VOLUME
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NUMBER
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10
2014
JOURNAL OF CLINICAL ONCOLOGY
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Combination Chemoradiation Therapy: The Whole Is More Than the Sum of the Parts Harvey J. Mamon, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA Joel E. Tepper, University of North Carolina–Chapel Hill, Chapel Hill, NC See accompanying article on page 385
For many years, oncologists have held the view that “radiation improves local control, but not survival.” Although this perspective is fairly common, it is not always accurate and does not recognize a more nuanced interplay between local control, systemic control, and cure. Solid tumors cannot be cured without achieving local control of the primary malignancy, and thus local control is a critical component of tumor cure. A more nuanced statement that could be true might be the following: “When surgery provides good local control, the local control advantage provided by radiation may not lead to a statistically significant survival advantage if the competing risk of distant metastases is very high or very low.” Radiation therapy also might not improve survival if systemic chemotherapy improved local control without radiation, or if salvage surgery were effective and local recurrence did not increase the risk of distant metastases. It is worth considering the relationship between local control and survival in several solid tumors. The initial randomized trials demonstrating the benefit of radiation in breast cancer suggested that irradiating the breast after lumpectomy, or the chest wall after mastectomy, improved local control but did not affect survival.1,2 The lack of a survival benefit, however, may have been attributable to a relatively small number of deaths in these studies. In fact, meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group suggest that improved local control does lead to improved cancer-specific and overall survival.3,4 In gastric cancer, the North American standard of care was established by Intergroup-0116, in which patients were randomly assigned to surgery alone versus surgery followed by adjuvant chemotherapy and radiation. In this study, the reduction in local and regional recurrences, from 47% to 24%, correlated closely with the improvement in overall survival, and the rate of distant metastases was similar in both arms.5,6 In fact, the observation that improved survival appeared attributable mainly to improved local control was the impetus for the successor Intergroup trial, CALGB 80101, which sought to further improve survival by more aggressively addressing the risk of distant metastases.7 Rectal cancer is a disease in which we frequently hear that radiation improves local control without affecting survival. Although there certainly are data that are consistent with this view, the totality of the data is more ambiguous. The results of NSABP R-02, for example, do support the hypothesis that radiation can improve local control without a survival benefit.8 In this trial, patients who underwent surgery for Journal of Clinical Oncology, Vol 32, No 5 (February 10), 2014: pp 367-369
locally advanced rectal cancer were randomly assigned to postoperative chemotherapy or postoperative chemoradiotherapy. Patients who received radiation had a statistically significant improvement in local control without an improvement in disease-free or overall survival. However, not all rectal cancer studies have come to the same conclusion. The Swedish Rectal Cancer trial, in which patients were randomly assigned to surgery alone versus preoperative short course radiation, showed statistically significant improvements in local control, cancer-specific survival, and overall survival in the irradiated patients.9 Conversely, EORTC 22921, a 1,000-patient study using a 2 ⫻ 2 design testing both pre- and postoperative chemotherapy and radiation, failed to demonstrate a statistically significant survival benefit in patients who received adjuvant chemotherapy.10 Perhaps most significant is GITSG 7175, a four-arm trial in which patients were randomly assigned to surgery alone, adjuvant chemotherapy, adjuvant radiation therapy, or adjuvant chemotherapy and radiation.11 This trial established the benefit of adjuvant therapy for rectal cancer and was thus the last large US phase III trial to contain a surgery-alone arm. In this study, both radiation and chemotherapy provided similar magnitude, nonsignificant benefits in disease-free survival, whereas only the combined chemoradiation arm resulted in a statistically significant improvement compared with surgery alone. The mechanisms behind the synergistic effect of combining chemotherapy and radiation have been well documented, as reviewed by Seiwert et al.12 Clinical trials in many types of solid tumors have confirmed that concurrent administration of chemotherapy and radiation leads to a better outcome than sequential administration, or using either modality alone. Examples include non–small-cell lung cancer,13 cervical cancer,14 head and neck cancer,15 and anal cancer.16 Thus, understanding the patterns of failure can help us understand ways in which we can both improve tumor control and decrease morbidity. In esophageal cancer, the trials comparing neoadjuvant chemoradiotherapy with surgery alone have had mixed results. Although some demonstrated a benefit,17 most showed a nonsignificant trend in favor of neoadjuvant therapy, though recent meta-analyses18,19 have consistently favored the use of neoadjuvant therapy. Most recently, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated that preoperative carboplatin and paclitaxel with concurrent radiation is an extremely well-tolerated regimen with a higher rate of R0 resections (92% v 69%) and improved © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
