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Oncology Scan—Promising Strategies for the Treatment of Locally-Advanced Non-Small Cell Lung Cancer
International Journal of
Radiation Oncology biology
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Oncology ScandPromising Strategies for the Treatment of Locally-Advanced Non-Small Cell Lung Cancer By Joe Y. Chang, MD, PhD, Associate Senior Editor The standard treatment for inoperable locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (chemo-RT) (1). However, the optimal radiation dose and fraction schema to be given concurrently with chemotherapy remains controversial (2). Retrospective and phase 2 clinical studies have shown that higher biological effective doses (BEDs) of radiation are associated with improved local control and potentially with survival (3, 4). Stereotactic ablative radiation therapy (SABR, also known as stereotactic body radiation therapy), in which BEDs in excess of 100 Gy are delivered to the planning target volume, has demonstrated local control rates exceeding 95% and survival comparable to that after surgery for stage I NSCLC (5, 6). However, a recent phase 3 randomized study (Radiation Therapy Oncology Group [RTOG] 0617) (2) indicated that a higher radiation dose (74 Gy, BED 88.8 Gy) given with concurrent chemotherapy was associated with poorer median survival as compared with the conventional 60-Gy dose (BED 72 Gy). After the findings of RTOG 0617 were presented at the American Society for Radiation Oncology Annual Meeting in Miami in 2011, the RTOG set the “standard radiation dose” for use with concurrent chemotherapy for stage III NSCLC as 60 Gy for future studies. The theme of this Oncology Scan focuses on 3 important issues in RT for locally advanced NSCLC: (1) Does radiation dose matter in stage III NSCLC? (2) How can radiation dose and delivery be optimized? and (3) Can molecular targeted therapy be safely incorporated into concurrent chemo-RT? Machtay et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: An analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012. (7) Summary: This study combined data from 7 RTOG trials in which chemo-RT given in different radiation regimens (from 60 Gy in 2-Gy once-daily fractions to 69.6 Gy in 1.2-Gy twice-daily fractions) was used for locally advanced NSCLC. The BED received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED), by using standard formulae.
Int J Radiation Oncol Biol Phys, Vol. 87, No. 1, pp. 1e4, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.04.013
A total of 1356 patients were analyzed for BED. The 2-year and 5-year overall survival rates were 38% and 15%, and the 2year and 5-year local-regional failure rates were 46% and 52%, respectively. Both BED and tBED were strongly associated with both overall survival and locoregional failure, with or without adjustment for other covariates, on multivariate analysis (P<.0001). A 1-Gy BED increase in RT dose intensity was associated with a 4% relative improvement in survival and a 3% relative decrease in the risk of local-regional failure, both of which were statistically significant. Comment: By combining results from prospective studies done by the RTOG, Machtay et al confirmed that delivering higher BEDs to the target with chemotherapy resulted in better local-regional control and survival in locally advanced NSCLC, a disease ruled by systemic relapse. Radiation Therapy Oncology Group protocol 9410 and other studies showed that concurrent chemo-RT improved overall survival as compared with sequential chemoRT, largely by improving local-regional control, not distant metastasis (1). However, in addition to local-regional control, 3 competing factors affect overall survival: (1) the presence or absence of distant metastasis and any disease outside the target volume; (2) the severe, potentially fatal toxicity associated with higher-dose RT and chemotherapy; and (3) the presence and severity of other comorbid conditions. The phase 3 randomized study RTOG 7301 showed that 60 Gy was superior to lower-dose radiation in terms of both local control and survival in stage III NSCLC treated with RT alone (8). Machtay et al demonstrated that BED is strongly associated with both overall survival and localregional control when the radiation dose is up to 69.6 Gy versus 60 Gy when either was given with chemotherapy. However, localregional failure rates were still high at approximately 40%-50%. Radiation Therapy Oncology Group protocol 9410 showed that 69.6 Gy with concurrent chemotherapy improved local failure within the target volume as compared with 60 Gy, but survival was not improved owing to treatment toxicity (1). Clearly there is room for improvement in local-regional control if we can minimize the toxicity of the treatment. Eliminating local-regional disease is required for a cure. The phase 1/2 RTOG 0117 study indicated that 74 Gy was the maximum tolerated dose when given with concurrent chemotherapy, but the median survival time of 25.9 months
