International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandGastrointestinal Cancers By Christopher G. Willett, MD, Senior Editor, Daniel Chang, MD, Brian Czito, MD, Jeffrey Meyer, MD, and Jennifer Wo, MD, Associate Editors This represents my last Oncology Scan as Senior Editor of the gastrointestinal (GI) group. It has been a real pleasure and privilege to work and interact with the GI Associate Editors, Drs Daniel Chang, Brian Czito, Jeffrey Meyer, and Jennifer Wo. They are a group of bright, hardworking, and thoughtful oncologists who contribute substantively to our field and will continue to do so. Dr Chang will now lead the GI editorial team, building from the strong, high-quality evidence foundation that we have established over the past 2 years. I would like to extend my personal thanks to Anthony Zietman, who provided passionate and thoughtful leadership as well as support to this rewarding and rich experience.
Ngan et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012. (1) Minsky BD. Short-course radiation versus long-course chemoradiation for rectal cancer: making progress. J Clin Oncol 2012. (2) Summary: In a recent report, the Trans-Tasman Radiation Oncology Group (TROG) reported on local recurrence (LR) rates in short-course (SC) and long-course (LC) neoadjuvant chemoradiation alone for rectal cancer. Eligibility criteria included patients with ultrasound staged or magnetic resonance imagestaged T3N0-2M0 rectal adenocarcinoma. These patients were randomly assigned to 1 of 2 courses of treatment: (1) SC of pelvic radiation therapy (5 5 Gy), early surgery, and 6 courses of adjuvant chemotherapy or (2) LC with 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks with continuous infusion fluorouracil, surgery in 4 to 6 weeks, and 4 courses of chemotherapy. Three hundred twenty-six patients were randomized, 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range 3.0-7.8 years). The 3-year LR rates between SC and LC were not statistically significantly different; the confidence interval for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected. Int J Radiation Oncol Biol Phys, Vol. 87, No. 5, pp. 861e863, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.09.006
Comment: Passionate debate persists regarding the relative merits and deficiencies of SC radiation therapy alone (25 Gy in 5 fractions) or LC chemoradiation in the preoperative treatment of patients with rectal cancer. The TROG study is the second major randomized clinical trial published to date that directly compares these 2 treatment approaches (1, 2) and reports no statistically significant differences in local control, overall survival, or late toxicity between strategies; these results are in line with the similarly designed and previously reported Polish trial (3). Are these findings sufficiently definitive to justify adoption of SC as the standard of care for neoadjuvant therapy of resectable rectal cancer? The GI editorial group judges not; the TROG trial is a small study (only 326 patients), and the study results are too early, given the long natural history of this disease and manifestation of late toxicity, to draw definitive conclusions. Clinically significant advantages to the long-course therapy also lie within the confidence intervals of the local recurrence risk. The ongoing Stockholm III trial is also investigating SC and LC therapy, comparing 25 Gy in 5 fractions, early surgery, delayed surgery, and LC radiation alone (50 Gy in 25 fractions). The editors favor the continued use of neoadjuvant LC chemoradiation in the treatment of resectable rectal cancer. This strategy allows a platform for continued evaluation of radiosensitizing agents that may improve on existing downstaging and complete pathologic response rates. Gordon et al. Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial. Ann Oncol 2013. (4) Summary: On the basis of the results of the Trastuzumab for Gastric Cancer (ToGA) trial (5), trastuzumab has been approved for treatment of patients with human epidermal growth factor receptor 2 (HER 2)-positive metastatic gastric and gastroesophageal cancer. Conflicting data exist in the literature regarding the potential prognostic and predictive role of HER 2 in the natural history of gastric cancer. To provide clarification of this question, investigators looked at the HER 2 status both as prognostic and predictive markers. This analysis was derived from the database of patients enrolled in the INT-0116/SWOG9008 phase 3 gastric cancer clinical trial. Available tissue specimens were
862
Oncology Scan
retrospectively evaluated for HER 2 gene amplification by fluorescence in situ hybridization (FISH) and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone. HER 2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER 2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER 2 amplification and treatment with respect to both disease-free survival (DFS; PZ.020) and overall survival (OS; PZ.034). Key data are summarized in Figure 1. Among patients with HER 2-nonamplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (PZ.003). Among patients with HER 2-amplified cancers, there was no significant difference in survival based on treatment arm. HER 2 status was not a prognostic marker among patients who received no postoperative chemoradiation. The investigators concluded that patients lacking HER 2 amplification benefited from treatment as indicated by both DFS and OS. Comment: The ToGA trial, a phase 3 trial of patients with metastatic gastric and gastroesophageal cancer, demonstrated a significant overall survival benefit for patients when trastuzumab was combined with chemotherapy (5). With the publication of these results in 2010, there has been keen interest in investigating the role of trastuzumab in the treatment of patients with localized distal esophageal, esophagogastric, and gastric cancer. The Radiation Therapy Oncology Group is currently conducting a phase 3
(a)
(b)
Fig. 1. Schema and results of analysis. MDFS Z median disease-free survival in months; MOS Z median overall survival in months.