367
Editorial
median overall survival (49.4 months v 20 months) compared with surgery alone, with a pathologic complete response rate of 29%.20 In the article that accompanies this editorial, the authors of the CROSS trial describe the patterns of failure in patients who received neoadjuvant chemoradiotherapy for esophageal cancer. The authors are to be congratulated for this meticulous analysis, which included patients in the CROSS trial and in the prior phase II study using the same regimen. Consistent with the concept of spatial cooperation, in which chemotherapy reduces the risk of distant metastases while both chemotherapy and radiation affect local control, the authors found that the addition of neoadjuvant chemoradiotherapy provided benefits in local, regional, and distant disease control relative to surgery alone. Of the local-regional recurrences, most of which occurred with synchronous distant metastases, 5% occurred within the radiation field, 2% at the margins and 6% outside of the field. Only 1% of recurrences occurred within the irradiated field without concurrent distant metastases. What can we learn from these findings? A longstanding question in oncology is whether tumors that are destined to metastasize already have micrometastases at the time of diagnosis, in which case aggressive local therapy would not be expected to improve survival, or whether persistent local disease becomes a nidus for new metastases.21 The answer likely varies among types of cancer, and also among patients with the same cancer diagnosis. However, the ability of surgical resection to cure many patients demonstrates that a large number of patients do not have systemic disease when diagnosed and may therefore benefit from improved local control. There is also molecular evidence to suggest that as cancer metastasizes, both the primary tumor and the metastases can be the source of additional metastases.22 The current study cannot directly answer the question of whether radiation therapy or chemotherapy is responsible for the altered patterns of failure and improved survival, as the treatment arm included both chemotherapy and radiation. However, the patterns of failure make a strong case that radiation therapy enhances local control, and that improved local control contributes to overall survival. The benefit of irradiation in local control is seen in the comparison of in-field to out of-field recurrences. In the patients treated with neoadjuvant chemoradiotherapy, anastomotic recurrences were reduced from 8.7% to 2.8% and mediastinal recurrences from 20.5% to 7% compared with the patients treated with surgery alone. However, the radiation fields did not include the celiac or supraclavicular nodes, and the rate of recurrence at these sites was the same in both arms, strongly suggesting (at least with this drug regimen) that radiation therapy is necessary for the decreased failures in the chest. Combined chemoradiotherapy reduces local recurrences in a way that chemotherapy alone does not. It is unclear how large an impact on systemic disease may be attributed to the chemotherapy given with radiation therapy. However, the relatively brief chemotherapy regimen is one that would not generally be considered to be adequate to produce a major reduction in systemic disease. Preoperative combined modality treatment produced a major local effect, reducing local-regional recurrences from 34% to14%. Systemically, there was a small but significant effect on hematogenous dissemination in favor of the chemoradiotherapy group (35% v 29%), that can realistically be considered to be the magnitude of the drug effect independent of radiation therapy. Finally, the reduction in hematogenous metastases and the reduction in 368
© 2014 by American Society of Clinical Oncology
isolated distant metastases are of much smaller magnitude than the overall improvement in recurrences, from 57.1% to 34.7%, suggesting that local and local-regional control are of critical importance to the overall outcome of the patients in this study. These findings are consistent with a model in which systemic therapy reduces the risk of distant metastases, and combined chemoradiotherapy improves local control, further improving the cure rate by reducing the rate of recurrence in patients without systemic disease, and by eliminating residual primary tumor cells as a source of potential subsequent metastases. The approach taken in the CROSS studies emphasizes the importance of controlling both systemic and localregional disease. Further improvements are still desperately needed and may result from identifying molecular subtypes that are sensitive to targeted agents such as antibody and small molecule kinase inhibitors or immune modulators. RTOG 1010, for example, is testing the addition of trastuzumab to carboplatin, paclitaxel, and radiation in patients with esophageal cancers that overexpress human epidermal growth factor 2. Although it is too early to know whether this study will be successful, it is likely that that combining the best therapies that we have available at present—namely radiation therapy, chemotherapy and surgery—with therapy targeted toward an individual’s tumor is the most promising strategy for improving outcomes in esophageal cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:12331241, 2002 2. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 3. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:20872106, 2005 4. Early Breast Cancer Trialists’ Collaborative Group, Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011 5. