Two phase III studies presented at the Best of ASCO meeting in Chicago shed more light on the role of maintenance therapy in patients with metastatic colorectal cancer undergoing first-line treatment with oxaliplatin-based chemotherapy. The two studies compared maintenance therapy with bevacizumab (Avastin) alone or combined with a fluoropyrimidine to observation. Maintenance therapy delayed progression compared to observation, without significantly altering overall survival (neither study was powered to detect a difference in overall survival).

“In a lot of modern chemotherapy regimen trials, there is this trend for people going off first-line therapy for reasons other than progressive disease,” noted Emily K. Bergsland, MD, a gastrointestinal oncologist at the Helen Diller Family Comprehensive Cancer Center and Professor of Clinical Medicine at the University of California, San Francisco. “So there is this feeling that patients would like and value breaks from therapy. We certainly could imagine that breaks from therapy might be associated with decreased toxicity, decreased time on treatment, which might translate to improved quality of life, more convenience for the patient, less time in the doctor’s office, and certainly decreased drug costs,” Dr. Bergsland said. “We don’t know the precise risks of going off therapy and having a complete treatment break. What are the risks of de-escalating therapy?” 

Delayed Progression Without a Clear Impact Overall Survival

“Data from the last several years have suggested that [in the metastatic colorectal cancer setting] a fluoropyrimidine plus bevacizumab (Avastin) is superior to bevacizumab alone or no therapy, but it has been controversial as to what the optimal maintenance is,” Dr. Bergsland stated.

In the AIO KRK 0207 noninferiority study,¹ investigators from Germany considered a fluoropyrimidine/bevacizumab as standard maintenance therapy and then assessed whether bevacizumab alone or observation would be inferior as maintenance therapy for patients with metastatic colorectal cancer. Study patients had received induction therapy with a fluoropyrimidine, oxaliplatin, and bevacizumab and had no disease progression at 6 months. The primary endpoint was time to failure of strategy. While results showed that bevacizumab was noninferior to maintenance therapy with a fluoropyrimidine plus bevacizumab, investigators could not say the same for observation, Dr. Bergsland said.

Time to first progression was 6.2 months with combination maintenance therapy, 4.8 in the bevacizumab-alone group, and 3.8 months with observation (P < .001 for observation vs bevacizumab or combination therapy). “Both of the maintenance strategies were superior to observation alone, and there did appear to be a trend toward improved disease-free survival with the more intensive therapy,” Dr. Bergsland stated.

“There was no obvious difference, though, in overall survival,” she continued. “That is important to point out,” she said, although overall survival was not the primary study endpoint. Preliminary overall survival was 23.8 months for combination maintenance, 26.2 with bevacizumab alone, and 23.1 with observation.

Capecitabine/Bevacizumab Maintenance

The CAIRO3 study² compared maintenance with capecitabine and bevacizumab vs observation in 558 patients with metastatic colorectal cancer that had not progressed after six cycles (about 4 months) of treatment with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). At first progression, CAPOX-B was reintroduced to 61% of patients in the observation arm and 47% in the treatment arm. (Patients who did not want to go back on CAPOX-B could receive another treatment.)

The primary endpoint of the trial was second progression, which was considered equal to first progression in patients not having CAPOX-B reintroduced after first progression for any reason. “There was statistically significant improvement with combination therapy,” Dr. Bergsland said. Capecitabine/bevacizumab “is superior to observation, 11.7 months vs 8.5. Similarly, statistically significant improvements in time to second progression” occurred regardless of the therapy patients received after their first progression, 13.9 months with combination therapy vs 11.1 months with observation (P < .001). First progression was 8.5 months with capecitabine/bevacizumab vs 4.1 months with observation (P < .001).

“There was no (significant) improvement in overall survival, however, whether looked at it from time from randomization or when they started induction for chemotherapy,” Dr. Bergsland added. Overall survival from time of randomization was 21.6 months with maintenance therapy vs 18.1 months for observation, and from induction was 25.9 months for those who received maintenance vs 22.4 months for those who did not. The study was not powered to detect differences in overall survival.

“In a subgroup analysis, it looked like patients with synchronous disease and resected primary tumors, as well as people with complete or partial response on induction therapy are the ones who seemed to benefit the most from maintenance therapy,” Dr. Bergsland said. Quality of life also seemed to be preserved.

Optimal Timing of Breaks Is Unclear

“These two studies suggest that the fluoropyrimidine delays progression compared to observation, without a major impact on survival, recognizing the caveats of this not being the primary endpoint of the study. I would say that the role of bevacizumab alone continues to be controversial,” Dr. Bergsland noted. “Once on maintenance therapy, patients don’t necessarily restart their induction therapy at progression. That is also important. In considering a planned maintenance strategy in which you are going to stop induction treatment, you need to think about whether you got the most out of that therapy,” she said, particularly in patients who might be reluctant to restart the induction regimen at a later date.

“It does appear that if you are looking for delayed progression and you want to give some sort of maintenance therapy, the strongest data support a fluoropyrimidine/bevacizumab regimen, but we have trouble at this point assessing the impact of these breaks on overall survival. The optimal timing is unclear, whether it should be a planned break after 4 or 6 months or we should treat to maximum response. We don’t know if a fluoropyrimidine alone would be okay or if we really need the bevacizumab,” Dr. Bergsland said. There are also issues of toxicity and drug costs to consider.

