Colorectal Cancer in the Spotlight at GI Cancers Symposium

Four studies presented at a media telebriefing prior to the Gastrointestinal Cancers Symposium 2015 highlighted key findings in colorectal cancer. The findings will be presented January 15-17, 2015, in San Francisco.

The studies were culled from more than 800 abstracts that will be viewed by 3,200 specialists and surgical, medical and radiation specialists from around the world.

Survival Advantage Shown for Ramucirumab Plus Chemotherapy in Second-Line CRC Treatment

The phase 3 international RAISE trial (Abstract 512) found that ramucirumab extends survival when given with chemotherapy to metastatic colorectal cancer patients who progress on treatment.

The RAISE study randomized 1,072 patients who progressed after first-line therapy to treatment with FOLFIRI (leucovorin, fluorouracil, irinotecan) plus ramucirumab or placebo. Response rates were similar between the two arms—13.4% with ramucirumab; 12.5% with placebo—but ramucirumab significantly improved both progression-free and overall survival.

Median time to disease progression in patients receiving ramucirumab plus FOLFIRI was 5.7 months compared with 4.5 months in the placebo arm (HR=0.79; P=0.0005). Median overall survival was 13.3 months and 11.7 months (HR=0.84; P=0.0219), respectively.

The regimen was well tolerated, though the addition of ramucirumab increased the incidence of Grade 3-4 neutropenia, fatigue, diarrhea, and hypertension.

“Though the rate of neutropenia was higher, the rate of febrile neutropenia, the clinically significant toxicity, was similar, 3.6% versus 2.7% in the placebo arm,” said Josep Tabernero, MD, Vall d’Hebron Institute of Oncology in Barcelona, Spain. According to Dr. Tabernero the adverse events were manageable.

The study validates angiogenesis as an important target in colorectal cancer. Other angiogenesis inhibitors approved in this malignancy include bevacizumab, ziv-aflibercept, and regorafenib.

Dr. Tabernero pointed out that the study population was representative of patients seen in everyday practice. He cautioned, however, that the findings should not be extrapolated to other regimens used in colorectal cancer. Ramucirumab is currently FDA-approved in gastric and non-small lung cancer.

Commenting on the study, moderator Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, acknowledged that improvements in 1 to 2 months in progression-free and overall survival appear modest. However, she said, “We want to offer patients all we can, because these agents [biologics] tend to be well tolerated and they can be combined with chemotherapy.”

Bevacizumab Works Best Combined with Intensive Chemotherapy

Updated results from the phase 3 TRIBE study (Abstract 657) conducted in Italy indicate that bevacizumab is more effective in metastatic colorectal cancer when combined with the FOLFOXIRI regimen than FOLFIRI. FOLFOXIRI plus bevacizumab extended overall survival by 4 months and doubled the 5-year survival rate over the control arm, reported Chiara Cremolini, MD, of the Tuscan Tumor Institute in Pisa.

In the U.S., FOLFOX (leucovorin, fluorouracil, oxaliplatin) and FOLFIRI (leucovorin, fluorouracil, irinotecan) are more commonly used than FOLFOXIRI, which adds oxaliplatin to the FOLFIRI regimen.

The study evaluated 508 patients randomized to bevacizumab plus either FOLFOXIRI or FOLFIRI for 6 months, after which they received maintenance bevacizumab with 5-FU/leucovorin. After a median follow-up of about 4 years, median overall survival was 29.8 months in the FOLFOXIRI arm versus 25.8 months in the FOLFIRI arm (HR=0.80; P=0.030).

“Looking at the final part of the shape of the survival curves, we see that the benefit of FOLFOXIRI plus bevacizumab increases over time, and the estimated 5-year survival is 24.9% versus 12.4%, which is double to that of FOLFIRI plus bevacizumab…Based on these results, FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer,” Dr. Cremolini concluded.

The study found a higher incidence of Grade 3-4 diarrhea, mucositis, neuropathy, and neutropenia, with the FOLFOXIRI regimen, but no increase in febrile neutropenia and or serious adverse events of treatment-related deaths. The incidence of severe neuropathy, which is a concern with oxaliplatin, was only 5%. 