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001 6. Smalley SR, Benedetti JK, Haller DG, et al: Updated analysis of SWOGdirected intergroup study 0116: A phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30:23272333, 2012 7. Fuchs CS, Tepper JE, Niedzwiecki D, et al: Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29:4003, 2011 8. Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92:388-396, 2000 9. Folkesson J, Birgisson H, Pahlman L, et al: Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23:5644-5650, 2005 10. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25:4379-4386, 2007 11. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 312:1465-1472, 1985 12. Seiwert TY, Salama JK, Vokes EE: The concurrent chemoradiation paradigm– general principles. Nat Clin Pract Oncol 4:86-100, 2007 13. Curran WJ Jr, Paulus R, Langer CJ, et al: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst 103:1452-1460, 2011 14. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26:5802-5812, 2008 15. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 16. UKCCCR Anal Cancer Trial Working Party and UK Co-ordinating Committee on Cancer Research: Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and
mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348:1049-1054, 1996 17. Tepper J, Krasna MJ, Niedzwiecki D, et al: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086-1092, 2008 18. Sjoquist KM, Burmeister BH, Smithers BM, et al: Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol 12:681-692, 2011 19. Kranzfelder M, Schuster T, Geinitz H, et al: Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 98:768-783, 2011 20. van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-2084, 2012 21. Punglia RS, Morrow M, Winer EP, et al: Local therapy and survival in breast cancer. N Engl J Med 356:2399-2405, 2007 22. Campbell PJ, Yachida S, Mudie LJ, et al: The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109-1113, 2010
DOI: 10.1200/JCO.2013.54.3108; published online ahead of print at www.jco.org on January 13, 2014
■ ■ ■
Best of ASCO Meetings Mark your calendar for the 2014 Best of ASCO Meetings in Boston (August 8-9), Chicago (August 15-16), or Seattle (August 22-23). Featuring practice-changing science and educational highlights from the ASCO Annual Meeting, the Best of ASCO Meetings offer in-depth analysis and discussion of the top scientific abstracts that will directly impact patient care. For additional details, visit boa.asco.org. Each year, ASCO, in conjunction with our cosponsors, organizes a wide array of high-quality meetings, providing educational and scientific programs to advance your understanding of cancer. Join us for one or more of ASCO’s meetings to interact with oncology experts, network with colleagues, and earn CME credit.
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
369
32
䡠
NUMBER
5
䡠
FEBRUARY
10
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Combination Chemoradiation Therapy: The Whole Is More Than the Sum of the Parts Harvey J. Mamon, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA Joel E. Tepper, University of North Carolina–Chapel Hill, Chapel Hill, NC See accompanying article on page 385
For many years, oncologists have held the view that “radiation improves local control, but not survival.” Although this perspective is fairly common, it is not always accurate and does not recognize a more nuanced interplay between local control, systemic control, and cure. Solid tumors cannot be cured without achieving local control of the primary malignancy, and thus local control is a critical component of tumor cure. A more nuanced statement that could be true might be the following: “When surgery provides good local control, the local control advantage provided by radiation may not lead to a statistically significant survival advantage if the competing risk of distant metastases is very high or very low.” Radiation therapy also might not improve survival if systemic chemotherapy improved local control without radiation, or if salvage surgery were effective and local recurrence did not increase the risk of distant metastases. It is worth considering the relationship between local control and survival in several solid tumors. The initial randomized trials demonstrating the benefit of radiation in breast cancer suggested that irradiating the breast after lumpectomy, or the chest wall after mastectomy, improved local control but did not affect survival.1,2 The lack of a survival benefit, however, may have been attributable to a relatively small number of deaths in these studies. In fact, meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group suggest that improved local control does lead to improved cancer-specific and overall survival.3,4 In gastric cancer, the North American standard of care was established by Intergroup-0116, in which patients were randomly assigned to surgery alone versus surgery followed by adjuvant chemotherapy and radiation. In this study, the reduction in local and regional recurrences, from 47% to 24%, correlated closely with the improvement in overall survival, and the rate of distant metastases was similar in both arms.5,6 In fact, the observation that improved survival appeared attributable mainly to improved local control was the impetus for the successor Intergroup trial, CALGB 80101, which sought to further improve survival by more aggressively addressing the risk of distant metastases.7 Rectal cancer is a disease in which we frequently hear that radiation improves local control without affecting survival. Although there certainly are data that are consistent with this view, the totality of the data is more ambiguous. The results of NSABP R-02, for example, do support the hypothesis that radiation can improve local control without a survival benefit.8 In this trial, patients who underwent surgery for Journal of Clinical Oncology, Vol 32, No 5 (February 10), 2014: pp 367-369
