International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandNovel Treatment Strategies for Gastrointestinal Cancers By Daniel T. Chang, MD, Senior Editor, Thomas Brunner, MD, Associate Editor, Jason Chia-Hsien Cheng, MD, PhD, Associate Editor, Stanley Liauw, MD, Associate Editor, Jeffrey Meyer, MD, PhD, Associate Editor, and Jennifer Wo, MD, Associate Editor
This edition of the Oncology Scan is the first with a new Gastrointestinal (GI) Editorial Team in place. We would first like to acknowledge Dr Brian Czito, who, after 2 years of fantastic service as one of the original associate editors, rotates out of the group. We also acknowledge the other outstanding members of our original group, Drs Jeffrey Meyer and Jennifer Wo, who are continuing on as associate editors. We welcome to our group Drs Stanley Liauw, Thomas Brunner, and Jason Chia-Hsien Cheng as new associate editors. For several years, they have been outstanding reviewers for this journal, and we are excited to have them join the editorial board. They each bring their own set of clinical and academic expertise in the field of GI cancers, and we look forward to working with them. Finally, we acknowledge Dr Christopher Willett, who was the first senior editor of the GI section. For 2 years, Dr Willett has provided invaluable leadership, mentorship, and support to the associate editors as he led our group in defining a vision and standard for the types of papers we sought to publish and organizing our selection process to ensure timely and constructive reviews. As a result, these past 2 years have seen a noticeable rise in the caliber of manuscripts received and ultimately selected for publication, and we hope to continue this success.
Von Hoff et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013. (1)
Summary: In this international phase 3 trial, patients with histologically confirmed metastatic pancreatic adenocarcinoma were randomized to albumin-bound paclitaxel (nabpaclitaxel) at 125 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks or gemcitabine alone at 1000 mg/m2 weekly for 7 or 8 weeks and then days 1, 8, and 15 every 4 weeks. All patients had to be newly diagnosed or Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 699e703, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.01.048
could have received only radiosensitizing 5-fluorouracil or gemcitabine 6 months before randomization. In total, 861 patients were randomized: 431 patients in the nab-paclitaxel and gemcitabine arm and 430 patients in the gemcitabine alone arm. The results demonstrated a statistically significant improvement in overall survival (OS) favoring the addition of nab-paclitaxel (8.5 months vs 6.7 months, respectively, P59 times upper limit of normal). Of note, the median duration of therapy was 3.9 months in the nab-paclitaxelgemcitabine arm versus 2.8 months for the gemcitabine alone arm, and the relative dose intensity was 81% and 75%, respectively. Neutropenia, leukopenia, and peripheral neuropathy rates were higher in the nab-paclitaxel arm, although the rate of febrile neutropenia was low in both groups. Serious adverse events were similar between the 2 arms (50% in the nab-paclitaxel-gemcitabine arm versus 43% in the gemcitabine alone arm). Fatal events occurred in 4% in both arms. Comment: For years, single-agent gemcitabine has been the standard of care for advanced pancreas cancer, and attempts to add agents onto the gemcitabine backbone have failed to improve survival (2-5). Recently, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) was shown to improve survival over gemcitabine
700
Oncology Scan
alone (6) but with a higher rate of grade 3 and 4 toxicity. The use of FOLFIRINOX has been limited by its tolerability and is reserved for young or medically fit patients, a limiting factor in its widespread adoption. Based on promising preclinical and phase 1 and 2 efficacy and tolerability data, Von Hoff et al performed this randomized trial comparing nab-paclitaxel and gemcitabine with gemcitabine alone and found the addition of nabpaclitaxel to have improved survival without significantly more toxicity. In addition, 10% of patients in this trial were >75 years of age, and 8% of patients had an Eastern Cooperative Oncology Group performance status of 2, both of which were exclusion criteria for the FOLFIRINOX trial, indicating potentially better tolerance for this regimen. Although direct efficacy comparisons between nab-paclitaxel/gemcitabine and FOLFIRINOX are not available, this trial offers an alternative regimen for patients with metastatic pancreatic cancer who are not candidates for FOLFIRINOX. Additional studies are needed to determine if this regimen should be incorporated into the adjuvant setting or for those with locally advanced, nonmetastatic disease.