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Oncology Scan
noted in the phase 2 component was considered promising (3). The primary objective of RTOG 0617, a 2 2 factorial trial, was to explore whether 74 Gy with concurrent chemotherapy, with or without cetuximab, would improve survival versus 60 Gy. A preliminary analysis at 11 months showed that overall survival was poorer in the group randomized to the higher radiation dose (20.7 vs 21.7 months), although details about patterns of failure, RT techniques used, quality assurance, and toxicity are still pending (2). Could it be that doses >70 Gy are not oncologically beneficial? If so, this would run counter to basic biology and a large body of amassed evidence. A more logical explanation is that 74 Gy is too toxic when given with the radiation-delivery techniques used in in this phase 3 study. A group from University of Texas MD Anderson Cancer Center found that using 4-dimensional CT image-guided adaptive proton therapy to a dose of 74 Gy (relative biological effectiveness) with concurrent chemo-RT achieved a local-regional control rate of approximately 80% and a median survival time of 29.4 months, with acceptable toxicity (9). Patternsof-failure analysis indicated that most local failures occurred within the 74-Gy (relative biological effectiveness) isodose line, which suggests that even 74 Gy is still an inadequate dose for some patients. In addition, prolonging the radiation course to 37 fractions may not be the best approach because of the potential for tumor repopulation. Thus, although 60 Gy with concurrent chemotherapy remains the “standard of care” for inoperable stage III NSCLC with the radiation-delivery techniques used in RTOG 0617, issues of dose escalation and acceleration should continue to be explored as new techniques and technologies emerge. Feddock et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: A prospective study. Int J Radiat Oncol Biol Phys 2013. (10) Summary: This prospective, single-institution study evaluated the feasibility of conventional chemoradiation (60 Gy) followed by SABR as a means of dose escalation for patients with stage IIIII NSCLC with residual disease. Thirty-five patients were without metastatic disease and had radiologic evidence of limited residual disease (5 cm) within the site of the primary tumor, as well as good or complete nodal responses after standard chemoradiation to a target dose of 60 Gy. These 35 patients were treated with SABR to achieve a total combined BED to the residual primary tumor of >100 Gy. The SABR boost consisted of 2 fractions of 10 Gy each (20 Gy total) for peripheral tumors, or 3 fractions of 6.5 Gy each (19.5 Gy total) for medial tumors, given a median 2 months after the completion of chemo-RT. Lymph nodes were not given a boost dose. At a median followup time of 13 months, 11.4% patients had developed acute grade 3 radiation pneumonitis (RP), 2.9% had developed late and persistent grade 3 RP, and none had developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the stereotactic body radiation therapy boost, and none were found to predict RP. Only advanced age (PZ.0147), a history of smoking (PZ.0505), and high mean lung dose from the conventional chemoradiation (PZ.0295) were associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, although the status of lymph node recurrence was not clear. Comment: Exactly how to deliver higher BEDs appropriately and precisely so as to increase tumor control while minimizing
International Journal of Radiation Oncology Biology Physics normal tissue toxicity is a hotly contested issue. Feddock et al showed that combining conventional chemo-RT with salvage SABR was both feasible and tolerable. The unique aspect of this strategy was in its selection of patients with residual disease, indicating the presence of radiation-resistant localized disease without distant metastasis. Thus, this strategy avoided overtreating patients who had achieved a complete clinical response to a conventional radiation dose; it also excluded patients who developed distant metastasis during or immediately after conventional RT, for whom local control may not be beneficial in terms of survival. The local control rates in this study were promising, but detailed information about patterns of failure was not provided. Although the goal in this study was to achieve a BED of >100 Gy to the primary tumor, the local control rate still seems to have been below 85% (a much lower rate than that achieved by SABR for stage I NSCLC), indicating that further dose escalation may be needed if possible. In addition, we still do not know what should be done for disease that persists in the hilum or mediastinal lymph nodes. Is it even possible to boost the dose to residual disease in lymph nodes to a BED of 100 Gy or more by using hypofractionated RT? Also unknown at this point are the optimal SABR dose in this setting and the optimal interval between conventional RT and