NEWS & VIEWS LUNG CANCER
Implementing lung-cancer screening—oncological ‘grey areas’ Thomas_Lauridsen/iStock/Thinkstock
Vivek Verma Refers to Jensen, T. S. et al. Final National Coverage Determination on Screening for Lung Cancer with Low Dose Computed Tomography (LDCT). CMS.gov: Centers for Medicare & Medicaid Services [online], http://www.cms.gov/medicare-coverage-database/ details/nca-decision-memo.aspx?NCAId=274 (2015)
Owing to the institution of annual low-dose CT for lung cancer screening in the USA, the presumed increase in detection of early stage lung cancers elicits many questions about so-called ‘grey areas’ of the management of this disease that have been inadequately addressed to date. Herein, important and potentially difficult ambiguous cases that oncologists might come across are discussed. The US Government Department of Health and Human Services Centers for Medicare and Medicaid Services (CMS) has made the landmark decision to approve annual low-dose CT (LDCT) screening for lung cancer in select individuals at high risk of the disease.1 This measure is to be implemented based on the inclusion criteria of the National Lung Screening Trial (NLST);2 specifically, asymptomatic 55–77-yearold individuals with a smoking history of ≥30 pack-years, including either current smokers or those who quit within the past 15 years, will be eligible for annual screening.1 This additional preventive service of the Medicare programme could potentially affect tens of millions of people throughout the USA. As illustrated in the NLST,2 an increased incidence of early stage lung cancer cases is likely to be observed in those who are screened. Although this measure will probably improve outcomes through earlier diagnosis of the disease at a stage when it is more amenable to treatment, the increased incidence of early stage lung cancer cases will necessitate renewed vigour when considering treatment options. The current standard of care for early stage operable lung cancer is lobectomy, with stereotactic ablative radiotherapy (SABR)—a precision radiotherapy modality also known as stereotactic body radiotherapy (SBRT)—reserved for the treatment of patients with inoperable disease. In reality, clinical medicine often strays from the textbook protocols because, inevitably, some
patients occupy the less-defined ‘grey areas’ of oncological management. Therefore, in light of the recent announcement by the CMS, it is probable that oncologists will increasingly face difficult management decisions. In turn, this recognition raises several salient clinical issues that will need to be addressed. First, operability status is a relatively subjective concept, and is dependent on whether the particular surgeon and/or institution is considered ‘surgically aggressive’. Although a certain proportion of the asymptomatic patients who are screened will have sufficiently low comorbidity to proceed with surgery, others will be classified in the ambiguous ‘potentially operable’ category. For these patients, the best treatment modality is less well defined; if lobectomy is not safely achievable, some advocate performing the sublobar wedge resection procedure, whereas others support the use of SABR. Current data support either option, owing to the identical disease-specific survival associated with both approaches.3 An overall survival advantage was reported in surgically treated patients with stage I non-small-cell lung cancer (NSCLC), possibly because they tended to be younger and with fewer comorbidities than the patients who underwent SABR.3 However, in a study that specifically examined patients with potentially operable stage I NSCLC, the median overall survival after SABR exceeded 5 years.4 In spite of these data, the relative paucity and
NATURE REVIEWS | CLINICAL ONCOLOGY
heterogeneity of this patient category continues to necessitate careful consultation with patients, including a balanced discussion of the risks and benefits of all treatment options, ensuring the patients understand that their personal decision is important for disease management. In addition to patients with clinically significant comorbidities, disease management in elderly patients is another major grey area. Elderly patients often present with comorbidities that portend a relatively shorter remaining lifespan and/or nonideal quality of life, but have disease that would, technically, be medically operable. The approach that constitutes optimal management for this group of patients remains unclear. Similar circumstances exist in the settings of prostate cancer, in which management is often dictated by estimating life expectancy, and breast cancer, in which increasing evidence supports hypofractionated radiotherapy, rather than conventional radiotherapy regimens, for certain elderly patients. In this regard, early stage lung cancer has not been nearly as well studied; however, a study has illustrated similar outcomes of SABR and surgery for elderly patients.5 Considering the patients in this study were aged ≥75 years, and the upper limit of screening recommended by the CMS is 77 years of age, another question that logically arises is how much the elderly age ‘threshold’, below