplatin has been shown to provide a suitable alternative to cisplatin for patients who are not candidates to cisplatin infusion (**Table 2**).

Gemcitabine could also be a choice when cisplatin is contraindicated. However, in the absence of level I evidence, and with the increased toxicity risk associated with Gemcitabine, carboplatin remains the preferred choice in case of intolerance to cisplatin, and deranged renal function tests.

#### **5.2. Radiation therapy**

same effect yet with drastic differences in terms of debilitating toxicities, hence surgery alone is the treatment of choice for initial smaller lesions (<4 cm) with other treatment modalities

80 Cervical Cancer - Screening, Treatment and Prevention - Universal Protocols for Ultimate Control

As cited above, the widely used treatment scheme for locally advanced cervical carcinoma

Surgery has been proven to not be superior to chemo-radiation, but carries twice a risk of

Adverse features arising post-surgery could be similar to other advanced diseases, including high grade disease, lympho-vascular space invasion (LVSI), positive lymph nodes, prompting

The largest comparison study to date by Landoni, compared 343 patients with early disease, contemporarily included in the locally advanced stage (IB - IIA) disease, to undergo an extensive surgery with pelvic lymph node dissection, with a possibility of Radiation Therapy boost in the presence residual disease. This arm was compared with upfront Radiation Therapy. The comparison yielded no differences in survival, but showed considerable difference in

Chemo-radiation has been proven to offer a high survival benefit which is greatly influenced by disease stage. Additionally, concurrent chemo-radiation decreases the recurrence risk.

Radiation consists of external beam radiotherapy session and a stage-variable boosting dose achieved by brachytherapy. Details on patient simulation, field size and dose specification

Concurrent radiation with chemotherapy has come to age relatively recently, with cisplatin-

Before this era, numerous institutional trials had been published with various chemotherapy

Among previously suggested regimens, hydroxyurea was used in the 1960s, perceived as being a radiosensitizer. Hydroxyurea induces a block on the G1-S phase of the cell cycle, hence enhancing cell kill by radiation; prevention of sub-lethal damage repair has also been

**5. Combined radiation and chemotherapy regimen**

based chemotherapy rising at the dawn of the twenty-first century.

consists of upfront radiotherapy concurrently with a platinum-based chemotherapy.

the use of multiple modalities of treatment with subsequent considerable toxicities.

offered as a salvage in case of recurrence.

increased toxicity rates.

toxicity rates [7].

are found below.

**5.1. Chemotherapy regimens**

regimens selections.

proven.

**4. Primary chemoradiation vs. surgery**

Radiation Therapy is provided by both External Beam Radiation (EBRT) and brachytherapy (BT) to increase local control.


such as lead or steel-made wires can be used for disease localization. The same needs to be

Locally Advanced Cervical Carcinoma Management http://dx.doi.org/10.5772/intechopen.74011 83

For a 4-field (antero-posterior, postero-anterior and lateral fields) treatment, the simulation is done in the supine position and CT or Fluoroscopic images taken. Patients are positioned with arms on the chest, knees and lower legs immobilized. Anterior and lateral tattoos are marked and aligned with lasers for lateral rotation prevention. Obese patients may benefit from prone

Intra-venous contrast CT scans are taken to help highlight the pelvic vessels used as reference

For centers using two-dimensional planning and fluoroscopic imaging, the same marking has

• Inferior: Below the ischial tuberosity or the inferior obturator foramen if bony landmarks

For advanced disease involving the lower vagina (stage IIIA), include at least a margin of 3 cm

Extensive Radiation Therapy has been suggested in the presence of para-aortic lymph nodes,

Stage IIIA is associated with inguinal nodes, and the field needs to include the vaginal introitus as the inferior border; with a common iliac nodes disease presence, the superior border is

Dosing should be up to 50 Gy delivered in 25 equal fractions, daily. This is usually given

Dose limiting organs are mainly the bladder, rectum, femoral heads, and with a lower instance,

As per the American Brachytherapy Society guidelines, brachytherapy for cervical cancer

The preferred brachytherapy technique is the High Dose Rate Brachytherapy, delivering above

within 5 days a week for 5 weeks, allowing a 2-day rest between weeks of treatment.

belly boards, to avoid small bowel inclusion in the radiation volume.

to be done, with fluorescent markers, and tattoos where applicable.

with the superior-most border being T12/L1, with kidney blocks [10].

needs to be applied for a disease not exceeding a size of 5 cm.

applied to the vagina and anus areas.

to delineate the pelvic nodes.

• Superior: Lumbar spine level 4/5

• Lateral: 1.5–2 cm away from the pelvic brim

• Anterior: 1 cm anterior to pubic symphysis

away from the distal most part of the disease.