SABR. Another promising strategy for increasing the BED is accelerated RT, such as that given in the continuous hyperfractionated accelerated radiation therapy protocol (54 Gy in 36 fractions of 1.5 Gy, given 3 times per day over 12 consecutive days, without chemotherapy) (11). That approach produced prolonged survival compared with conventional RT (60 Gy in 30 fractions), hypofractionated RT (ie, that given in <30 fractions) (12, 13), and an integrated dose boost to high-risk regions. A major concern in hypofractionated RT is the greater risk of late effects when higher BEDs are delivered to critical structures. Use of image guided RT with precise targeting and delivery is crucial for minimizing side effects. Adaptive therapy that is based on functional imaging and allows the target volume to be reduced and the dose to high-risk regions to be increased may have promise for improving the therapeutic ratio in the future. In the ongoing RTOG 1106/ American College of Radiology Imaging Network 6697 study, patients are randomly assigned to conventional concurrent chemoRT (60 Gy in 30 fractions) with or without individualized dose escalation/acceleration to residual positron emission tomographyavid lesions midway through the treatment, to a normal-tissuetolerated dose based on doseevolume constraints, or up to a maximum dose of 85.5 Gy in 30 fractions, in fraction sizes up to 4.25 Gy per fraction in the adaptive phase, for stage III NSCLC. The results of this trial may help to address this issue.
Socinski et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small cell lung cancer: Results of a phase 1/2 trial. J Clin Oncol 2012. (14) Summary: This phase 1/2 trial incorporated bevacizumab and erlotinib with induction and concurrent chemo-RT for stage III NSCLC. Patients received induction chemotherapy (carboplatin and paclitaxel with bevacizumab) followed by concurrent chemotherapy weekly with bevacizumab and thoracic radiation therapy (74 Gy in 37 fractions). In the phase 1 portion of the trial, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, during RT.
Volume 87 Number 1 2013 Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3-6 weeks later for 6 cycles. Forty-five eligible patients were enrolled. The objective response rates to induction therapy and overall treatment were 39% and 60%. The median progression-free and overall survival times were 10.2 months and 18.4 months, respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with 1 patient with grade 3 tracheoesophageal fistula), which was often prolonged. The authors concluded that the use of bevacizumab and erlotinib as administered in this trial was not feasible. Comment: Combining molecular targeted therapy with standard concurrent chemo-RT is actively being investigated as a way of improving the therapeutic ratio on the basis of the potential of targeted therapy to sensitize tumors to radiation, reduce distant metastasis, and maintain toxicity at tolerable levels (15). Vascular endothelial growth factor and epidermal growth factor receptor (EGFR) have been clinically validated as therapeutic targets in stage IV NSCLC (15). Bevacizumab, a recombinant humanized monoclonal antibody that binds vascular endothelial growth factor, was found to improve survival in combination with chemotherapy for patients with nonsquamous stage IV NSCLC who had not previously received chemotherapy (15). However, giving bevacizumab with concurrent chemoradiation was reported to confer a high risk of tracheoesophageal fistulae (16). Findings from the RTOG 0324 phase 2 study showed that combining cetuximab, an anti-EGFR monoclonal antibody, with concurrent chemotherapy and 63 Gy of RT was feasible for stage III NSCLC; indeed, the median overall survival time in that study was 22.7 months (17). We all await the final report of the randomized phase 3 study RTOG 0617 for the final answer regarding the role of cetuximab in this setting. Phase II studies of erlotinib, a smallmolecule anti-EGFR tyrosine kinase inhibitor, with concurrent chemo-RT have shown this combination to be tolerable and survival times to be promising (18). Socinski et al reported combining bevacizumab and erlotinib with concurrent chemotherapy and high-dose RT (74 Gy), delivered with 2-dimensional RT techniques, and elective nodal irradiation. The clinical outcomes of this study were disappointing, with severe toxicity and no improvement in survival. This study again showed that it is not safe to combine bevacizumab with RT in this setting. In addition, the use of out-of-date RT techniques in this study may also have contributed to the appearance of severe side effects, particularly esophagitis. Though the prospect of combining molecular target therapy with standard concurrent chemo-RT is intriguing, more is not always better. The need to minimize side effects is particularly crucial when multiple therapeutic agents or modalities are used. Personalization of targeted therapy according to the genetic profiles of tumors may significantly improve the efficacy of this approach (19). Dose escalation or acceleration to the target seems to increase local control, but it also increases side effects when high doses are delivered to normal tissues. In summary, the radiation dose does matter for local-regional control, toxicity, and survival in locally advanced NSCLC. The current “standard dose” of 60 Gy is associated with local-regional failure rates of 40%-50%. Not all cancers are created equal, and dose escalation/acceleration is certainly needed for some patients. Even after treatment with 74 Gy, approximately 20% of tumors still recur locally within target volume within the lifetime of the patient, and more may recur if the patients lived longer. Radiation is