locally advanced rectal cancer were randomly assigned to postoperative chemotherapy or postoperative chemoradiotherapy. Patients who received radiation had a statistically significant improvement in local control without an improvement in disease-free or overall survival. However, not all rectal cancer studies have come to the same conclusion. The Swedish Rectal Cancer trial, in which patients were randomly assigned to surgery alone versus preoperative short course radiation, showed statistically significant improvements in local control, cancer-specific survival, and overall survival in the irradiated patients.9 Conversely, EORTC 22921, a 1,000-patient study using a 2 ⫻ 2 design testing both pre- and postoperative chemotherapy and radiation, failed to demonstrate a statistically significant survival benefit in patients who received adjuvant chemotherapy.10 Perhaps most significant is GITSG 7175, a four-arm trial in which patients were randomly assigned to surgery alone, adjuvant chemotherapy, adjuvant radiation therapy, or adjuvant chemotherapy and radiation.11 This trial established the benefit of adjuvant therapy for rectal cancer and was thus the last large US phase III trial to contain a surgery-alone arm. In this study, both radiation and chemotherapy provided similar magnitude, nonsignificant benefits in disease-free survival, whereas only the combined chemoradiation arm resulted in a statistically significant improvement compared with surgery alone. The mechanisms behind the synergistic effect of combining chemotherapy and radiation have been well documented, as reviewed by Seiwert et al.12 Clinical trials in many types of solid tumors have confirmed that concurrent administration of chemotherapy and radiation leads to a better outcome than sequential administration, or using either modality alone. Examples include non–small-cell lung cancer,13 cervical cancer,14 head and neck cancer,15 and anal cancer.16 Thus, understanding the patterns of failure can help us understand ways in which we can both improve tumor control and decrease morbidity. In esophageal cancer, the trials comparing neoadjuvant chemoradiotherapy with surgery alone have had mixed results. Although some demonstrated a benefit,17 most showed a nonsignificant trend in favor of neoadjuvant therapy, though recent meta-analyses18,19 have consistently favored the use of neoadjuvant therapy. Most recently, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated that preoperative carboplatin and paclitaxel with concurrent radiation is an extremely well-tolerated regimen with a higher rate of R0 resections (92% v 69%) and improved © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
367
Editorial
median overall survival (49.4 months v 20 months) compared with surgery alone, with a pathologic complete response rate of 29%.20 In the article that accompanies this editorial, the authors of the CROSS trial describe the patterns of failure in patients who received neoadjuvant chemoradiotherapy for esophageal cancer. The authors are to be congratulated for this meticulous analysis, which included patients in the CROSS trial and in the prior phase II study using the same regimen. Consistent with the concept of spatial cooperation, in which chemotherapy reduces the risk of distant metastases while both chemotherapy and radiation affect local control, the authors found that the addition of neoadjuvant chemoradiotherapy provided benefits in local, regional, and distant disease control relative to surgery alone. Of the local-regional recurrences, most of which occurred with synchronous distant metastases, 5% occurred within the radiation field, 2% at the margins and 6% outside of the field. Only 1% of recurrences occurred within the irradiated field without concurrent distant metastases. What can we learn from these findings? A longstanding question in oncology is whether tumors that are destined to metastasize already have micrometastases at the time of diagnosis, in which case aggressive local therapy would not be expected to improve survival, or whether persistent local disease becomes a nidus for new metastases.21 The answer likely varies among types of cancer, and also among patients with the same cancer diagnosis. However, the ability of surgical resection to cure many patients demonstrates that a large number of patients do not have systemic disease when diagnosed and may therefore benefit from improved local control. There is also molecular evidence to suggest that as cancer metastasizes, both the primary tumor and the metastases can be the source of additional metastases.22 The current study cannot directly answer the question of whether radiation therapy or chemotherapy is responsible for the altered patterns of failure and improved survival, as the treatment arm included both chemotherapy and radiation. However, the patterns of failure make a strong case that radiation therapy enhances local control, and that improved local control contributes to overall survival. The benefit of irradiation in local control is seen in the comparison of in-field to out of-field recurrences. In the patients treated with neoadjuvant chemoradiotherapy, anastomotic recurrences were reduced from 8.7% to 2.8% and mediastinal recurrences from 20.5% to 7% compared with the patients treated with surgery alone. However, the radiation fields did not include the celiac or supraclavicular