Noncolorectal GI Cancer Evidence Incorporated into Guidelines

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The noncolorectal gastrointestinal cancer studies selected for this year’s Best of ASCO meetings include some whose results are being folded into practice guidelines or are good candidates for incorporation, according to Alexandria T. Phan, MD, Associate Professor at The University of Texas MD Anderson Cancer Center, Houston, who presented the data at Best of ASCO San Diego.

Chemoradiation in Anal Cancer

In the ACT II trial, 940 patients with treatment-naive anal carcinoma of clinical stage T3-4, N0-3 or T1-2, N1-3 were randomly assigned at study entry, and treatment was based on a 2×2 factorial design. Patients were randomly assigned into four arms: mitomycin plus radiation therapy with chemotherapy maintenance, mitomycin plus radiation therapy without chemotherapy maintenance, cisplatin plus radiation therapy with chemotherapy maintenance, and cisplatin plus radiation therapy without chemotherapy maintenance.

The rate of complete response at 26 weeks was statistically indistinguishable between mitomycin and cisplatin (83% vs 84%). “There is internal consistency, with an excellent complete response rate,” Dr. Phan commented.

In the entire trial population, patients who had a complete response had superior progression-free survival (83% vs 45%, HR = 0.21, P < .001) and overall survival (93% vs 61%; HR = 0.21, P < .001).

Importantly, the rate of complete response increased with time. “The timing of when response is assessed makes a difference,” noted Dr. Phan. Fully 60% of patients who had not achieved a complete response at 11 weeks had achieved one by 26 weeks (Table 1). Meanwhile, complete response remained a significant predictor of outcome (Table 2).

“The complete response rate is a good surrogate marker for progression-free survival and overall survival if measured at the right time,” Dr. Phan commented. “In anal cancer, you should wait for 26 weeks postchemoradiation before you do a biopsy and surgery because of continuing disease regression,” she recommended, noting that National Comprehensive Cancer Network guidelines now call for repeated evaluation in patients with persistent disease.2

FOLFOX4 in Chemoradiation for Esophageal Cancer

In the PRODIGE 5/ACCORD 17 trial, 267 patients with untreated esophageal cancer who were not surgical candidates were randomly assigned evenly to definitive chemoradiation using FOLFOX4 (leucovorin, fluorouracil [5-FU], oxaliplatin) vs definitive chemoradiation using cisplatin and 5-FU, each followed by more of the same chemotherapy.3

In contrast to results of an earlier phase II trial,4 this phase III trial found that the FOLFOX4 and cisplatin/5-FU groups did not differ significantly with respect to median progression-free survival (9.7 vs 9.4 months) or overall survival (20.2 vs 17.5 months). However, there were fewer deaths due to toxicity on FOLFOX4 (one vs six).

“This was a negative study.… In esophageal cancer, nothing has changed: Concurrent chemoradiation with cisplatin and 5-FU is still the standard,” Dr. Phan asserted. “But FOLFOX with radiation may be preferred for patients with a borderline ECOG [performance status],” and “the fact that there are fewer toxic deaths with FOLFOX-radiation may allow for a better platform to add other radiosensitizing drugs in the future,” she noted.

“Early promising results from randomized phase II trials should always be confirmed in a larger randomized phase III trial,” Dr. Phan added.

Panitumumab in Advanced Esophagogastric Cancer

The REAL3 trial tested addition of panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR), to the EOX chemotherapy regimen (epirubicin, oxaliplatin, capecitabine [Xeloda]) in 553 patients with advanced cancer of the esophagus, gastroesophageal junction, or stomach.5 “The EOX doses had to be modified because of toxicity to accommodate the addition of panitumumab,” Dr. Phan noted.

Compared with chemotherapy alone, chemotherapy plus panitumumab was actually associated with worse median overall survival (8.8 vs 11.3 months, HR = 1.37, P = .01) and median progression-free survival (6.0 vs 7.4 months, HR = 1.22, P = .068). The rate of objective response did not differ significantly between groups.

“The final outcome is disappointing.… There is no benefit of panitumumab in unselected patients,” Dr. Phan commented.

“So what went wrong with the REAL3 trial?” she asked. “Perhaps it’s the wrong biological subgroup that we picked. There may have been too many toxicities. Perhaps the modified EOX was too low in dose intensity compared to the EOX. And maybe we picked the wrong chemotherapy backbone—maybe it should be irinotecan,” she suggested.

“In advanced gastroesophageal adenocarcinoma, the EGFR pathway may not be relevant,” Dr. Phan concluded, noting that the similar EXPAND trial, which used cetuximab (Erbitux) instead, recently reported negative results as well.6

Preventing Sorafenib Skin Reaction

In a phase II trial—the largest ever of a supportive measure in patients receiving anticancer drugs—investigators randomly assigned 871 patients starting sorafenib (Nexavar) for advanced hepatocellular carcinoma to prophylactic urea-based skin cream (Eucerin, 10% urea) three times daily plus best supportive care, or to best supportive care alone.7

The group given the urea-based cream had a lower 12-week incidence of any-grade hand-foot skin reaction (56% vs 74%, P < .0001) and of grade 2/3 reaction (21% vs 29%, P = .004). There was also a prolongation of time to onset (median, 84 vs 34 days; P < .0001).

The severity of hand-foot symptoms was lower in the urea-based cream group compared with the control group from week 4 onward, but the impact on daily activities was reduced only transiently.

“To me, this is actually the most useful study because it was very impressive how many patients were enrolled in this.… It’s called a phase II trial, but it actually should be called a phase III,” Dr. Phan maintained.

She noted that it was unclear who was assessing the hand-foot skin reaction in the trial, but it ultimately did not matter because patient-reported quality of life was better with the cream.

“The urea-based cream is already recommended for grade 1 hand and foot skin reaction,” Dr. Phan pointed out.8 “The cost of the urea-based cream is so much cheaper than the cost of seeing the dermatologist to get treatment for hand and foot skin reaction. Therefore, I think it’s reasonable to say that urea-based cream should be used prophylactically for all patients starting on sorafenib.” ■

Disclosure: Dr. Phan reported no potential conflicts of interest.


1. Glynne-Jones R, James R, Meadows H, et al: Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II. 2012 ASCO Annual Meeting. Abstract 4004. Presented June 2, 2012.

2. NCCN Clinical Practice Guidelines in Oncology. Anal carcinoma. Version 2.2012. Available at Accessed August 28, 2012.

3. Conroy T, Galais M-P, Raoul J-L, et al: Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial. 2012 ASCO Annual Meeting. Abstract LBA4003. Presented June 2, 2012.

4. Conroy T, Yataghène Y, Etienne PL, et al: Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer 103:1349-1355, 2010.

5. Waddell TS, Chau I, Barbachano Y, et al: A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). 2012 ASCO Annual Meeting. Abstract LBA4000. Presented June 2, 2012.

6. Merck Serono: EXPAND trial of erbitux in advanced gastric cancer does not meet primary endpoint [press release], July 5, 2012. Available at Accessed August 28, 2012.

7. Ren Z, Zhu K, Kang H, et al: A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. 2012 ASCO Annual Meeting. Abstract 4008. Presented June 2, 2012.

8. Lacouture ME, Wu S, Robert C, et al: Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001-1011, 2008.