Oncology Scan
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a double-edged sword in terms of balancing antitumor efficacy with toxicity. Moreover, neither radiation nor radiation delivery techniques are created equal. Questions remain as to who needs radiation escalation/acceleration, to which locations, and how boost doses should be given. Knowledge-guided RT dose escalation/ acceleration using optimized cutting-edge technologies, including but not limited to image guided radiation therapy, SABR, intensity modulated radiation therapy, and proton therapy, will likely lead to improved clinical outcomes, but further studies are needed. Additional discussion of the controversial role of RT for NSCLC was covered in the previous thoracic-themed Oncology Scan (20). Personalized approaches based on tumor genetic makeup to guide the use of systemic therapy for selected patients, and personalized radiation therapy to maximize local control with dose escalation/ acceleration while minimizing toxicity, are all crucial for improving the therapeutic ratio in NSCLC.
References 1. Curran WJ Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase 3 trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-1460. 2. Bradley JD, Paulus R, Komaki R, et al. Randomized phase 3 comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy cetuximab for stage IIIA/IIIB non-small cell lung cancer: preliminary findings on radiation dose in RTOG 0617. Abstract presented at the 53rd Annual Meeting of the American Society for Radiation Oncology; Oct 3, 2011; Miami Beach, FL. 3. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase 2 component of a phase 1/2 dose intensification study using threedimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small cell lung cancer: RTOG 0117. J Clin Oncol 2010;28:2475-2480. 4. Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: Long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005;63:324-333. 5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303: 1070-1076. 6. Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012;84:1060-1070. 7. Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: An analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012;82:425-434. 8. Perez CA, Stanley K, Grundy G, et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: Report by the Radiation Therapy Oncology Group. Cancer 1982;50:1091-1099. 9. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer 2011;117:4707-4713. 10. Feddock J, Arnold S, Shelton BJ, et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: A prospective study. Int J Radiat Oncol Biol Phys 2013;85:1325-1331. 11. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: A randomised multicentre trial. CHART Steering Committee. Lancet 1997;350:161-165. 12. Osti MF, Agolli L, Valeriani M, et al. Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced
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13.
14.
15.
16.
Oncology Scan stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013; 85:e157-e163. Gomez DR, Gillin M, Liao Z, et al. Phase 1 study of dose escalated hypofractionated proton beam therapy in thoracic malignancies. Int J Radiat Onco Biol Phys 2013;86:665-670. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small cell lung cancer: Results of a phase I/II trial. J Clin Oncol 2012;30:3953-3959. Ausborn NL, Le QT, Bradley JD, et al. Molecular profiling to optimize treatment in non-small cell lung cancer: A review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 2012;83:e453-e464. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated
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17.
18.
19.
20.
with chemoradiation and bevacizumab. J Clin Oncol 2010;28: 43-48. Blumenschein GR Jr., Paulus R, Curran WJ, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small cell lung cancer: RTOG 0324. J Clin Oncol 2011;29: 2312-2318. Komaki R, Blumenschein GR, Wistuba II, et al. Phase II trial of erlotinib and radiotherapy following chemoradiotherapy for patients with stage III non-small cell lung cancer (Abstr.). J Clin Oncol 2011; 29:7020. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42. Machtay M, Schipper M, Kong FM. Oncology scanethoracic cancers. Int J Radiat Oncol Biol Phys 2013;85:571-574.