nodes, and the rate of recurrence at these sites was the same in both arms, strongly suggesting (at least with this drug regimen) that radiation therapy is necessary for the decreased failures in the chest. Combined chemoradiotherapy reduces local recurrences in a way that chemotherapy alone does not. It is unclear how large an impact on systemic disease may be attributed to the chemotherapy given with radiation therapy. However, the relatively brief chemotherapy regimen is one that would not generally be considered to be adequate to produce a major reduction in systemic disease. Preoperative combined modality treatment produced a major local effect, reducing local-regional recurrences from 34% to14%. Systemically, there was a small but significant effect on hematogenous dissemination in favor of the chemoradiotherapy group (35% v 29%), that can realistically be considered to be the magnitude of the drug effect independent of radiation therapy. Finally, the reduction in hematogenous metastases and the reduction in 368
© 2014 by American Society of Clinical Oncology
isolated distant metastases are of much smaller magnitude than the overall improvement in recurrences, from 57.1% to 34.7%, suggesting that local and local-regional control are of critical importance to the overall outcome of the patients in this study. These findings are consistent with a model in which systemic therapy reduces the risk of distant metastases, and combined chemoradiotherapy improves local control, further improving the cure rate by reducing the rate of recurrence in patients without systemic disease, and by eliminating residual primary tumor cells as a source of potential subsequent metastases. The approach taken in the CROSS studies emphasizes the importance of controlling both systemic and localregional disease. Further improvements are still desperately needed and may result from identifying molecular subtypes that are sensitive to targeted agents such as antibody and small molecule kinase inhibitors or immune modulators. RTOG 1010, for example, is testing the addition of trastuzumab to carboplatin, paclitaxel, and radiation in patients with esophageal cancers that overexpress human epidermal growth factor 2. Although it is too early to know whether this study will be successful, it is likely that that combining the best therapies that we have available at present—namely radiation therapy, chemotherapy and surgery—with therapy targeted toward an individual’s tumor is the most promising strategy for improving outcomes in esophageal cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:12331241, 2002 2. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 3. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:20872106, 2005 4. Early Breast Cancer Trialists’ Collaborative Group, Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011 5. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001 6. Smalley SR, Benedetti JK, Haller DG, et al: Updated analysis of SWOGdirected intergroup study 0116: A phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30:23272333, 2012 7. Fuchs CS, Tepper JE, Niedzwiecki D, et al: Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29:4003, 2011 8. Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92:388-396, 2000 9. Folkesson J, Birgisson H, Pahlman L, et al: Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23:5644-5650, 2005 10. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25:4379-4386, 2007 11. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 312:1465-1472, 1985 12. Seiwert TY, Salama JK, Vokes EE: The concurrent chemoradiation paradigm– general principles. Nat Clin Pract Oncol 4:86-100, 2007 13. Curran WJ Jr, Paulus R, Langer CJ, et al: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst 103:1452-1460, 2011 14. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26:5802-5812, 2008 15. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 16. UKCCCR Anal Cancer Trial Working Party and UK Co-ordinating Committee on Cancer Research: Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and
mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348:1049-1054, 1996 17. Tepper J, Krasna MJ, Niedzwiecki D, et al: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086-1092, 2008 18. Sjoquist KM, Burmeister BH, Smithers BM, et al: Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol 12:681-692, 2011 19. Kranzfelder M, Schuster T, Geinitz H, et al: Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 98:768-783, 2011 20. van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-2084, 2012 21. Punglia RS, Morrow M, Winer EP, et al: Local therapy and survival in breast cancer. N Engl J Med 356:2399-2405, 2007 22. Campbell PJ, Yachida S, Mudie LJ, et al: The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109-1113, 2010
DOI: 10.1200/JCO.2013.54.3108; published online ahead of print at www.jco.org on January 13, 2014
■ ■ ■
Best of ASCO Meetings Mark your calendar for the 2014 Best of ASCO Meetings in Boston (August 8-9), Chicago (August 15-16), or Seattle (August 22-23). Featuring practice-changing science and educational highlights from the ASCO Annual Meeting, the Best of ASCO Meetings offer in-depth analysis and discussion of the top scientific abstracts that will directly impact patient care. For additional details, visit boa.asco.org. Each year, ASCO, in conjunction with our cosponsors, organizes a wide array of high-quality meetings, providing educational and scientific programs to advance your understanding of cancer. Join us for one or more of ASCO’s meetings to interact with oncology experts, network with colleagues, and earn CME credit.
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
369