which surgery is considered the best option and above which SABR might be equivalent, can be decreased while maintaining similar outcomes for both treatment modalities. Hence, further VOLUME 12 | MAY 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS research to delineate treatment options for this group of patients, whether predicated on new primary data or subgroup analyses of existing data, would be welcomed. Even before annual LDCT screening was approved, radiation oncology referrals for early stage lung cancers were often the result of patient refusal of surgery, despite the disease being medically operable. At times, this scenario presents difficulties, especially when taking into account the primary tumour location. For instance, it is important for patients to understand that for some small, peripherally located tumours, sublobar resection is often feasible without compromising survival—although such decisions should be made on a caseby-case basis. Moreover, patients with centrally located tumours—p articularly larger tumours—are probably suboptimal candidates for SABR (although decreasing the dose per fraction is commonly performed), based on substantial toxi city seen in previous trials in this setting.6 Understanding patients’ desires is important; however, patients with anatomically unfavourable neoplasms requiring a clinical management approach that differs from their personal treatment preference emphasize an important requirement for multidisciplinary oncological counselling. Another emerging and highly debated issue is whether surgical resection is indeed superior to SABR in patients with operable early stage lung cancer. To date, clinical trials that evaluated this question have been hampered by the fact that the vast majority of patients with operable disease and a good performance status underwent surgery, rather than SABR; thus, whether SABR is a feasible option for patients fit to undergo surgery has been confounded by variable degrees of comorbidities between treatment groups. At present, most available studies demonstrate a greater benefit of lobectomy over SABR in patients with medically operable disease, but data that call into question the superiority of surgery are increasing. For instance, in a Japanese case-series of patients with medically operable stage I lung cancer who chose to undergo SABR, 7 survival seemed highly comparable to—and in many cases, better than—outcomes reported in historical
MAY 2015 | VOLUME 12
surgical series. Although the potential for intertrial distortion and bias in such comparisons is clear, the results of Japan Clinical Oncology Group Trial 0403, which is evaluating SABR in patients both operable and medically inoperable T1N0M0 lung cancer, are eagerly anticipated.8 The favourable surgical outcomes in patients with early stage lung cancer are often attributed to regional lymph-node sampling, which is not possible by SABR. In particular, occult regional lymph-node involvement, despite negative results on PET scanning, was thought to result in lessfavourable outcomes with SABR. However, one of the earliest trials of SABR for the treatment of inoperable early stage lung cancer demonstrated a good locoregional control rate (87.2% at 3 years);9 instead, a large proportion of recurrences occurred at distant sites (3‑year disseminated recurrence rate of 22.1%).9 These findings indicate that regional nodal control is probably not the major culprit for disease progression after SABR. Furthermore, the 3‑year disseminated recurrence risk for T2N0 tumours was 47.0%, compared with 14.7% for T1N0 tumours, suggesting that tumour size influences the risk of distant recurrence. By contrast, studies have demonstrated that larger tumours do not necessarily have a higher risk of regional nodal failure.10 Thus, exploring chemotherapy plus SABR in patients at high risk of disease dissemination has had some merit (provided that patients are able to tolerate chemotherapy), but this chemo radiotherapy approach remains experimental. At present, consideration of T‑stage (primarily as a predictor of disseminated recurrence risk) has a key role in the clinical counselling of patients with medically operable disease opting for SABR regarding differential rates of failure. Annual LDCT screening for lung cancer is now a reality in the USA for select individuals. However, this measure raises a plethora of questions that need to be addressed not only in clinical trials, but also through clinical experience in the upcoming era of screen-detected lung cancer. Clinical grey areas in patient management exist for many types of cancers; however, considering the relative infancy of treating early stage lung neoplasms with advanced surgical and
radiot herapeutic techniques, it is likely that considerable advances will be made as further clinical data elucidate how to best address many of these ambiguous issues. Department of Radiation Oncology, University of Nebraska Medical Center, 987521 Nebraska Medical Center, Ground Floor, Clarkson Tower, Omaha, NE 68198, USA. [email protected] doi:10.1038/nrclinonc.2015.65 Published online 7 April 2015 Competing interests The author declares no competing interests. 1.