Radiation Oncology biology
physics
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Oncology ScandPromising Strategies for the Treatment of Locally-Advanced Non-Small Cell Lung Cancer By Joe Y. Chang, MD, PhD, Associate Senior Editor The standard treatment for inoperable locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (chemo-RT) (1). However, the optimal radiation dose and fraction schema to be given concurrently with chemotherapy remains controversial (2). Retrospective and phase 2 clinical studies have shown that higher biological effective doses (BEDs) of radiation are associated with improved local control and potentially with survival (3, 4). Stereotactic ablative radiation therapy (SABR, also known as stereotactic body radiation therapy), in which BEDs in excess of 100 Gy are delivered to the planning target volume, has demonstrated local control rates exceeding 95% and survival comparable to that after surgery for stage I NSCLC (5, 6). However, a recent phase 3 randomized study (Radiation Therapy Oncology Group [RTOG] 0617) (2) indicated that a higher radiation dose (74 Gy, BED 88.8 Gy) given with concurrent chemotherapy was associated with poorer median survival as compared with the conventional 60-Gy dose (BED 72 Gy). After the findings of RTOG 0617 were presented at the American Society for Radiation Oncology Annual Meeting in Miami in 2011, the RTOG set the “standard radiation dose” for use with concurrent chemotherapy for stage III NSCLC as 60 Gy for future studies. The theme of this Oncology Scan focuses on 3 important issues in RT for locally advanced NSCLC: (1) Does radiation dose matter in stage III NSCLC? (2) How can radiation dose and delivery be optimized? and (3) Can molecular targeted therapy be safely incorporated into concurrent chemo-RT? Machtay et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: An analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012. (7) Summary: This study combined data from 7 RTOG trials in which chemo-RT given in different radiation regimens (from 60 Gy in 2-Gy once-daily fractions to 69.6 Gy in 1.2-Gy twice-daily fractions) was used for locally advanced NSCLC. The BED received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED), by using standard formulae.
Int J Radiation Oncol Biol Phys, Vol. 87, No. 1, pp. 1e4, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.04.013
A total of 1356 patients were analyzed for BED. The 2-year and 5-year overall survival rates were 38% and 15%, and the 2year and 5-year local-regional failure rates were 46% and 52%, respectively. Both BED and tBED were strongly associated with both overall survival and locoregional failure, with or without adjustment for other covariates, on multivariate analysis (P<.0001). A 1-Gy BED increase in RT dose intensity was associated with a 4% relative improvement in survival and a 3% relative decrease in the risk of local-regional failure, both of which were statistically significant. Comment: By combining results from prospective studies done by the RTOG, Machtay et al confirmed that delivering higher BEDs to the target with chemotherapy resulted in better local-regional control and survival in locally advanced NSCLC, a disease ruled by systemic relapse. Radiation Therapy Oncology Group protocol 9410 and other studies showed that concurrent chemo-RT improved overall survival as compared with sequential chemoRT, largely by improving local-regional control, not distant metastasis (1). However, in addition to local-regional control, 3 competing factors affect overall survival: (1) the presence or absence of distant metastasis and any disease outside the target volume; (2) the severe, potentially fatal toxicity associated with higher-dose RT and chemotherapy; and (3) the presence and severity of other comorbid conditions. The phase 3 randomized study RTOG 7301 showed that 60 Gy was superior to lower-dose radiation in terms of both local control and survival in stage III NSCLC treated with RT alone (8). Machtay et al demonstrated that BED is strongly associated with both overall survival and localregional control when the radiation dose is up to 69.6 Gy versus 60 Gy when either was given with chemotherapy. However, localregional failure rates were still high at approximately 40%-50%. Radiation Therapy Oncology Group protocol 9410 showed that 69.6 Gy with concurrent chemotherapy improved local failure within the target volume as compared with 60 Gy, but survival was not improved owing to treatment toxicity (1). Clearly there is room for improvement in local-regional control if we can minimize the toxicity of the treatment. Eliminating local-regional disease is required for a cure. The phase 1/2 RTOG 0117 study indicated that 74 Gy was the maximum tolerated dose when given with concurrent chemotherapy, but the median survival time of 25.9 months
2
Oncology Scan