International Journal of Radiation Oncology Biology Physics
in the cetuximab arm and 76.9% in the control arm. The OS was worse in the cetuximab arm compared with the control arm (median 22.1 months vs 25.1 months, PZ.043). The investigators found no difference in quality of life between the 2 arms in terms of physical function, role function, fatigue, dysphagia, and eating restrictions. After interim analysis of the phase 2 portion, the planned phase 3 portion was closed due to futility. Comment: After cetuximab was found to improve survival when combined with RT for head and neck cancer (8), investigators have sought to determine its role against epithelial cancers at other disease sites. The SCOPE1 trial presented here tested the addition of cetuximab to cisplatin and capecitabine with RT but found no benefit with worse toxicity. Similar results were seen in the Radiation Therapy Oncology Group (RTOG) 0522 trial for head and neck cancer when combining cetuximab with cisplatin and RT (9). Preliminary results of the recently closed RTOG 0436, which is a randomized trial of cetuximab combined with cisplatin, paclitaxel, and RT in patients treated definitively with esophageal cancer, also showed no improvement in survival with the addition of cetuximab (10). Currently, there is no role for cetuximab combined with standard chemoradiation for esophageal cancer.
Crosby et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): A multicentre, phase 2/3 randomised trial. Lancet Oncol 2013. (7)
Summary: The SCOPE1 trial was a phase 2/3 randomized trial conducted in the United Kingdom comparing cisplatin/ capecitabine and radiation with or without cetuximab. Patients were eligible if they had stage I, II, or III disease and were recommended definitive chemoradiation. All patients were required to have endoscopic ultrasound staging, but positron emission tomography (PET) was optional. Treatment in the control arm was cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. The experimental arm included cetuximab 400 mg/m2 on day 1 followed by 250 mg/m2 weekly for 12 weeks. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin. No elective nodal radiation was used. In total, 258 patients were enrolled and randomized, consisting of 129 patients in each arm. Of note, 73% of patients had squamous cell carcinoma, and 25% had adenocarcinoma. Compliance was lower in the cetuximab arm compared with the control arm, with more patients requiring a dose reduction in capecitabine (75% vs 66%, respectively) and more patients requiring discontinuing cisplatin (20% vs 9%, respectively) or capecitabine (28% vs 15%, respectively). Fewer patients in the cetuximab arm received the full RT dose compared with the control arm (78% vs 90%, respectively). More patients in the cetuximab arm had nonhematologic toxicity (PZ.004). At 24 weeks, the proportion of patients that were failure-free was 66.4%
Degiuli et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg 2014. (11)
Summary: In this randomized trial from Italy, patients with histologically proven gastric cancer who were felt to be deemed curable and medically operable were randomized to either a D1 or a D2 dissection. Patients in the D2 arm were not required to undergo a pancreaticosplenectomy. If the pancreas was felt to be directly invaded, pancreatectomy was performed. Quality control in this trial was strict, including only surgeons who had previously enrolled patients on an earlier phase 2 trial allowed to participate. The number of nodes and nodal stations removed were carefully monitored and compared with international guidelines. Noncompliance was defined as >2 lymph node stations not resected that should have been, and contamination was defined as having >2 lymph node stations resected that should not have been. No chemotherapy or radiation therapy was given preoperatively or adjuvantly. With a follow-up of 8.8 years, 133 patients were randomized to a D1 dissection, and 134 patients were randomized to a D2 dissection. Contamination in the D1 arm was 18%, and noncompliance in the D2 arm was 33.6%. No difference was seen in operative mortality (3% vs 2.2%, respectively, PZ.725). The 5-year OS (66.5% vs 64.2%, respectively, PZ.695) and the 5-year disease-specific survival (DSS, 71% vs 72.6, respectively) did not differ between D1 and D2 dissection. In subgroup analysis, patients with pT1 disease had higher OS (92% vs 81%, respectively) and
Volume 89 Number 4 2014
DSS (98% vs 83%, respectively, PZ.015) with D1 dissection compared with D2 dissection. For patients with pT2-4 disease and lymph nodeepositive disease, the 5-year OS was 35% and 51% for D1 and D2 dissection, respectively, and the 5-year DSS was 38% and 59%, respectively (PZ.055). On subgroup analysis, patients aged >70 years had better survival with D1 versus D2 dissection (75% vs 51%, respectively, PZ.018). D2 dissection was not significantly associated with survival on multivariate analysis. Comment: D2 lymph node dissection for gastric cancer is considered standard practice in Asia, and retrospective data from Japan shows a higher survival rate with this procedure (12). In the Western world, randomized trials from the United Kingdom and the Netherlands failed to show improved survival with D2 versus a D1 dissection with possible increased perioperative morbidity and mortality (13-15). As a result, D2 dissections are less routine in the United States. An oft-cited criticism of the landmark Intergroup 0116 trial is the fact that only 10% of patients had a D2 dissection (16), and postoperative chemoradiation has not been routinely used in Asia because of the perceived lack of relevance of these results applied to an Asian population. Investigators from Taiwan showed an improvement in survival for an extended D3 versus D1 dissection (17). Deguili et al report the results of another trial comparing D1 versus D2 dissection, showing again no apparent benefit in OS with D2 dissection. What differs in this trial is the fact that a pancreaticosplenectomy was not required in the D2 dissection unless there was evidence of direct tumor invasion, whereas it was a requirement in the UK and Dutch trials for proximal tumors. Resection of the pancreas and spleen was shown to contribute to perioperative mortality in those trials, which may have obscured any advantage in survival. The updated Dutch trial results showed fewer deaths due to gastric cancer in the D2 dissection arm, whereas deaths due to other causes was similar (15). In the current trial, the investigators found a suggestion of improved DSS for patients who underwent D2 dissection, particularly for those with locally advanced, lymph nodeepositive disease. Although the results suggest that a more aggressive lymph node dissection is warranted for those patients with locally advanced disease, this is only a subgroup analysis, and the issue of stage migration must be considered. Overall, this trial does not support benefit of D2 dissection in Western patients.