International Journal of Radiation Oncology Biology Physics trial looking at the efficacy of trastuzumab in the neoadjuvant treatment of patients with HER 2-positive esophageal cancer. The study by Gordon et al examines the role of HER 2 expression in gastric cancers from an important data setdthe tumors of patients from the Intergroup-0116 trial. This trial established the role of adjuvant radiation therapy and 5-fluorouracil/leucovorin in patients with resected gastric cancer. Interestingly, the study shows that patients with HER 2-negative tumors and receiving adjuvant therapy had a markedly improved overall and diseasefree survival compared with patients not receiving adjuvant therapy. No difference in outcome was observed for patients with HER 2-positive tumors. There are clear limitations to this study; it is retrospective, only 258 of the 559 patients had tissue available for analysis, and only 28 patients of the 258 had HER 2 over expression in their cancer. However, the study results do support further analysis of HER 2 status as a potential predictive assay in future clinical trials.
James et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 232 factorial trial. Lancet Oncol 2013. (6)
Willett et al. ACT II: treatment of anal cancer comes full circle. Lancet Oncol 2013. (7) Summary: The investigators of the Anal Cancer Trial (ACT II) trial report the results of the largest phase 3 trial ever conducted in anal cancer. Nine hundred forty patients with T1 to T4 squamous cell carcinomas of the anal canal and anal margin were first randomized to receive mitomycin-C (MMC; 12 mg/m2 day 1, nZ472) or cisplatin (CisP; 60 mg/m2 days 1 and 29, nZ468) with 5-fluorouracil (5FU) (1000 mg/m2 on days 1-4 and 29-32) and radiation therapy (50.4 Gy in 28 daily fractions). A second randomization assigned patients to 2 courses of maintenance chemotherapy (5FU/CisP 5 and 8 weeks following chemoradiation, nZ448) or no maintenance (nZ446). By a 22 factorial design, this trial design permitted sufficient statistical power to address 2 questions: (1) what is the direct comparison of MMC and CisP in patients receiving chemoradiation by the endpoints of the complete response (CR) rate at 26 weeks and acute toxicity rates? and (2) what is the value of maintenance chemotherapy as assessed by 3 year progression free survival (PFS)? Median follow-up was 5.1 years. The CR rates at 26 weeks postchemoradiation were 90.5% for MMC (391/432) and 89.6% for CisP (386/431). Overall acute toxicity (grade 3-4) rates during chemoradiation were similar: 71% (334/472) versus 72% (337/468), respectively. Any nonhematologic grade 3-4 toxicities for MMC versus CisP were 62% versus 68%, and any hematological grade 3-4 toxicities were 26% versus 16%. Three-year PFS rates were 74% (maintenance) and 73% (no maintenance). The investigators concluded that chemoradiation with 5FU/CisP had similar CR and overall toxicity to 5FU/MMC but less hematologic toxicity. Maintenance chemotherapy did not improve PFS. On the basis of these data, the investigators advocate 5FU/MMC and 50.4 Gy in 28 fractions as standard practice and ascribe their excellent outcomes to an efficient radiobiological schedule.