noted in the phase 2 component was considered promising (3). The primary objective of RTOG 0617, a 2 2 factorial trial, was to explore whether 74 Gy with concurrent chemotherapy, with or without cetuximab, would improve survival versus 60 Gy. A preliminary analysis at 11 months showed that overall survival was poorer in the group randomized to the higher radiation dose (20.7 vs 21.7 months), although details about patterns of failure, RT techniques used, quality assurance, and toxicity are still pending (2). Could it be that doses >70 Gy are not oncologically beneficial? If so, this would run counter to basic biology and a large body of amassed evidence. A more logical explanation is that 74 Gy is too toxic when given with the radiation-delivery techniques used in in this phase 3 study. A group from University of Texas MD Anderson Cancer Center found that using 4-dimensional CT image-guided adaptive proton therapy to a dose of 74 Gy (relative biological effectiveness) with concurrent chemo-RT achieved a local-regional control rate of approximately 80% and a median survival time of 29.4 months, with acceptable toxicity (9). Patternsof-failure analysis indicated that most local failures occurred within the 74-Gy (relative biological effectiveness) isodose line, which suggests that even 74 Gy is still an inadequate dose for some patients. In addition, prolonging the radiation course to 37 fractions may not be the best approach because of the potential for tumor repopulation. Thus, although 60 Gy with concurrent chemotherapy remains the “standard of care” for inoperable stage III NSCLC with the radiation-delivery techniques used in RTOG 0617, issues of dose escalation and acceleration should continue to be explored as new techniques and technologies emerge. Feddock et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: A prospective study. Int J Radiat Oncol Biol Phys 2013. (10) Summary: This prospective, single-institution study evaluated the feasibility of conventional chemoradiation (60 Gy) followed by SABR as a means of dose escalation for patients with stage IIIII NSCLC with residual disease. Thirty-five patients were without metastatic disease and had radiologic evidence of limited residual disease (5 cm) within the site of the primary tumor, as well as good or complete nodal responses after standard chemoradiation to a target dose of 60 Gy. These 35 patients were treated with SABR to achieve a total combined BED to the residual primary tumor of >100 Gy. The SABR boost consisted of 2 fractions of 10 Gy each (20 Gy total) for peripheral tumors, or 3 fractions of 6.5 Gy each (19.5 Gy total) for medial tumors, given a median 2 months after the completion of chemo-RT. Lymph nodes were not given a boost dose. At a median followup time of 13 months, 11.4% patients had developed acute grade 3 radiation pneumonitis (RP), 2.9% had developed late and persistent grade 3 RP, and none had developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the stereotactic body radiation therapy boost, and none were found to predict RP. Only advanced age (PZ.0147), a history of smoking (PZ.0505), and high mean lung dose from the conventional chemoradiation (PZ.0295) were associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, although the status of lymph node recurrence was not clear. Comment: Exactly how to deliver higher BEDs appropriately and precisely so as to increase tumor control while minimizing
International Journal of Radiation Oncology Biology Physics normal tissue toxicity is a hotly contested issue. Feddock et al showed that combining conventional chemo-RT with salvage SABR was both feasible and tolerable. The unique aspect of this strategy was in its selection of patients with residual disease, indicating the presence of radiation-resistant localized disease without distant metastasis. Thus, this strategy avoided overtreating patients who had achieved a complete clinical response to a conventional radiation dose; it also excluded patients who developed distant metastasis during or immediately after conventional RT, for whom local control may not be beneficial in terms of survival. The local control rates in this study were promising, but detailed information about patterns of failure was not provided. Although the goal in this study was to achieve a BED of >100 Gy to the primary tumor, the local control rate still seems to have been below 85% (a much lower rate than that achieved by SABR for stage I NSCLC), indicating that further dose escalation may be needed if possible. In addition, we still do not know what should be done for disease that persists in the hilum or mediastinal lymph nodes. Is it even possible to boost the dose to residual disease in lymph nodes to a BED of 100 Gy or more by using hypofractionated RT? Also unknown at this point are the optimal SABR dose in this setting and the optimal interval between conventional RT and SABR. Another promising strategy for increasing the BED is accelerated RT, such as that given in the