Gomez-Martin et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J Clin Oncol 2013. (18)
Summary: In this retrospective study from Spain, 90 patients with metastatic gastric cancer with HER 2 overexpression by immunohistochemistry (IHC), dual color silver in situ hybridization, or fluorescent in situ hybridization (FISH) treated with trastuzumab were included.
Oncology Scan
701
Gene copy number (GCN) of HER 2 or the HER 2/CEP17 ratio was assessed with dual color silver in situ hybridization or FISH from tumor samples and correlated with outcome. In total, 66 cases were included for analysis. Using receiver operator characteristic curve analysis, the investigators found that a HER 2/CEP17 ratio of 4.7 was the optimal cutoff predicting sensitivity (complete/partial response or stable disease by RECIST [Response Evaluation Criteria In Solid Tumors] 12 weeks) to trastuzumab and 4.45 for predicting OS at 12 months. For GCN, the optimal cutoff for predicting sensitivity was 9.4 and 10.0 for predicting OS at 12 months. Patients considered to be sensitive had longer OS (21.66 vs 14.03 months, PZ.005) compared with those who were not sensitive. For a HER 2/ CEP17 ratio cutoff of 4.45, the OS was 21.3 months compared with 13.6 months for a ratio of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandNovel Treatment Strategies for Gastrointestinal Cancers By Daniel T. Chang, MD, Senior Editor, Thomas Brunner, MD, Associate Editor, Jason Chia-Hsien Cheng, MD, PhD, Associate Editor, Stanley Liauw, MD, Associate Editor, Jeffrey Meyer, MD, PhD, Associate Editor, and Jennifer Wo, MD, Associate Editor
This edition of the Oncology Scan is the first with a new Gastrointestinal (GI) Editorial Team in place. We would first like to acknowledge Dr Brian Czito, who, after 2 years of fantastic service as one of the original associate editors, rotates out of the group. We also acknowledge the other outstanding members of our original group, Drs Jeffrey Meyer and Jennifer Wo, who are continuing on as associate editors. We welcome to our group Drs Stanley Liauw, Thomas Brunner, and Jason Chia-Hsien Cheng as new associate editors. For several years, they have been outstanding reviewers for this journal, and we are excited to have them join the editorial board. They each bring their own set of clinical and academic expertise in the field of GI cancers, and we look forward to working with them. Finally, we acknowledge Dr Christopher Willett, who was the first senior editor of the GI section. For 2 years, Dr Willett has provided invaluable leadership, mentorship, and support to the associate editors as he led our group in defining a vision and standard for the types of papers we sought to publish and organizing our selection process to ensure timely and constructive reviews. As a result, these past 2 years have seen a noticeable rise in the caliber of manuscripts received and ultimately selected for publication, and we hope to continue this success.
