New Therapies for GI Cancers Fall Short

Results from several large clinical trials on cancers of the colon, rectum, and anus have failed to fulfill hopes for better treatments. Findings presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 29 through June 2 in Orlando, indicate that in most cases, the current standards of care should remain the treatments of choice. However, one potentially practice-changing trial suggested that many patients with advanced colorectal cancer can forgo standard surgery and receive chemotherapy as first-line care.

“These large, conclusive trials tell us what works, and importantly, tell us what doesn't work,” said Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center in Wilmington, Del, who was not involved in any of the studies.

A retrospective study questioned surgery as the standard of care for certain types of colorectal cancer. The trial found that many patients with metastatic, stage 4 colorectal cancer can do without surgery and be treated up front with chemotherapy instead.

In the study, researchers from Memorial Sloan-Kettering Cancer Center in New York City found that 217 of the 233 participants (93%) did not have complications that required removal of the primary tumor. Only 16 patients required colon surgery for symptom management. The patients in the trial received 1 of 3 triple-drug chemotherapy combinations (the regimens known as FOLFOX [folinic acid, fluorouracil, and oxaliplatin], IFL [irinotecan, leucovorin, and fluorouracil], and FOLFIRI [irinotecan, leucovorin, and fluorouracil]) as their initial treatment. Some were also treated with the monoclonal antibody bevacizumab.

Surgery has been the recommended initial treatment of stage 4 colorectal cancer because until recently, most cases did not respond to chemotherapy. However, advances in drug development have produced additional options for patients with this disease.

“We know that surgery for the colon tumor is of uncertain benefit,” said senior author Philip Paty, MD, vice chairman of clinical research at Memorial Sloan-Kettering Cancer Center. He added that in some cases, it is an unnecessary procedure that carries risks of morbidity and mortality, and in some cases may make the patient less fit for chemotherapy. “We believe a nonsurgical approach should be regarded as the standard of care for this patient population,” he said. However, surgery is needed for patients with stage 4 colorectal cancer with symptoms due to tumor obstruction.

Two trials indicate that adding potentially promising drugs to standard therapies for colon and rectal cancers does not provide further benefits to patients.

Source: American Cancer Society

A phase 3 study led by Norman Wolmark, MD, of the Allegheny General Hospital in Pittsburgh, tested the use of bevacizumab as an adjuvant treatment for stage 2 or 3 colon cancer. The antibody, which targets the vascular endothelial growth factor receptor, is currently approved for metastatic colorectal, breast, and lung cancers.

The NSABPC-08 trial, which is part of the National Surgical Adjuvant Breast and Bowel Project, included 2710 patients whose tumors had been surgically removed. Patients were randomly assigned to receive 6 months of standard adjuvant chemotherapy or 6 months of adjuvant chemotherapy combined with bevacizumab plus an additional 6 months of bevacizumab after the chemotherapy ended. After a median follow-up of 3 years, the disease-free survival rate was 77.4% among patients in the bevacizumab group compared with 75.5% among patients in the control group, a difference that was not statistically significant. Interestingly, however, during the year in which patients received bevacizumab, the investigators observed a benefit in disease-free survival that subsequently diminished when follow-up was completed.

“During the 1 year that bevacizumab was given, we had a robust effect, but once the bevacizumab was stopped, that effect disappeared. So clearly, strong consideration should be given to clinical trials that use bevacizumab for periods of time well beyond 1 year,” said Wolmark. He added that it will also be important to study how to use bevacizumab most effectively.

Another phase 3 study, the Studio Terapia Adjuvante Retto (STAR) 01 trial, examined the addition of oxaliplatin (a platinum-based chemotherapy drug that cross-links DNA) to standard treatment for locally advanced rectal cancer prior to surgery. The trial revealed that oxaliplatin therapy does not improve tumor shrinkage, but preliminary data suggest that it may reduce the number of distant metastases.

The study, conducted in Italy, included 747 patients who were randomized to receive standard preoperative fluorouracil-based chemoradiotherapy or the standard treatment plus oxaliplatin. The investigators found no significant difference in tumor reduction between the 2 groups: 16% of patients in both groups had no tumor present at the time of surgery, and 29% in the oxaliplatin group had mildly invasive tumors without nodal involvement compared with 30% in the control group. An unplanned analysis revealed that only 0.5% of patients in the oxaliplatin group had distant metastases when the primary tumor was removed compared with 3% in the control group. The investigators noted that longer follow-up is needed to assess whether oxaliplatin affects tumor recurrence rates or survival.

The largest study to date on anal cancer supported the current standard. The ACT II phase 3 trial found that a continuous radiation therapy delivery program combined with the antimetabolite fluorouracil and the antibiotic mitomycin C remains the best treatment option for patients with anal cancer. The trial also found that cisplatin chemotherapy is not superior to mitomycin C. (Both agents inhibit DNA replication and transcription by cross-linking DNA, among other effects.) The study also showed no benefit to adding maintenance chemotherapy to the standard of care.

Researchers at the National Cancer Research Institute in the United Kingdom randomized 940 patients to receive radiation therapy given at the same time as fluorouracil with either mitomycin C or cisplatin. Patients were also randomized to receive follow-up maintenance therapy with cisplatin and fluorouracil after chemoradiation or no maintenance therapy.

After a median follow-up of 3 years, there was no significant difference in outcome in the mitomycin C and cisplatin groups. The complete response rate at 6 months was 94% in the former group and 95% in the latter group. Recurrence-free survival at 3 years was 75% both in patients who received maintenance therapy and in those who did not. Overall survival at 3 years was 85% in patients who received maintenance therapy and 84% in those who did not.

While patients with anal cancer will not have access to additional treatment options as a result of these trial results, the investigators were encouraged by the high response rates. “These findings are good news in spite of the lack of evidence for an improvement in giving either cisplatin or maintenance therapy, since the standard chemoradiation schedule given in this trial was highly effective,” said lead author Roger James, MD, FRCP, FRCR, a radiation oncologist at Maidstone Hospital in Kent, England.