continuous hyperfractionated accelerated radiation therapy protocol (54 Gy in 36 fractions of 1.5 Gy, given 3 times per day over 12 consecutive days, without chemotherapy) (11). That approach produced prolonged survival compared with conventional RT (60 Gy in 30 fractions), hypofractionated RT (ie, that given in <30 fractions) (12, 13), and an integrated dose boost to high-risk regions. A major concern in hypofractionated RT is the greater risk of late effects when higher BEDs are delivered to critical structures. Use of image guided RT with precise targeting and delivery is crucial for minimizing side effects. Adaptive therapy that is based on functional imaging and allows the target volume to be reduced and the dose to high-risk regions to be increased may have promise for improving the therapeutic ratio in the future. In the ongoing RTOG 1106/ American College of Radiology Imaging Network 6697 study, patients are randomly assigned to conventional concurrent chemoRT (60 Gy in 30 fractions) with or without individualized dose escalation/acceleration to residual positron emission tomographyavid lesions midway through the treatment, to a normal-tissuetolerated dose based on doseevolume constraints, or up to a maximum dose of 85.5 Gy in 30 fractions, in fraction sizes up to 4.25 Gy per fraction in the adaptive phase, for stage III NSCLC. The results of this trial may help to address this issue.
Socinski et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small cell lung cancer: Results of a phase 1/2 trial. J Clin Oncol 2012. (14) Summary: This phase 1/2 trial incorporated bevacizumab and erlotinib with induction and concurrent chemo-RT for stage III NSCLC. Patients received induction chemotherapy (carboplatin and paclitaxel with bevacizumab) followed by concurrent chemotherapy weekly with bevacizumab and thoracic radiation therapy (74 Gy in 37 fractions). In the phase 1 portion of the trial, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, during RT.
Volume 87 Number 1 2013 Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3-6 weeks later for 6 cycles. Forty-five eligible patients were enrolled. The objective response rates to induction therapy and overall treatment were 39% and 60%. The median progression-free and overall survival times were 10.2 months and 18.4 months, respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with 1 patient with grade 3 tracheoesophageal fistula), which was often prolonged. The authors concluded that the use of bevacizumab and erlotinib as administered in this trial was not feasible. Comment: Combining molecular targeted therapy with standard concurrent chemo-RT is actively being investigated as a way of improving the therapeutic ratio on the basis of the potential of targeted therapy to sensitize tumors to radiation, reduce distant metastasis, and maintain toxicity at tolerable levels (15). Vascular endothelial growth factor and epidermal growth factor receptor (EGFR) have been clinically validated as therapeutic targets in stage IV NSCLC (15). Bevacizumab, a recombinant humanized monoclonal antibody that binds vascular endothelial growth factor, was found to improve survival in combination with chemotherapy for patients with nonsquamous stage IV NSCLC who had not previously received chemotherapy (15). However, giving bevacizumab with concurrent chemoradiation was reported to confer a high risk of tracheoesophageal fistulae (16). Findings from the RTOG 0324 phase 2 study showed that combining cetuximab, an anti-EGFR monoclonal antibody, with concurrent chemotherapy and 63 Gy of RT was feasible for stage III NSCLC; indeed, the median overall survival time in that study was 22.7 months (17). We all await the final report of the randomized phase 3 study RTOG 0617 for the final answer regarding the role of cetuximab in this setting. Phase II studies of erlotinib, a smallmolecule anti-EGFR tyrosine kinase inhibitor, with concurrent chemo-RT have shown this combination to be tolerable and survival times to be promising (18). Socinski et al reported combining bevacizumab and erlotinib with concurrent chemotherapy and high-dose RT (74 Gy), delivered with 2-dimensional RT techniques, and elective nodal irradiation. The clinical outcomes of this study were disappointing, with severe toxicity and no improvement in survival. This study again showed that it is not safe to combine bevacizumab with RT in this setting. In addition, the use of out-of-date RT techniques in this study may also have contributed to the appearance of severe side effects, particularly esophagitis. Though the prospect of combining molecular target therapy with standard concurrent chemo-RT is intriguing, more is not always better. The need to minimize side effects is particularly crucial when multiple therapeutic agents or modalities are used. Personalization of targeted therapy according to the genetic profiles of tumors may significantly improve the efficacy of this approach (19). Dose escalation or acceleration to the target seems to increase local control, but it also increases side effects when high doses are delivered to normal tissues. In summary, the radiation dose does matter for local-regional control, toxicity, and survival in locally advanced NSCLC. The current “standard dose” of 60 Gy is associated with local-regional failure rates of 40%-50%. Not all cancers are created equal, and dose escalation/acceleration is certainly needed for some patients. Even after treatment with 74 Gy, approximately 20% of tumors still recur locally within target volume within the lifetime of the patient, and more may recur if the patients lived longer. Radiation is