Von Hoff et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013. (1)
Summary: In this international phase 3 trial, patients with histologically confirmed metastatic pancreatic adenocarcinoma were randomized to albumin-bound paclitaxel (nabpaclitaxel) at 125 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks or gemcitabine alone at 1000 mg/m2 weekly for 7 or 8 weeks and then days 1, 8, and 15 every 4 weeks. All patients had to be newly diagnosed or Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 699e703, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.01.048
could have received only radiosensitizing 5-fluorouracil or gemcitabine 6 months before randomization. In total, 861 patients were randomized: 431 patients in the nab-paclitaxel and gemcitabine arm and 430 patients in the gemcitabine alone arm. The results demonstrated a statistically significant improvement in overall survival (OS) favoring the addition of nab-paclitaxel (8.5 months vs 6.7 months, respectively, P59 times upper limit of normal). Of note, the median duration of therapy was 3.9 months in the nab-paclitaxelgemcitabine arm versus 2.8 months for the gemcitabine alone arm, and the relative dose intensity was 81% and 75%, respectively. Neutropenia, leukopenia, and peripheral neuropathy rates were higher in the nab-paclitaxel arm, although the rate of febrile neutropenia was low in both groups. Serious adverse events were similar between the 2 arms (50% in the nab-paclitaxel-gemcitabine arm versus 43% in the gemcitabine alone arm). Fatal events occurred in 4% in both arms. Comment: For years, single-agent gemcitabine has been the standard of care for advanced pancreas cancer, and attempts to add agents onto the gemcitabine backbone have failed to improve survival (2-5). Recently, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) was shown to improve survival over gemcitabine
700
Oncology Scan
alone (6) but with a higher rate of grade 3 and 4 toxicity. The use of FOLFIRINOX has been limited by its tolerability and is reserved for young or medically fit patients, a limiting factor in its widespread adoption. Based on promising preclinical and phase 1 and 2 efficacy and tolerability data, Von Hoff et al performed this randomized trial comparing nab-paclitaxel and gemcitabine with gemcitabine alone and found the addition of nabpaclitaxel to have improved survival without significantly more toxicity. In addition, 10% of patients in this trial were >75 years of age, and 8% of patients had an Eastern Cooperative Oncology Group performance status of 2, both of which were exclusion criteria for the FOLFIRINOX trial, indicating potentially better tolerance for this regimen. Although direct efficacy comparisons between nab-paclitaxel/gemcitabine and FOLFIRINOX are not available, this trial offers an alternative regimen for patients with metastatic pancreatic cancer who are not candidates for FOLFIRINOX. Additional studies are needed to determine if this regimen should be incorporated into the adjuvant setting or for those with locally advanced, nonmetastatic disease.
International Journal of Radiation Oncology Biology Physics
in the cetuximab arm and 76.9% in the control arm. The OS was worse in the cetuximab arm compared with the control arm (median 22.1 months vs 25.1 months, PZ.043). The investigators found no difference in quality of life between the 2 arms in terms of physical function, role function, fatigue, dysphagia, and eating restrictions. After interim analysis of the phase 2 portion, the planned phase 3 portion was closed due to futility. Comment: After cetuximab was found to improve survival when combined with RT for head and neck cancer (8), investigators have sought to determine its role against epithelial cancers at other disease sites. The SCOPE1 trial presented here tested the addition of cetuximab to cisplatin and capecitabine with RT but found no benefit with worse toxicity. Similar results were seen in the Radiation Therapy Oncology Group (RTOG) 0522 trial for head and neck cancer when combining cetuximab with cisplatin and RT (9). Preliminary results of the recently closed RTOG 0436, which is a randomized trial of cetuximab combined with cisplatin, paclitaxel, and RT in patients treated definitively with esophageal cancer, also showed no improvement in survival with the addition of cetuximab (10). Currently, there is no role for cetuximab combined with standard chemoradiation for esophageal cancer.
Crosby et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): A multicentre, phase 2/3 randomised trial. Lancet Oncol 2013. (7)
Summary: The SCOPE1 trial was a phase 2/3 randomized trial conducted in the United Kingdom comparing cisplatin/ capecitabine and radiation with or without cetuximab. Patients were eligible if they had stage I, II, or III disease and were recommended definitive chemoradiation. All patients were required to have endoscopic ultrasound staging, but positron emission tomography (PET) was optional. Treatment in the control arm was cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. The experimental arm included cetuximab 400 mg/m2 on day 1 followed by 250 mg/m2 weekly for 12 weeks. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin. No elective nodal radiation was used. In total, 258 patients were enrolled and randomized, consisting of 129 patients in each arm. Of note, 73% of patients had squamous cell carcinoma, and 25% had adenocarcinoma. Compliance was lower in the cetuximab arm compared with the control arm, with more patients requiring a dose reduction in capecitabine (75% vs 66%, respectively) and more patients requiring discontinuing cisplatin (20% vs 9%, respectively) or capecitabine (28% vs 15%, respectively). Fewer patients in the cetuximab arm received the full RT dose compared with the control arm (78% vs 90%, respectively). More patients in the cetuximab arm had nonhematologic toxicity (PZ.004). At 24 weeks, the proportion of patients that were failure-free was 66.4%