Volume 87 Number 5 2013 Comment: The results of the ACT-II trial provide important clarification of the role of concurrent CisP versus MMC with radiation therapy in the treatment of anal cancer. In a contemporary trial by the Radiation Therapy Oncology Group (RTOG 9811), patients were randomized to treatment with induction 5-FU/ CisP followed by concurrent 5-FU/CisP with radiation therapy versus concurrent 5-FU/MMC and radiation therapy without induction (8). The long-term results of the study demonstrated that radiation therapy and chemotherapy with concurrent 5FU-MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction þ concurrent 5FU-CisP. The results also indicated borderline significance for CFS, CF, and LRF, and confirmed that RTþ5FU/MMC remains the preferred standard of care. Defining the exact impact of CisP as an alternative to MMC is complicated in RTOG 98-11 because of the induction arm of the study and the lack of a true comparison of concurrent CisP to MMC. In its trial design, ACT-II directly compared concurrent CisP to MMC. The results showed no statistical difference in complete response rate at 26 weeks. Although there was a statistically higher rate of hematologic toxicity in patients receiving MMC (26%) versus CisP (16%), this did not translate into higher rate of clinical events. It should be noted that the ACT-II trial design mandated a single dose of MMC at 12 mg/m2 per the protocol used in other European trials, which differs from the regimen used in the United States and previous RTOG trials of 10 mg/m2 given on days 1 and 29. The rate of grade 3 and 4 hematologic toxicity in RTOG 98-11 was 61%, much higher than the 26% seen in the control arm of ACT-II, suggesting the potential higher risk of the more intensified MMC dosing. As it stands currently, MMC and 5FU remains the standard of care chemotherapy agents for anal cancer.
Oncology Scan
863
References 1. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of shortcourse radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: TransTasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30:3827-3833. 2. Minsky BD. Short-course radiation versus long-course chemoradiation for rectal cancer: making progress. J Clin Oncol 2012;30:3777-3778. 3. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215-1223. 4. Gordon MA, Gundacker HM, Benedetti J, et al. Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial. Ann Oncol 2013;24:1754-1761. 5. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697. 6. James RD, Glynne-Johnes R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): A randomised phase 3, open-label, 2 x 2 factorial trial. Lancet Oncol 2013;14:516-524. 7. Willett CG, Czito BG, Palta M. ACT II: Treatment of anal cancer comes full circle. Lancet Oncol 2013;14:443-445. 8. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 2012;30:4344-4351.
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandGastrointestinal Cancers By Christopher G. Willett, MD, Senior Editor, Daniel Chang, MD, Brian Czito, MD, Jeffrey Meyer, MD, and Jennifer Wo, MD, Associate Editors This represents my last Oncology Scan as Senior Editor of the gastrointestinal (GI) group. It has been a real pleasure and privilege to work and interact with the GI Associate Editors, Drs Daniel Chang, Brian Czito, Jeffrey Meyer, and Jennifer Wo. They are a group of bright, hardworking, and thoughtful oncologists who contribute substantively to our field and will continue to do so. Dr Chang will now lead the GI editorial team, building from the strong, high-quality evidence foundation that we have established over the past 2 years. I would like to extend my personal thanks to Anthony Zietman, who provided passionate and thoughtful leadership as well as support to this rewarding and rich experience.
Ngan et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012. (1) Minsky BD. Short-course radiation versus long-course chemoradiation for rectal cancer: making progress. J Clin Oncol 2012. (2) Summary: In a recent report, the Trans-Tasman Radiation Oncology Group (TROG) reported on local recurrence (LR) rates in short-course (SC) and long-course (LC) neoadjuvant chemoradiation alone for rectal cancer. Eligibility criteria included patients with ultrasound staged or magnetic resonance imagestaged T3N0-2M0 rectal adenocarcinoma. These patients were randomly assigned to 1 of 2 courses of treatment: (1) SC of pelvic radiation therapy (5 5 Gy), early surgery, and 6 courses of adjuvant chemotherapy or (2) LC with 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks with continuous infusion fluorouracil, surgery in 4 to 6 weeks, and 4 courses of chemotherapy. Three hundred twenty-six patients were randomized, 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range 3.0-7.8 years). The 3-year LR rates between SC and LC were not statistically significantly different; the confidence interval for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected. Int J Radiation Oncol Biol Phys, Vol. 87, No. 5, pp. 861e863, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.09.006