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a double-edged sword in terms of balancing antitumor efficacy with toxicity. Moreover, neither radiation nor radiation delivery techniques are created equal. Questions remain as to who needs radiation escalation/acceleration, to which locations, and how boost doses should be given. Knowledge-guided RT dose escalation/ acceleration using optimized cutting-edge technologies, including but not limited to image guided radiation therapy, SABR, intensity modulated radiation therapy, and proton therapy, will likely lead to improved clinical outcomes, but further studies are needed. Additional discussion of the controversial role of RT for NSCLC was covered in the previous thoracic-themed Oncology Scan (20). Personalized approaches based on tumor genetic makeup to guide the use of systemic therapy for selected patients, and personalized radiation therapy to maximize local control with dose escalation/ acceleration while minimizing toxicity, are all crucial for improving the therapeutic ratio in NSCLC.
References 1. Curran WJ Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase 3 trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-1460. 2. Bradley JD, Paulus R, Komaki R, et al. Randomized phase 3 comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy cetuximab for stage IIIA/IIIB non-small cell lung cancer: preliminary findings on radiation dose in RTOG 0617. Abstract presented at the 53rd Annual Meeting of the American Society for Radiation Oncology; Oct 3, 2011; Miami Beach, FL. 3. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase 2 component of a phase 1/2 dose intensification study using threedimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small cell lung cancer: RTOG 0117. J Clin Oncol 2010;28:2475-2480. 4. Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: Long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005;63:324-333. 5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303: 1070-1076. 6. Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012;84:1060-1070. 7. Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: An analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012;82:425-434. 8. Perez CA, Stanley K, Grundy G, et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: Report by the Radiation Therapy Oncology Group. Cancer 1982;50:1091-1099. 9. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer 2011;117:4707-4713. 10. Feddock J, Arnold S, Shelton BJ, et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: A prospective study. Int J Radiat Oncol Biol Phys 2013;85:1325-1331. 11. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: A randomised multicentre trial. CHART Steering Committee. Lancet 1997;350:161-165. 12. Osti MF, Agolli L, Valeriani M, et al. Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced
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13.
14.
15.
16.
Oncology Scan stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013; 85:e157-e163. Gomez DR, Gillin M, Liao Z, et al. Phase 1 study of dose escalated hypofractionated proton beam therapy in thoracic malignancies. Int J Radiat Onco Biol Phys 2013;86:665-670. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small cell lung cancer: Results of a phase I/II trial. J Clin Oncol 2012;30:3953-3959. Ausborn NL, Le QT, Bradley JD, et al. Molecular profiling to optimize treatment in non-small cell lung cancer: A review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 2012;83:e453-e464. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated
International Journal of Radiation Oncology Biology Physics
17.
18.
19.
20.
with chemoradiation and bevacizumab. J Clin Oncol 2010;28: 43-48. Blumenschein GR Jr., Paulus R, Curran WJ, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small cell lung cancer: RTOG 0324. J Clin Oncol 2011;29: 2312-2318. Komaki R, Blumenschein GR, Wistuba II, et al. Phase II trial of erlotinib and radiotherapy following chemoradiotherapy for patients with stage III non-small cell lung cancer (Abstr.). J Clin Oncol 2011; 29:7020. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42. Machtay M, Schipper M, Kong FM. Oncology scanethoracic cancers. Int J Radiat Oncol Biol Phys 2013;85:571-574.