Therapeutic outcomes for patients with most of the cancers originating in the upper gastrointestinal track still remain disappointing.
Therapeutic outcomes for patients with most of the cancers originating in the upper gastrointestinal track still remain disappointing. However, along with improving delivery of our current multimodality treatments, incorporating new novel and targeted therapies in the treatment of upper GI cancers holds promise for better outcomes in our patients. To that end, this year’s American Society of Clinical Oncology meeting featured important data from recent and ongoing studies in the therapies for gastrointestinal non-colorectal malignancies.
Oral Abstract Session
On behalf of our group, I presented data from the CALGB 80403/ECOG 1206, a randomized phase II study, which was conceived at an NCI strategy meeting of the GI cancer Intergroup. At that time, consensus was that there was no superior chemotherapy regimen or targeted therapy that merited a phase III study, so it was recommended that promising agents be randomized to a phase II study and that the most promising targeted agent be added to each treatment arm. Response rate was determined to be the primary endpoint because it would be the fastest way to determine which experimental regimen [ECF (epirubicin, cisplatin, fluorouracil), IC (irinotecan, cisplatin), and FOLFOX (leucovorin, fluorouracil, oxaliplatin)] was most promising and could subsequently be randomized against standard chemotherapy. All three regimens had shown efficacy in phase II and III trials.
Cetuximab, a chimerized monoclonal antibody to the EGF-receptor that has shown activity in treating NSCLC, colorectal cancer, and oropharyngeal cancer, was chosen as the study’s molecularly targeted agent and was added to each treatment arm. It is important to note that EGF-receptor expression occurs in three-fourths of patients with esophageal adenocarcinoma and squamous cell carcinoma. It is also important to note that a KRAS mutated gene is detected in only 2% of esophageal cancers.
Patients with chemo-naive, metastatic, measurable adenocarcinoma or squamous cell carcinoma of the esophagus or gastro-esophageal junction were randomized to three regimens: (A) epirubicin 50 mg/m2/day 1, cisplatin 60 mg/m2/day 1, 5-FU 200 mg/m2/day 1-21 q 21days; (B) irinotecan 65 mg/m2/day 1, 8, cisplatin 35 mg/m2/day 1, 8 q 21 day; (C) oxaliplatin 85 mg/m2/day 1, leucovorin 500 mg/m2/day 1, 5-FU 500 mg/m2/day 1, 5-FU 1,200 mg/m2/days 1-2 q 14d. In addition to these standard regimens, all patients in the trial received cetuximab at a 400mg/m2 loading dose and subsequently at 250mg/m2 weekly. Patients were stratified by histology-ADC vs. SCC and ECOG performance status-0 and 1 vs 2. With 64 measurable adenocarcinoma patients treated per regimen, the study had a 90% power (1-sided) to detect an improvement in major response from 25% to 40%.
All three regimens had response rates greater than 40% and met the criteria for further development. ECF-C had a higher response rate but FOLFOX-C was less toxic. IC-C appeared to be the least efficacious of the three treatment arms. After reviewing all the data it was determined that the FOLFOX-C regimen was best suited for continuing study in a phase III trial.
Thierry Conroy, MD, delivered the interim analysis results of PRODIGE 4/ACCORD 11/0402, a randomized phase III trial comparing FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) vs gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.
Metastatic pancreatic ductal carcinoma is an incurable disease with few good treatment options; gemcitabine is considered the cornerstone agent in this disease site. However, studies in single-agent gemcitabine have only shown median survival rates of 6 to 7 months. Although gemcitabine-based doublets generally failed to increase survival, some trials indicated possible benefits of combination chemotherapy in patients with good performance status.
Based on the results of FOLFIRINOX regimen in a phase II study, which showed median survival of 9.5 months, Dr. Conroy and colleagues initiated a phase II →III trial comparing FOLFIRINOX regimen to gemcitabine alone. The phase II data (N=88) were presented at the ASCO 2007 meeting, and based on those encouraging interim results (31.8% response rate in the FOLFIRINOX arm vs 11.4% response in the gemcitabine arm), the investigators moved forward with the phase III component of the study in which 342 patients were enrolled between 01/2005 and 10/2009.
Median survival in the FOLFIRINOX arm was 11.1 month as compared with 6.8 months in the gemcitabine arm, which Dr. Conroy noted is consistent with the literature.