Comment: Passionate debate persists regarding the relative merits and deficiencies of SC radiation therapy alone (25 Gy in 5 fractions) or LC chemoradiation in the preoperative treatment of patients with rectal cancer. The TROG study is the second major randomized clinical trial published to date that directly compares these 2 treatment approaches (1, 2) and reports no statistically significant differences in local control, overall survival, or late toxicity between strategies; these results are in line with the similarly designed and previously reported Polish trial (3). Are these findings sufficiently definitive to justify adoption of SC as the standard of care for neoadjuvant therapy of resectable rectal cancer? The GI editorial group judges not; the TROG trial is a small study (only 326 patients), and the study results are too early, given the long natural history of this disease and manifestation of late toxicity, to draw definitive conclusions. Clinically significant advantages to the long-course therapy also lie within the confidence intervals of the local recurrence risk. The ongoing Stockholm III trial is also investigating SC and LC therapy, comparing 25 Gy in 5 fractions, early surgery, delayed surgery, and LC radiation alone (50 Gy in 25 fractions). The editors favor the continued use of neoadjuvant LC chemoradiation in the treatment of resectable rectal cancer. This strategy allows a platform for continued evaluation of radiosensitizing agents that may improve on existing downstaging and complete pathologic response rates. Gordon et al. Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial. Ann Oncol 2013. (4) Summary: On the basis of the results of the Trastuzumab for Gastric Cancer (ToGA) trial (5), trastuzumab has been approved for treatment of patients with human epidermal growth factor receptor 2 (HER 2)-positive metastatic gastric and gastroesophageal cancer. Conflicting data exist in the literature regarding the potential prognostic and predictive role of HER 2 in the natural history of gastric cancer. To provide clarification of this question, investigators looked at the HER 2 status both as prognostic and predictive markers. This analysis was derived from the database of patients enrolled in the INT-0116/SWOG9008 phase 3 gastric cancer clinical trial. Available tissue specimens were
862
Oncology Scan
retrospectively evaluated for HER 2 gene amplification by fluorescence in situ hybridization (FISH) and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone. HER 2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER 2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER 2 amplification and treatment with respect to both disease-free survival (DFS; PZ.020) and overall survival (OS; PZ.034). Key data are summarized in Figure 1. Among patients with HER 2-nonamplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (PZ.003). Among patients with HER 2-amplified cancers, there was no significant difference in survival based on treatment arm. HER 2 status was not a prognostic marker among patients who received no postoperative chemoradiation. The investigators concluded that patients lacking HER 2 amplification benefited from treatment as indicated by both DFS and OS. Comment: The ToGA trial, a phase 3 trial of patients with metastatic gastric and gastroesophageal cancer, demonstrated a significant overall survival benefit for patients when trastuzumab was combined with chemotherapy (5). With the publication of these results in 2010, there has been keen interest in investigating the role of trastuzumab in the treatment of patients with localized distal esophageal, esophagogastric, and gastric cancer. The Radiation Therapy Oncology Group is currently conducting a phase 3
(a)
(b)
Fig. 1. Schema and results of analysis. MDFS Z median disease-free survival in months; MOS Z median overall survival in months.
International Journal of Radiation Oncology Biology Physics trial looking at the efficacy of trastuzumab in the neoadjuvant treatment of patients with HER 2-positive esophageal cancer. The study by Gordon et al examines the role of HER 2 expression in gastric cancers from an important data setdthe tumors of patients from the Intergroup-0116 trial. This trial established the role of adjuvant radiation therapy and 5-fluorouracil/leucovorin in patients with resected gastric cancer. Interestingly, the study shows that patients with HER 2-negative tumors and receiving adjuvant therapy had a markedly improved overall and diseasefree survival compared with patients not receiving adjuvant therapy. No difference in outcome was observed for patients with HER 2-positive tumors. There are clear limitations to this study; it is retrospective, only 258 of the 559 patients had tissue available for analysis, and only 28 patients of the 258 had HER 2 over expression in their cancer. However, the study results do support further analysis of HER 2 status as a potential predictive assay in future clinical trials.