Jensen, T. S., Chin, J., Ashby, L., Hermansen, J. & Hutter, J. D. Final National Coverage Determination on Screening for Lung Cancer with Low Dose Computed Tomography (LDCT). CMS.gov: Centers for Medicare & Medicaid Services [online], http:// www.cms.gov/medicare-coverage-database/ details/nca-decision-memo.aspx?NCAId=274 (2015). 2. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395–409 (2011). 3. Grills, I. S. et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non‑small‑cell lung cancer. J. Clin. Oncol. 28, 928–935 (2010). 4. Lagerwaard, F. J. et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 83, 348–353 (2012). 5. Palma, D. et al. Treatment of stage I NSCLC in elderly patients: a population-based matchedpair comparison of stereotactic radiotherapy versus surgery. Radiother. Oncol. 101, 240–244 (2011). 6. Timmerman, R. et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J. Clin. Oncol. 24, 4833–4839 (2006). 7. Onishi, H. et al. Stereotactic body radiotherapy (SBRT) for operable stage I non‑small‑cell lung cancer: can SBRT be comparable to surgery? Int. J. Radiat. Oncol. Biol. Phys. 81, 1352–1358 (2011). 8. Nagata, Y. et al. A phase II trial of stereotactic body radiation therapy for operable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group (JCOG0403). Int. J. Radiat. Oncol. Biol. Phys. 78, S27–S28 (2010). 9. Timmerman, R. et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303, 1070–1076 (2010). 10. Marwaha, G., Stephans, K. L., Woody, N. M., Reddy, C. A. & Videtic, G. M. Lung stereotactic body radiation therapy: regional nodal failure is not predicted by tumor size. J. Thorac. Oncol. 9, 1693–1697 (2014).
www.nature.com/nrclinonc © 2015 Macmillan Publishers Limited. All rights reserved
Implementing lung-cancer screening—oncological ‘grey areas’ Thomas_Lauridsen/iStock/Thinkstock
Vivek Verma Refers to Jensen, T. S. et al. Final National Coverage Determination on Screening for Lung Cancer with Low Dose Computed Tomography (LDCT). CMS.gov: Centers for Medicare & Medicaid Services [online], http://www.cms.gov/medicare-coverage-database/ details/nca-decision-memo.aspx?NCAId=274 (2015)
Owing to the institution of annual low-dose CT for lung cancer screening in the USA, the presumed increase in detection of early stage lung cancers elicits many questions about so-called ‘grey areas’ of the management of this disease that have been inadequately addressed to date. Herein, important and potentially difficult ambiguous cases that oncologists might come across are discussed. The US Government Department of Health and Human Services Centers for Medicare and Medicaid Services (CMS) has made the landmark decision to approve annual low-dose CT (LDCT) screening for lung cancer in select individuals at high risk of the disease.1 This measure is to be implemented based on the inclusion criteria of the National Lung Screening Trial (NLST);2 specifically, asymptomatic 55–77-yearold individuals with a smoking history of ≥30 pack-years, including either current smokers or those who quit within the past 15 years, will be eligible for annual screening.1 This additional preventive service of the Medicare programme could potentially affect tens of millions of people throughout the USA. As illustrated in the NLST,2 an increased incidence of early stage lung cancer cases is likely to be observed in those who are screened. Although this measure will probably improve outcomes through earlier diagnosis of the disease at a stage when it is more amenable to treatment, the increased incidence of early stage lung cancer cases will necessitate renewed vigour when considering treatment options. The current standard of care for early stage operable lung cancer is lobectomy, with stereotactic ablative radiotherapy (SABR)—a precision radiotherapy modality also known as stereotactic body radiotherapy (SBRT)—reserved for the treatment of patients with inoperable disease. In reality, clinical medicine often strays from the textbook protocols because, inevitably, some