Dr. Cremolini acknowledged that the regimen, which tends to be more difficult and leads to more dose reductions and delays, “is not a regimen for every patient.” In her opinion, it is probably not suitable for patients older than age 75 or younger patients with poor performance status.

Dr. Krishnamurthi indicated that in the U.S, the “uptake was not high, when the data first came out, because we are already combining chemotherapy with bevacizumab,” however, with more evidence of efficacy and safety, she predicted, “I think we will see more use of FOLFOXIRI with bevacizumab.”

High Vitamin D Associated with Improved Survival

Newly diagnosed colorectal cancer patients with high vitamin D levels prior to treatment live longer than those with the lowest levels, according to a prospective analysis of data from a phase 3 study (Abstract 507).

The study adds to a growing body of evidence that vitamin D has an anti-tumor effect. Randomized studies are now underway to confirm the benefit of vitamin D supplementation before and after a cancer diagnosis, said Kimmie Ng, MD, MPD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“The ultimate goal is to translate this research into an effective intervention for patients,” she said.

Dr. Ng and colleagues measured the serum levels of vitamin D (25-hydroxyvitamin D) in 1,043 patients enrolling in CALGB 80405, the phase 3 trial evaluating three different first-line treatments for advanced colorectal cancer. Patients’ vitamin D levels ranged from a mean low of 8 ng/mL to a mean high of 27.5 ng/mL. The average for all patients was 17.2 ng/mL, which is below the recommended healthy range of 20 to 30 ng/mL. Few patients report taking vitamin D supplements.

Divided into quintiles according to their baseline level, and being adjusted for other prognostic factors for survival as well as healthy behaviors, patients with the highest levels of vitamin D had a median overall survival of 32.6 months, compared with 24.5 months for those in the lowest quintile (HR=0.67; P=0.002).

Higher vitamin D levels were also associated with longer time to disease progression, 12.2 months vs. 10.1 months (HR=0.80; P=0.02). The benefit was seen across the three treatment arms and did not differ by KRAS status, nor was benefit ameliorated when other prognostic factors were adjusted for.

Despite the encouraging results, Dr. Ng said it is premature to recommend vitamin D as a treatment for colorectal cancer. She noted that the findings do not indicate that raising a low baseline vitamin D level will improve outcomes, only that baseline levels were associated with different outcomes.

“Watch and Wait” is Acceptable for Some Rectal Cancer Patients

Some rectal cancer patients who achieve a complete response to neoadjuvant chemoradiation may not need surgery, according to a retrospective review of data on 145 patients with stage I-III rectal cancer.

Philip Paty, MD, of Memorial Sloan Kettering Cancer Center, New York, said the results should “encourage more doctors to consider a ‘watch and wait’ approach in patients with clinical complete response as an alternative to immediate rectal surgery, at least for some patients.”

Avoidance of surgery would allow patients to preserve rectal function, which is very important to patients, he explained. “Most patients who qualify for this approach are very interested in it,” he said.

The study was a retrospective look at 73 patients who achieved a clinical complete response after neoadjuvant chemoradiation and were treated with a non-operative management approach (with frequent monitoring, every 3 months for the first 1.5 years). Their outcomes were compared with those of 72 patients who achieved a pathologic complete response (pCR) and underwent resection.

Of the 73 patients who were observed, 74% achieved a durable and sustained clinical response and no surgical intervention was required.  Nineteen patients (19%), however, had local regrowth of tumor, and all had successful salvage surgery.

Altogether, 98% of patients achieved local control (one patient had a recurrence after resection of the tumor regrowth), and 77% had rectal preservation. The disease-specific and overall survival rates were similar between the two groups, suggesting that the nonoperative approach for these patients did not compromise outcomes.

“We set the bar very high, and found that nonoperative management appears to compare favorably,” said Dr. Paty.

He acknowledged that “practicing ‘watch and wait’ can be difficult for surgeons” but this approach is being increasingly accepted.

“Centers are adopting it, and many leaders in clinical trials of rectal cancer recognize that this option is not only reasonable, but perhaps it is necessary to inform patients that it is an option,” he said.

Complete responses are typically observed in up to 50% of patients with stage I disease and 30% to 40% with stage II-III tumors, making these patients candidates for nonoperative management.

Dr. Krishnamurthi indicated she would feel better about observing these patients once the investigators can report longer follow-up.

By Caroline Helwick

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