James et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 232 factorial trial. Lancet Oncol 2013. (6)
Willett et al. ACT II: treatment of anal cancer comes full circle. Lancet Oncol 2013. (7) Summary: The investigators of the Anal Cancer Trial (ACT II) trial report the results of the largest phase 3 trial ever conducted in anal cancer. Nine hundred forty patients with T1 to T4 squamous cell carcinomas of the anal canal and anal margin were first randomized to receive mitomycin-C (MMC; 12 mg/m2 day 1, nZ472) or cisplatin (CisP; 60 mg/m2 days 1 and 29, nZ468) with 5-fluorouracil (5FU) (1000 mg/m2 on days 1-4 and 29-32) and radiation therapy (50.4 Gy in 28 daily fractions). A second randomization assigned patients to 2 courses of maintenance chemotherapy (5FU/CisP 5 and 8 weeks following chemoradiation, nZ448) or no maintenance (nZ446). By a 22 factorial design, this trial design permitted sufficient statistical power to address 2 questions: (1) what is the direct comparison of MMC and CisP in patients receiving chemoradiation by the endpoints of the complete response (CR) rate at 26 weeks and acute toxicity rates? and (2) what is the value of maintenance chemotherapy as assessed by 3 year progression free survival (PFS)? Median follow-up was 5.1 years. The CR rates at 26 weeks postchemoradiation were 90.5% for MMC (391/432) and 89.6% for CisP (386/431). Overall acute toxicity (grade 3-4) rates during chemoradiation were similar: 71% (334/472) versus 72% (337/468), respectively. Any nonhematologic grade 3-4 toxicities for MMC versus CisP were 62% versus 68%, and any hematological grade 3-4 toxicities were 26% versus 16%. Three-year PFS rates were 74% (maintenance) and 73% (no maintenance). The investigators concluded that chemoradiation with 5FU/CisP had similar CR and overall toxicity to 5FU/MMC but less hematologic toxicity. Maintenance chemotherapy did not improve PFS. On the basis of these data, the investigators advocate 5FU/MMC and 50.4 Gy in 28 fractions as standard practice and ascribe their excellent outcomes to an efficient radiobiological schedule.
Volume 87 Number 5 2013 Comment: The results of the ACT-II trial provide important clarification of the role of concurrent CisP versus MMC with radiation therapy in the treatment of anal cancer. In a contemporary trial by the Radiation Therapy Oncology Group (RTOG 9811), patients were randomized to treatment with induction 5-FU/ CisP followed by concurrent 5-FU/CisP with radiation therapy versus concurrent 5-FU/MMC and radiation therapy without induction (8). The long-term results of the study demonstrated that radiation therapy and chemotherapy with concurrent 5FU-MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction þ concurrent 5FU-CisP. The results also indicated borderline significance for CFS, CF, and LRF, and confirmed that RTþ5FU/MMC remains the preferred standard of care. Defining the exact impact of CisP as an alternative to MMC is complicated in RTOG 98-11 because of the induction arm of the study and the lack of a true comparison of concurrent CisP to MMC. In its trial design, ACT-II directly compared concurrent CisP to MMC. The results showed no statistical difference in complete response rate at 26 weeks. Although there was a statistically higher rate of hematologic toxicity in patients receiving MMC (26%) versus CisP (16%), this did not translate into higher rate of clinical events. It should be noted that the ACT-II trial design mandated a single dose of MMC at 12 mg/m2 per the protocol used in other European trials, which differs from the regimen used in the United States and previous RTOG trials of 10 mg/m2 given on days 1 and 29. The rate of grade 3 and 4 hematologic toxicity in RTOG 98-11 was 61%, much higher than the 26% seen in the control arm of ACT-II, suggesting the potential higher risk of the more intensified MMC dosing. As it stands currently, MMC and 5FU remains the standard of care chemotherapy agents for anal cancer.
Oncology Scan
863
References 1. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of shortcourse radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: TransTasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30:3827-3833. 2. Minsky BD. Short-course radiation versus long-course chemoradiation for rectal cancer: making progress. J Clin Oncol 2012;30:3777-3778. 3. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215-1223. 4. Gordon MA, Gundacker HM, Benedetti J, et al. Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial. Ann Oncol 2013;24:1754-1761. 5. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697. 6. James RD, Glynne-Johnes R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): A randomised phase 3, open-label, 2 x 2 factorial trial. Lancet Oncol 2013;14:516-524. 7. Willett CG, Czito BG, Palta M. ACT II: Treatment of anal cancer comes full circle. Lancet Oncol 2013;14:443-445. 8. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 2012;30:4344-4351.