patients occupy the less-defined ‘grey areas’ of oncological management. Therefore, in light of the recent announcement by the CMS, it is probable that oncologists will increasingly face difficult management decisions. In turn, this recognition raises several salient clinical issues that will need to be addressed. First, operability status is a relatively subjective concept, and is dependent on whether the particular surgeon and/or institution is considered ‘surgically aggressive’. Although a certain proportion of the asymptomatic patients who are screened will have sufficiently low comorbidity to proceed with surgery, others will be classified in the ambiguous ‘potentially operable’ category. For these patients, the best treatment modality is less well defined; if lobectomy is not safely achievable, some advocate performing the sublobar wedge resection procedure, whereas others support the use of SABR. Current data support either option, owing to the identical disease-specific survival associated with both approaches.3 An overall survival advantage was reported in surgically treated patients with stage I non-small-cell lung cancer (NSCLC), possibly because they tended to be younger and with fewer comorbidities than the patients who underwent SABR.3 However, in a study that specifically examined patients with potentially operable stage I NSCLC, the median overall survival after SABR exceeded 5 years.4 In spite of these data, the relative paucity and
NATURE REVIEWS | CLINICAL ONCOLOGY
heterogeneity of this patient category continues to necessitate careful consultation with patients, including a balanced discussion of the risks and benefits of all treatment options, ensuring the patients understand that their personal decision is important for disease management. In addition to patients with clinically significant comorbidities, disease management in elderly patients is another major grey area. Elderly patients often present with comorbidities that portend a relatively shorter remaining lifespan and/or nonideal quality of life, but have disease that would, technically, be medically operable. The approach that constitutes optimal management for this group of patients remains unclear. Similar circumstances exist in the settings of prostate cancer, in which management is often dictated by estimating life expectancy, and breast cancer, in which increasing evidence supports hypofractionated radiotherapy, rather than conventional radiotherapy regimens, for certain elderly patients. In this regard, early stage lung cancer has not been nearly as well studied; however, a study has illustrated similar outcomes of SABR and surgery for elderly patients.5 Considering the patients in this study were aged ≥75 years, and the upper limit of screening recommended by the CMS is 77 years of age, another question that logically arises is how much the elderly age ‘threshold’, below which surgery is considered the best option and above which SABR might be equivalent, can be decreased while maintaining similar outcomes for both treatment modalities. Hence, further VOLUME 12 | MAY 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS research to delineate treatment options for this group of patients, whether predicated on new primary data or subgroup analyses of existing data, would be welcomed. Even before annual LDCT screening was approved, radiation oncology referrals for early stage lung cancers were often the result of patient refusal of surgery, despite the disease being medically operable. At times, this scenario presents difficulties, especially when taking into account the primary tumour location. For instance, it is important for patients to understand that for some small, peripherally located tumours, sublobar resection is often feasible without compromising survival—although such decisions should be made on a caseby-case basis. Moreover, patients with centrally located tumours—p articularly larger tumours—are probably suboptimal candidates for SABR (although decreasing the dose per fraction is commonly performed), based on substantial toxi city seen in previous trials in this setting.6 Understanding patients’ desires is important; however, patients with anatomically unfavourable neoplasms requiring a clinical management approach that differs from their personal treatment preference emphasize an important requirement for multidisciplinary oncological counselling. Another emerging and highly debated issue is whether surgical resection is indeed superior to SABR in patients with operable early stage lung cancer. To date, clinical trials that evaluated this question have been hampered by the fact that the vast majority of patients with operable disease and a good performance status underwent surgery, rather than SABR; thus, whether SABR is a feasible option for patients fit to undergo surgery has been confounded by variable degrees of comorbidities between treatment groups. At present, most available studies demonstrate a greater benefit of lobectomy over SABR in patients with medically operable disease, but data that call into question the superiority of surgery are increasing. For instance, in a Japanese case-series of patients with medically operable stage I lung cancer who chose to undergo SABR, 7 survival seemed highly comparable to—and in many cases, better than—outcomes reported in historical
