Introductory Chapter: Recent Progress in Lung Cancer Treatment - The Value of Multiple Perspectives

*Henry Soo-Min Park*

## **1. Introduction**

The remarkable advances in lung cancer management that we have witnessed in the past two decades did not arise in a vacuum. Surgeons, radiation oncologists, medical oncologists, pulmonologists, palliative care specialists, radiologists, pathologists, laboratory scientists, and patients have long collaborated to make the vision of improved cure rates, survival, and quality-of-life a reality.

## **2. Surgery**

Minimally invasive surgery (MIS) has altered the landscape of thoracic surgery. Thoracotomies had been standard-of-care for lung cancer resections until the advent of video-assisted thoracoscopic surgery in the mid-1990s. While initially utilized primarily for patients with favorable anatomy and good pulmonary function, this has been increasingly adopted for use in more frail patients with more technically challenging anatomy [1]. Robotic-assisted thoracoscopic surgery was approved in the early-2000s with the help of even more sophisticated technology that imitated the manual dexterity of an open procedure.

With both approaches, there were initial concerns that there would be higher rates of complications as well as margin-positive resections that could translate into more intensive adjuvant regimens or poorer survival outcomes. Both techniques have substantial learning curves, but surgeons and centers gradually accumulated experience and increased the proportion of patients who underwent surgeries with a minimally invasive approach. Over a relatively short period of time, adoption of MIS has led to improved perioperative outcomes like pain, complications, length of hospital stay, and in-hospital costs without compromising oncologic outcomes [2, 3]. Not only has MIS allowed surgical patients to regain independence sooner than they would have otherwise, but also patients who may have not previously considered surgery due to the risk of morbidity might now be candidates for this potentially curative modality.

## **3. Radiotherapy and other ablative therapies**

Nonsurgical local approaches have also expanded in scope due to developments in technology. Radiotherapy can now be administered with exceptional accuracy

and precision despite physiologic lung motion. This is largely due to improvements in image-guidance, 4-dimensional motion management, and beam modulation approaches that allow for higher biologically effective doses to the target, less scatter doses to normal organs, and more convenient treatment schedules.

Due to these advances, more ablative doses were made possible in the form of stereotactic body radiotherapy (SBRT), also known as stereotactic ablative body radiotherapy. Since its development in the mid-2000s, SBRT has been proven to be a valid alternative to surgical resection in early-stage disease, showing local control in the 90–98% range at 3–5 years with acceptable toxicity [4, 5]. SBRT has also been increasingly utilized in oligometastatic and oligoprogressive disease, with survival benefits demonstrated when used as consolidative therapy after systemic therapy [6, 7].

For inoperable locoregionally advanced non-small cell lung cancer, fractionated radiotherapy has been traditionally combined with chemotherapy with curative intent. With improved knowledge on appropriate radiotherapy dosing and the advent of consolidative immunotherapy, we can achieve better outcomes than we have ever seen before [8, 9]. Furthermore, image-guided ablative therapies like radiofrequency ablation, microwave ablation, and cryoablation have a wide range of potential indications. They can be particularly effective in situations that are not amenable to surgical or radiotherapeutic interventions due to safety concerns.

### **4. Systemic therapy**

For more advanced disease, precision medicine has greatly expanded in its ability to address specific mutations and biomarkers with customized combinations of chemotherapy, targeted therapy, and immunotherapy. Drugs can now specifically target mutations like EGFR and ALK, effectively controlling even the most widespread metastases. Outcomes have continued to improve with refinements in successive generations of these agents [10, 11]. In addition, immunotherapy has been successfully used as monotherapy for patients with PD-L1 expressing tumors [12], or added to chemotherapy for patients with high, low, and no PD-L1 expression [13]. This has led to standard treatment regimens for most patients with stage IV non-small cell lung cancer. These combinations have also extended to extensivestage small cell lung cancer, with the addition of concurrent and maintenance immunotherapy representing the first major pharmacologic advance in the upfront treatment of this disease in several decades [14, 15].

Even for tumors that develop resistance to initial therapies, novel blood-based and tissue-based diagnostic testing can help clinicians formulate a truly personalized approach to oncologic management, leading to the possibility of long-term survival that was unimaginable even a decade ago. Combining these systemic therapies with local therapies in the oligometastatic and oligoprogressive setting has led to unique regimens that have dramatically altered disease trajectories.