FOLFIRINOX is the first non-gemcitabine-containing therapy that has shown a significantly longer overall survival, progression-free survival and higher response rate than gemcitabine alone. However, FOLFIRINOX also caused significantly higher rates of febrile neutropenia, peripheral neuropathy, vomiting, fatigue, and diarrhea than gemcitabine. Thus, this new therapy should be reserved only for the strongest, healthiest patients.
Ate van der Gaast, MD, presented the results from the CROSS study, a large randomized phase III trial comparing adjuvant chemoradiotherapy followed by surgery vs surgery alone in patients with locally advanced esophageal cancer.
From 2004 to 2008, 363 patients with localized esophageal or esophagogastric junction cancer were randomized to surgery alone or paclitaxel 50 mg/m2 plus carboplatin (AUC = 2) on days 1, 8, 15, 22 and 29 with concurrent radiotherapy (23 fractions of 1.8 Gy = 41.4 Gy). Surgery was conducted within 6 weeks of completing chemoradiotherapy.
The regimen was well tolerated, with more than 90% of patients completing all five cycles of therapy. The R0 resection rate was increased from 67% to 92% (p < 0.001) for those patients undergoing neoadjuvant chemoradiation. These patients had a pathologic complete response rate of 32%.
After a median follow-up of 32 months, the 3-year survival rate was 48% for surgery alone vs 59% for chemoradiation plus surgery. Patients who received chemoradiation plus surgery experienced a significant improvement in overall survival (hazard ratio, 0.67). Median survival was 49 months for the combined modality group vs 26 months for those receiving surgery alone.
Therefore, neoadjuvant chemoradiotherapy with weekly administrations of carboplatin and paclitaxel and concurrent radiotherapy followed by surgery is a new standard for patients with locally advanced esophageal and esophagogastric cancer.
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer death. However, in Asia the incidence of HCC is markedly higher, comprising almost 50% of all tumor diagnoses.
Shukui Qin, MD, who reported data from the EACH trial, noted that Asian patients often present with metastatic HCC, ineligible for surgery or localized treatments. Median survival is only about 3 months with supportive care; systemic chemotherapies are commonly used but there is no evidence of a survival benefit.
Patients in China, Taiwan, South Korea, and Thailand were eligible for the trial if they had advanced and/or unresectable HCC with at least one measurable lesion, and were treatment-naive except for surgery, or had progressed after previous interventional/local therapy.
The trial randomized 184 patients to FOLFOX4 every 2 weeks and 187 patients to doxorubicin 50 mg/m2 every 3 weeks. Treatment was continued until progression of disease, toxicity, death, or eligibility for resection. The average age of participants was 49 years, and 89% were men.
When compared with doxorubicin, the FOLFOX4 regimen significantly improved median progression-free survival from 1.80 to 2.97 months (P = .0003) and overall survival from 4.90 to 6.47 months (P = 0.0425). Thus, FOLFOX has become another treatment option for patients with advanced HCC.
Clinical Science Symposium
Randomized run-in study of bevacizumab and everolimus in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker
J. C. Yao, MD presented the results of this study, noting that the incidence of pancreatic neuroendocrine tumors was on the rise. Phase II studies with the VEGF inhibitor bevacizumab have shown single-agent activity, as have phase II studies looking at the mTOR inhibitor everolimus. Both agents have entered into phase III trials, evaluating their efficacy in the treatment of neuroendocrine tumors. Recent data from the RADIANT-3 trial, which looked at everolimus versus best supportive care in advanced pancreatic neuroendocrine tumors, showed a significant improvement in progression-free survival. Other data, previously presented by Dr. Yao, has suggested that perfusion CT can serve as a functional biomarker.
The investigators randomized LGNET patients with lesion(s) ≥ 3 cm to therapy with bevacizumab or everolimus for one 21-day cycle. On cycle 2 day 1, the alternate agent was added (bevacizumab plus everolimus). Perfusion CTs assessing tumor blood flow, blood volume blood volume, mean transit time, and permeability surface were mandatory. Primary objectives were to determine the effects of bevacizumab or everolimus as well as the combination on blood flow. Response was evaluated by RECIST every 9 weeks.
The researchers found that bevacizumab decreased tumor blood flow. The addition of everolimus to bevacizumab was associated with further decrease in blood flow. By intention-to-treat analysis, 26% of patients had a partial response to this combination. Response was associated with decreased tumor blood flow by perfusion CT (P < 0.05). Median progression-free survival was 14.4 months.
The combination of bevacizumab and everolimus is a promising treatment in patients with LGNETs. Perfusion CT may become a surrogate marker for selection of patients likely to benefit from this therapy.