MAY 2015 | VOLUME 12
surgical series. Although the potential for intertrial distortion and bias in such comparisons is clear, the results of Japan Clinical Oncology Group Trial 0403, which is evaluating SABR in patients both operable and medically inoperable T1N0M0 lung cancer, are eagerly anticipated.8 The favourable surgical outcomes in patients with early stage lung cancer are often attributed to regional lymph-node sampling, which is not possible by SABR. In particular, occult regional lymph-node involvement, despite negative results on PET scanning, was thought to result in lessfavourable outcomes with SABR. However, one of the earliest trials of SABR for the treatment of inoperable early stage lung cancer demonstrated a good locoregional control rate (87.2% at 3 years);9 instead, a large proportion of recurrences occurred at distant sites (3‑year disseminated recurrence rate of 22.1%).9 These findings indicate that regional nodal control is probably not the major culprit for disease progression after SABR. Furthermore, the 3‑year disseminated recurrence risk for T2N0 tumours was 47.0%, compared with 14.7% for T1N0 tumours, suggesting that tumour size influences the risk of distant recurrence. By contrast, studies have demonstrated that larger tumours do not necessarily have a higher risk of regional nodal failure.10 Thus, exploring chemotherapy plus SABR in patients at high risk of disease dissemination has had some merit (provided that patients are able to tolerate chemotherapy), but this chemo radiotherapy approach remains experimental. At present, consideration of T‑stage (primarily as a predictor of disseminated recurrence risk) has a key role in the clinical counselling of patients with medically operable disease opting for SABR regarding differential rates of failure. Annual LDCT screening for lung cancer is now a reality in the USA for select individuals. However, this measure raises a plethora of questions that need to be addressed not only in clinical trials, but also through clinical experience in the upcoming era of screen-detected lung cancer. Clinical grey areas in patient management exist for many types of cancers; however, considering the relative infancy of treating early stage lung neoplasms with advanced surgical and
radiot herapeutic techniques, it is likely that considerable advances will be made as further clinical data elucidate how to best address many of these ambiguous issues. Department of Radiation Oncology, University of Nebraska Medical Center, 987521 Nebraska Medical Center, Ground Floor, Clarkson Tower, Omaha, NE 68198, USA. [email protected] doi:10.1038/nrclinonc.2015.65 Published online 7 April 2015 Competing interests The author declares no competing interests. 1.
Jensen, T. S., Chin, J., Ashby, L., Hermansen, J. & Hutter, J. D. Final National Coverage Determination on Screening for Lung Cancer with Low Dose Computed Tomography (LDCT). CMS.gov: Centers for Medicare & Medicaid Services [online], http:// www.cms.gov/medicare-coverage-database/ details/nca-decision-memo.aspx?NCAId=274 (2015). 2. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395–409 (2011). 3. Grills, I. S. et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non‑small‑cell lung cancer. J. Clin. Oncol. 28, 928–935 (2010). 4. Lagerwaard, F. J. et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 83, 348–353 (2012). 5. Palma, D. et al. Treatment of stage I NSCLC in elderly patients: a population-based matchedpair comparison of stereotactic radiotherapy versus surgery. Radiother. Oncol. 101, 240–244 (2011). 6. Timmerman, R. et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J. Clin. Oncol. 24, 4833–4839 (2006). 7. Onishi, H. et al. Stereotactic body radiotherapy (SBRT) for operable stage I non‑small‑cell lung cancer: can SBRT be comparable to surgery? Int. J. Radiat. Oncol. Biol. Phys. 81, 1352–1358 (2011). 8. Nagata, Y. et al. A phase II trial of stereotactic body radiation therapy for operable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group (JCOG0403). Int. J. Radiat. Oncol. Biol. Phys. 78, S27–S28 (2010). 9. Timmerman, R. et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303, 1070–1076 (2010). 10. Marwaha, G., Stephans, K. L., Woody, N. M., Reddy, C. A. & Videtic, G. M. Lung stereotactic body radiation therapy: regional nodal failure is not predicted by tumor size. J. Thorac. Oncol. 9, 1693–1697 (2014).
www.nature.com/nrclinonc © 2015 Macmillan Publishers Limited. All rights reserved