• Posterior: Entire Sacrum to be included

The borders are:

are used

to be raised up to L3/4.

the small bowel and ovaries.

**5.4. Brachytherapy**

12 Gy/hour.

**Table 2.** Summary—cisplatin treatment planning and dosage.

Total doses above 45 Gy are preferred as they are proven to offer a survival advantage.

Radiation therapy is offered to post-operative patients confirmed to have adverse features (mainly Lympho-Vascular Space Invasion, positive pelvic nodes, involved parametria and positive surgical margins), with stages IA2, IB. It is also the definitive treatment, with concurrent chemotherapy for stage IIB- IVA.

The typical dose given by EBRT varies between 45 and 50 Gy depending on the stage and prior treatment. For patients treated with a prior hysterectomy, lower doses (typically below 45 Gy) are preferred to avoid radiation induced bowel toxicity; higher doses are safe to be delivered on an intact uterus and cervix.

Current RTOG and GOG protocols suggest total doses for cervical carcinoma treated with definitive radiation therapy to be around 80–90 Gy to a point defined within the paracervical triangle, namely the point A.

The point A has been varied over the years, and is defined as being at 2 cm above the external cervical os and 2 cm lateral to uterus midline. This corresponds to the paracervical triangle, where the uterine vessels cross the ureter, medial to the broad ligament.

Given the proximity of the cervix to the major pelvic organs and the femoral heads, the external beam radiation doses are limited to an overall dose of 50 Gy. Institutional practices vary, some preferring doses below 45 Gy before proceeding to brachytherapy, with options of lowering the field size to boost to gross residual and nodal disease to doses up to 50 Gy.

Addition of brachytherapy has shown high rates of cancer-specific and overall survival benefits when compared to external beam radiation therapy alone. The objective of brachytherapy addition is to reach the desired total dose of 80–90 Gy to the disease site while minimizing toxicity to organs at risk.

#### **5.3. External beam radiation techniques**

The distal most part of the disease needs to be marked with radiopaque gold seeds for disease localization prior to treatment imaging. In the absence of gold seeds, radiopaque materials such as lead or steel-made wires can be used for disease localization. The same needs to be applied to the vagina and anus areas.

For a 4-field (antero-posterior, postero-anterior and lateral fields) treatment, the simulation is done in the supine position and CT or Fluoroscopic images taken. Patients are positioned with arms on the chest, knees and lower legs immobilized. Anterior and lateral tattoos are marked and aligned with lasers for lateral rotation prevention. Obese patients may benefit from prone belly boards, to avoid small bowel inclusion in the radiation volume.

Intra-venous contrast CT scans are taken to help highlight the pelvic vessels used as reference to delineate the pelvic nodes.

For centers using two-dimensional planning and fluoroscopic imaging, the same marking has to be done, with fluorescent markers, and tattoos where applicable.

The borders are:

Total doses above 45 Gy are preferred as they are proven to offer a survival advantage.

Prior to Treatment Work-up Complete Blood Count - with a low Absolute Neutrophil Count, consider

Serum Electrolytes (K<sup>+</sup>

infusion

82 Cervical Cancer - Screening, Treatment and Prevention - Universal Protocols for Ultimate Control

 IV weekly Pre-medications Hydration – 2 l Normal Saline (0.9%) over 2 hours prior and after a cisplatin

100 ml of Normal Saline (0.9%)

fitness of the patient to receive cisplatin

, Na+ )

adding Filgrastim (if available) prior to chemotherapy infusion Renal Function Tests - use the Glomerular Filtration Rate to determine

Ondansetron 16 mg IV and Dexamethasone 16 mg IV, both mixed with

rent chemotherapy for stage IIB- IVA.

**Cisplatin - dosage and premedications Details**

Dosage 40 mg/m<sup>2</sup>

**Table 2.** Summary—cisplatin treatment planning and dosage.

delivered on an intact uterus and cervix.

triangle, namely the point A.

toxicity to organs at risk.