Degiuli et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg 2014. (11)
Summary: In this randomized trial from Italy, patients with histologically proven gastric cancer who were felt to be deemed curable and medically operable were randomized to either a D1 or a D2 dissection. Patients in the D2 arm were not required to undergo a pancreaticosplenectomy. If the pancreas was felt to be directly invaded, pancreatectomy was performed. Quality control in this trial was strict, including only surgeons who had previously enrolled patients on an earlier phase 2 trial allowed to participate. The number of nodes and nodal stations removed were carefully monitored and compared with international guidelines. Noncompliance was defined as >2 lymph node stations not resected that should have been, and contamination was defined as having >2 lymph node stations resected that should not have been. No chemotherapy or radiation therapy was given preoperatively or adjuvantly. With a follow-up of 8.8 years, 133 patients were randomized to a D1 dissection, and 134 patients were randomized to a D2 dissection. Contamination in the D1 arm was 18%, and noncompliance in the D2 arm was 33.6%. No difference was seen in operative mortality (3% vs 2.2%, respectively, PZ.725). The 5-year OS (66.5% vs 64.2%, respectively, PZ.695) and the 5-year disease-specific survival (DSS, 71% vs 72.6, respectively) did not differ between D1 and D2 dissection. In subgroup analysis, patients with pT1 disease had higher OS (92% vs 81%, respectively) and
Volume 89 Number 4 2014
DSS (98% vs 83%, respectively, PZ.015) with D1 dissection compared with D2 dissection. For patients with pT2-4 disease and lymph nodeepositive disease, the 5-year OS was 35% and 51% for D1 and D2 dissection, respectively, and the 5-year DSS was 38% and 59%, respectively (PZ.055). On subgroup analysis, patients aged >70 years had better survival with D1 versus D2 dissection (75% vs 51%, respectively, PZ.018). D2 dissection was not significantly associated with survival on multivariate analysis. Comment: D2 lymph node dissection for gastric cancer is considered standard practice in Asia, and retrospective data from Japan shows a higher survival rate with this procedure (12). In the Western world, randomized trials from the United Kingdom and the Netherlands failed to show improved survival with D2 versus a D1 dissection with possible increased perioperative morbidity and mortality (13-15). As a result, D2 dissections are less routine in the United States. An oft-cited criticism of the landmark Intergroup 0116 trial is the fact that only 10% of patients had a D2 dissection (16), and postoperative chemoradiation has not been routinely used in Asia because of the perceived lack of relevance of these results applied to an Asian population. Investigators from Taiwan showed an improvement in survival for an extended D3 versus D1 dissection (17). Deguili et al report the results of another trial comparing D1 versus D2 dissection, showing again no apparent benefit in OS with D2 dissection. What differs in this trial is the fact that a pancreaticosplenectomy was not required in the D2 dissection unless there was evidence of direct tumor invasion, whereas it was a requirement in the UK and Dutch trials for proximal tumors. Resection of the pancreas and spleen was shown to contribute to perioperative mortality in those trials, which may have obscured any advantage in survival. The updated Dutch trial results showed fewer deaths due to gastric cancer in the D2 dissection arm, whereas deaths due to other causes was similar (15). In the current trial, the investigators found a suggestion of improved DSS for patients who underwent D2 dissection, particularly for those with locally advanced, lymph nodeepositive disease. Although the results suggest that a more aggressive lymph node dissection is warranted for those patients with locally advanced disease, this is only a subgroup analysis, and the issue of stage migration must be considered. Overall, this trial does not support benefit of D2 dissection in Western patients.
Gomez-Martin et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J Clin Oncol 2013. (18)
Summary: In this retrospective study from Spain, 90 patients with metastatic gastric cancer with HER 2 overexpression by immunohistochemistry (IHC), dual color silver in situ hybridization, or fluorescent in situ hybridization (FISH) treated with trastuzumab were included.
Oncology Scan
701
Gene copy number (GCN) of HER 2 or the HER 2/CEP17 ratio was assessed with dual color silver in situ hybridization or FISH from tumor samples and correlated with outcome. In total, 66 cases were included for analysis. Using receiver operator characteristic curve analysis, the investigators found that a HER 2/CEP17 ratio of 4.7 was the optimal cutoff predicting sensitivity (complete/partial response or stable disease by RECIST [Response Evaluation Criteria In Solid Tumors] 12 weeks) to trastuzumab and 4.45 for predicting OS at 12 months. For GCN, the optimal cutoff for predicting sensitivity was 9.4 and 10.0 for predicting OS at 12 months. Patients considered to be sensitive had longer OS (21.66 vs 14.03 months, PZ.005) compared with those who were not sensitive. For a HER 2/ CEP17 ratio cutoff of 4.45, the OS was 21.3 months compared with 13.6 months for a ratio of