#### **5. Palliative care**

Palliative management of bone metastases has improved due to enhanced patient selection algorithms and surgical stabilization techniques by orthopedic surgeons and neurosurgeons, in addition to the judicious use of radiotherapy. Brain metastasis management has also evolved through increased utilization of upfront stereotactic radiosurgery [16] rather than whole-brain radiotherapy, mitigating potential cognitive effects without a survival detriment [17]. Furthermore,

**5**

**Author details**

Henry Soo-Min Park

Department of Therapeutic Radiology, Yale School of Medicine,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

New Haven, Connecticut, United States of America

\*Address all correspondence to: henry.park@yale.edu

provided the original work is properly cited.

*Introductory Chapter: Recent Progress in Lung Cancer Treatment - The Value of Multiple...*

contributed not only to improved quality-of-life, but also to survival [18].

integration of early palliative care for patients with advanced lung cancers has also

Moving forward, utilization of cutting-edge technologies like circulating tumor biomarkers, machine learning, gas plasma, and nanotechnology may offer exciting new opportunities in screening, diagnosis, and therapy. While these may be in earlier stages of development than more standard modalities, they represent

If the inspirational innovations discussed in this chapter are any indication, the

*DOI: http://dx.doi.org/10.5772/intechopen.97822*

**6. Future directions and conclusions**

promising avenues for research and clinical application.

future of personalized care for patients with lung cancer is exciting.

*Introductory Chapter: Recent Progress in Lung Cancer Treatment - The Value of Multiple... DOI: http://dx.doi.org/10.5772/intechopen.97822*

integration of early palliative care for patients with advanced lung cancers has also contributed not only to improved quality-of-life, but also to survival [18].

## **6. Future directions and conclusions**

*Lung Cancer - Modern Multidisciplinary Management*

therapy [6, 7].

**4. Systemic therapy**

and precision despite physiologic lung motion. This is largely due to improvements in image-guidance, 4-dimensional motion management, and beam modulation approaches that allow for higher biologically effective doses to the target, less scatter

Due to these advances, more ablative doses were made possible in the form of stereotactic body radiotherapy (SBRT), also known as stereotactic ablative body radiotherapy. Since its development in the mid-2000s, SBRT has been proven to be a valid alternative to surgical resection in early-stage disease, showing local control in the 90–98% range at 3–5 years with acceptable toxicity [4, 5]. SBRT has also been increasingly utilized in oligometastatic and oligoprogressive disease, with survival benefits demonstrated when used as consolidative therapy after systemic

For inoperable locoregionally advanced non-small cell lung cancer, fractionated radiotherapy has been traditionally combined with chemotherapy with curative intent. With improved knowledge on appropriate radiotherapy dosing and the advent of consolidative immunotherapy, we can achieve better outcomes than we have ever seen before [8, 9]. Furthermore, image-guided ablative therapies like radiofrequency ablation, microwave ablation, and cryoablation have a wide range of potential indications. They can be particularly effective in situations that are not amenable to surgical or radiotherapeutic interventions due to safety concerns.

For more advanced disease, precision medicine has greatly expanded in its ability to address specific mutations and biomarkers with customized combinations of chemotherapy, targeted therapy, and immunotherapy. Drugs can now specifically target mutations like EGFR and ALK, effectively controlling even the most widespread metastases. Outcomes have continued to improve with refinements in successive generations of these agents [10, 11]. In addition, immunotherapy has been successfully used as monotherapy for patients with PD-L1 expressing tumors [12], or added to chemotherapy for patients with high, low, and no PD-L1 expression [13]. This has led to standard treatment regimens for most patients with stage IV non-small cell lung cancer. These combinations have also extended to extensivestage small cell lung cancer, with the addition of concurrent and maintenance immunotherapy representing the first major pharmacologic advance in the upfront

Even for tumors that develop resistance to initial therapies, novel blood-based and tissue-based diagnostic testing can help clinicians formulate a truly personalized approach to oncologic management, leading to the possibility of long-term survival that was unimaginable even a decade ago. Combining these systemic therapies with local therapies in the oligometastatic and oligoprogressive setting has

led to unique regimens that have dramatically altered disease trajectories.

Palliative management of bone metastases has improved due to enhanced patient selection algorithms and surgical stabilization techniques by orthopedic surgeons and neurosurgeons, in addition to the judicious use of radiotherapy. Brain metastasis management has also evolved through increased utilization of upfront stereotactic radiosurgery [16] rather than whole-brain radiotherapy, mitigating potential cognitive effects without a survival detriment [17]. Furthermore,

treatment of this disease in several decades [14, 15].

doses to normal organs, and more convenient treatment schedules.

**4**

**5. Palliative care**

Moving forward, utilization of cutting-edge technologies like circulating tumor biomarkers, machine learning, gas plasma, and nanotechnology may offer exciting new opportunities in screening, diagnosis, and therapy. While these may be in earlier stages of development than more standard modalities, they represent promising avenues for research and clinical application.