**5.3. External beam radiation techniques**

Radiation therapy is offered to post-operative patients confirmed to have adverse features (mainly Lympho-Vascular Space Invasion, positive pelvic nodes, involved parametria and positive surgical margins), with stages IA2, IB. It is also the definitive treatment, with concur-

The typical dose given by EBRT varies between 45 and 50 Gy depending on the stage and prior treatment. For patients treated with a prior hysterectomy, lower doses (typically below 45 Gy) are preferred to avoid radiation induced bowel toxicity; higher doses are safe to be

Current RTOG and GOG protocols suggest total doses for cervical carcinoma treated with definitive radiation therapy to be around 80–90 Gy to a point defined within the paracervical

The point A has been varied over the years, and is defined as being at 2 cm above the external cervical os and 2 cm lateral to uterus midline. This corresponds to the paracervical triangle,

Given the proximity of the cervix to the major pelvic organs and the femoral heads, the external beam radiation doses are limited to an overall dose of 50 Gy. Institutional practices vary, some preferring doses below 45 Gy before proceeding to brachytherapy, with options of lowering the field size to boost to gross residual and nodal disease to doses up to 50 Gy. Addition of brachytherapy has shown high rates of cancer-specific and overall survival benefits when compared to external beam radiation therapy alone. The objective of brachytherapy addition is to reach the desired total dose of 80–90 Gy to the disease site while minimizing

The distal most part of the disease needs to be marked with radiopaque gold seeds for disease localization prior to treatment imaging. In the absence of gold seeds, radiopaque materials

where the uterine vessels cross the ureter, medial to the broad ligament.


For advanced disease involving the lower vagina (stage IIIA), include at least a margin of 3 cm away from the distal most part of the disease.

Extensive Radiation Therapy has been suggested in the presence of para-aortic lymph nodes, with the superior-most border being T12/L1, with kidney blocks [10].

Stage IIIA is associated with inguinal nodes, and the field needs to include the vaginal introitus as the inferior border; with a common iliac nodes disease presence, the superior border is to be raised up to L3/4.

Dosing should be up to 50 Gy delivered in 25 equal fractions, daily. This is usually given within 5 days a week for 5 weeks, allowing a 2-day rest between weeks of treatment.

Dose limiting organs are mainly the bladder, rectum, femoral heads, and with a lower instance, the small bowel and ovaries.

#### **5.4. Brachytherapy**

As per the American Brachytherapy Society guidelines, brachytherapy for cervical cancer needs to be applied for a disease not exceeding a size of 5 cm.

The preferred brachytherapy technique is the High Dose Rate Brachytherapy, delivering above 12 Gy/hour.

The point of interest for brachytherapy delivery is defined in the contemporary method as per the Manchester point A - 2 cm superior to the external cervical os and 2 cm lateral to the central uterine canal. The objective is to deliver a cumulative dose of 80–90 Gy.

**References**

[1] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics,

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[2] Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. International Journal of Gynaecology and Obstetrics. 2009;**105**(2):107. Epub 2009 Apr 1

[3] Sharma A, Kulkarni V, Bhaskaran U, Singha M, Mujtahedi S, Chatrath A, Sridhar M, Thapar R, Mithra PP, Kumar N, Holla R, Darshan BB, Kumar A. Profile of cervical cancer patients attending Tertiary Care Hospitals of Mangalore, Karnataka: A 4 year retrospective study. Journal of Natural Science, Biology, and Medicine. 2017 Jan-Jun;**8**(1):125-112

[4] Musa J, Nankat J, Achenbach CJ, Shambe IH, Taiwo BO, Mandong B, Daru PH, Murphy RL, Sagay AS. Cervical cancer survival in a resource-limited setting-North Central Nigeria.

[5] Chirenje ZM, Rusakaniko S, Akino V, Mlingo M. A review of cervical cancer patients presenting in Harare and Parirenyatwa Hospitals in 1998. The Central African Journal of

[6] Mlange R, Matovelo D, Rambau P, Kidenya B. Patient and disease characteristics associated with late tumour stage at presentation of cervical cancer in northwestern Tanzania.

[7] Landoni F, Maneo A, Colombo A, Placa F, Milani R, Perego P, Favini G, Ferri L, Mangioni C. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical can-

[8] Hreshchyshyn MM, Aron BS, Boronow RC, Franklin EW, Shingleton HM, Blessing JA. Hydroxyurea or placebo combined with radiation to treat stages iiib and iv cervical cancer confined to the pelvis. International Journal of Radiation Oncology, Biology, Physics.

[9] Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB–IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. Journal of Clinical Oncology. 1999;**17**:1339-1348

[10] Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer an update of Radiation Therapy Oncology Group trial (RTOG) 90-01. Journal of Clinical Oncology.

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Due to nodal disease associated with locally advanced cervical cancer, a Manchester point B is defined at 3 cm lateral to point A. With this system, bladder, vaginal and rectal points are also defined. Care needs to be taken to minimize the radiation dose to the bladder and rectum by anteriorly and posteriorly packing through the vagina and around the brachytherapy applicators.

Brachytherapy delivery is provided once weekly over a time interval of 3–6 weeks. Total radiotherapy treatment (EBRT and BT) should be completed within a time period of 7–8 weeks.