If the inspirational innovations discussed in this chapter are any indication, the future of personalized care for patients with lung cancer is exciting.

## **Author details**

Henry Soo-Min Park Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, United States of America

\*Address all correspondence to: henry.park@yale.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] McKenna RJ Jr. Lobectomy by video-assisted thoracic surgery with mediastinal node sampling for lung cancer. J Thorac Cardiovasc Surg 1994;107:879-882.

[2] Park HS, Detterbeck FC, Boffa DJ, Kim AW. Impact of hospital volume of thoracoscopic lobectomy on primary lung cancer outcomes. Ann Thorac Surg 2012;93(2):372-379.

[3] Tchouta LN, Park HS, Boffa DJ, et al. Hospital volume and outcomes of robot-assisted lobectomies. Chest 2017;151(2):329-339.

[4] Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303(11):1070-1076.

[5] Timmerman RD, Hu C, Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medially inoperable stage I non-small cell lung cancer. JAMA Oncol 2018;4(9):1287-1288.

[6] Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic nonsmall-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019;37(18):1558-1565.

[7] Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomized, phase 2, open-label trial. Lancet 2019;393(10185):2051-2058.

[8] Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342-2350.

[9] Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC – an update from the PACIFIC trial. J Thorac Oncol 2021;Epub ahead of print.

[10] Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFRmutated advanced NSCLC. N Engl J Med 2020;382(1):41-50.

[11] Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4- ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol 2019;14(7):1233-1243.

[12] Mok TS, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1 expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393(10183):1819-1830.

[13] Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–smallcell lung cancer. N Engl J Med 2018;378:2078-2092.

[14] Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-2229.

[15] Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum– etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394(10212): 1929-1939.

**7**

*Introductory Chapter: Recent Progress in Lung Cancer Treatment - The Value of Multiple...*

*DOI: http://dx.doi.org/10.5772/intechopen.97822*

[16] Kann BH, Park HS, Johnson SB, et al. Radiosurgery for brain metastases:

[17] Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation

[18] Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med 2010;363:733-742.

therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA

2016;316(4):401-409.

changing practice patterns and disparities in the United States. J Natl Compr Canc Netw 2017;15(12):

1494-1502.

*Introductory Chapter: Recent Progress in Lung Cancer Treatment - The Value of Multiple... DOI: http://dx.doi.org/10.5772/intechopen.97822*

[16] Kann BH, Park HS, Johnson SB, et al. Radiosurgery for brain metastases: changing practice patterns and disparities in the United States. J Natl Compr Canc Netw 2017;15(12): 1494-1502.

[17] Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 2016;316(4):401-409.

[18] Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med 2010;363:733-742.

**6**

*Lung Cancer - Modern Multidisciplinary Management*

[9] Faivre-Finn C, Vicente D, Kurata T,

durvalumab after chemoradiotherapy in stage III NSCLC – an update from the

[10] Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with

osimertinib in untreated, EGFRmutated advanced NSCLC. N Engl J

[11] Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4- ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol 2019;14(7):1233-1243.

[12] Mok TS, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1 expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393(10183):1819-1830.

[13] Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-

[14] Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med

[15] Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum– etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394(10212):

cell lung cancer. N Engl J Med

2018;378:2078-2092.

2018;379:2220-2229.

1929-1939.

Med 2020;382(1):41-50.

et al. Four-year survival with

PACIFIC trial. J Thorac Oncol 2021;Epub ahead of print.

[1] McKenna RJ Jr. Lobectomy by video-assisted thoracic surgery with mediastinal node sampling for lung cancer. J Thorac Cardiovasc Surg

[2] Park HS, Detterbeck FC, Boffa DJ, Kim AW. Impact of hospital volume of thoracoscopic lobectomy on primary lung cancer outcomes. Ann Thorac Surg

[3] Tchouta LN, Park HS, Boffa DJ, et al. Hospital volume and outcomes of robot-assisted lobectomies. Chest

[4] Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303(11):1070-1076.

Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medially inoperable stage I non-small

[6] Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs.

maintenance therapy or observation for patients with oligometastatic nonsmall-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol

[7] Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomized, phase 2, open-label trial. Lancet 2019;393(10185):2051-2058.

[8] Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III

1994;107:879-882.

**References**

2012;93(2):372-379.

2017;151(2):329-339.

[5] Timmerman RD, Hu C,

cell lung cancer. JAMA Oncol

2018;4(9):1287-1288.

2019;37(18):1558-1565.

NSCLC. N Engl J Med 2018;379:2342-2350.

**9**

Section 2

Surgical Advances