“We know that on an individual basis, drug-free intervals are often really valued. I think future strategies will be focused on identifying biomarkers to help us select which patients stand to benefit from maintenance therapy and which ones don’t,” she commented.

Utility of Mismatch Repair Status

A pooled analysis of data from 17 adjuvant trials in the ACCENT database involving 7,803 patients with stage II/III colorectal cancer found that mismatch repair status is a prognostic marker in untreated stage II/III disease, with a stronger effect in stage II.³ The study does not change the standard of care, Dr. Bergsland said, “but confirms prior recommendations that patients with stage II colon cancer and [deficient mismatch repair] do not require adjuvant therapy and that [mismatch repair] status should not guide therapy in stage III disease.”

Among patients with stage II disease treated with surgery alone, 5-year recurrence-free rates were higher among patients with deficient mismatch repair, 89% vs 74% for those with preserved mismatch repair, as were 5-year overall survival rates, 90% vs 78%. These findings confirm prior recommendations that patients with stage II colon cancer and deficient mismatch repair do not require adjuvant therapy, Dr. Bergsland said. These patients “should not receive fluorouracil [5-FU] due to excellent prognosis.” She added that treatment of high-risk stage II colorectal cancer remains controversial.

Among patients with stage III disease who have been treated with 5-FU, 5-year overall survival “favors people with defective mismatch repair,” Dr. Bergsland said—77% for patients with deficient mismatch repair vs 71% for patients with preserved mismatch repair. “This is actually one of the most interesting things about this abstract,” she said, “because it suggests that there isn’t a negative reaction between mismatch repair and 5-FU, at least in these patients. In fact, these patients do a little bit better than people with preserved mismatch repair.”

Patients with stage III tumors and deficient mismatch repair “likely still benefit from 5-FU, and may benefit from the addition of oxaliplatin” (reported at the ASCO Annual Meeting by Tougeron, et al⁴). The favorable prognosis of deficient mismatch repair stage III patients treated with 5-FU means that mismatch repair “should not guide therapy in these patients,” Dr. Bergsland stated.

The 17 studies used microsatellite instability, immunohistochemical analysis for MLH1/MSH2/MLH6, or both processes to determine mismatch repair status. Tumors with microsatellite instability–high or an absent protein were classified as deficient mismatch repair; the remainder were mismatch repair–proficient, the investigators explained.³

Patients classified as deficient mismatch repair included 23.1% of stage II and 14.9% of stage III patients and were more likely to be female (19% vs 14% males), have higher T stage, and right-side tumor location (left 9% vs right 27%). Patients in the trials had been treated with surgery alone (571), 5-FU monotherapy (3,878), 5-FU plus oxaliplatin (2,299), or 5-FU plus irinotecan (1,055).

Locally Advanced Rectal Cancer

Adding oxaliplatin as a radiosensitizer to 5-FU–based neoadjuvant chemoradiotherapy and as part of systemic adjuvant chemotherapy significantly improved disease-free survival for patients with locally advanced rectal cancer, according to results from the phase III CAO/ARO/AIO-04 study from Germany.⁵ The increase in disease-free survival, however, “did not translate into a significant increase in overall survival,” Dr. Bergsland stated (overall survival was a secondary endpoint). Overall survival at 3 years was 75.9% for those receiving oxaliplatin vs 71.2% for those who did not, and at 5 years, 68.8% vs 64.3%. An improved pathologic complete response rate among patients who received oxaliplatin (17% vs 13%, P = .038) did not translate into more sphincter-sparing procedures. 

The goal of the trial was to integrate more effective systemic treatment following the CAO/ARO/AIO-94, which, the investigators stated, established preoperative chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy with 5-FU as standard treatment for locally advanced rectal cancer.

For the CAO/ARO/AIO-04 trial, patients with clinical T3/4 or clinical node-positive rectal cancer were randomly assigned to arm 1 (n = 637) and received either preoperative 50.4 Gy plus infusional 5-FU at 1 g/m² on days 1 to 5 and 29 to 33, followed by total mesorectal excision and four cycles of bolus 5-FU 500 mg/m² for 5 days) or to arm 2 (n = 628) and received preoperative 50.4 Gy plus infusional 5-FU at 250 mg/m² days 1 to 14 and 22 to 35, oxaliplatin at 50 mg/m² on days 1, 8, 22, and 29, followed by total mesorectal excision and eight cycles of adjuvant oxaliplatin at 100 mg/m² on day 1, leucovorin at 400 mg/m² on day 1, and infusional 5-FU at 2,400 mg/m² on days 1 to 2.

At a median follow-up of 50 months, 198 patients in arm 1 had a disease-free survival–related event, as compared with 159 patients in arm 2. Disease-free survival at 3 years was 71.2% in arm 1 vs 75.9% in arm 2. Grade 3/4 late overall treatment-related toxicity occurred in 23% of patients in arm 1 and 26% in arm 2. Among patients receiving oxaliplatin, 7% experienced grade 3/4 sensory neuropathy during treatment, but this decreased to 3% at 1 year of follow-up.

Other trials of oxaliplatin-based adjuvant/neoadjuvant therapy for rectal cancer have shown inconsistent results, and “the evidence does not support use of oxaliplatin as a radiosensitizer in the setting of neoadjuvant chemotherapy,” according to Dr. Bergsland. “I don’t think this will change the standard of care that much,” Dr. Bergsland said. The addition of oxaliplatin to a fluoropyrimidine may be beneficial in the adjuvant setting, and “additional tools are needed to determine which patients are most likely to benefit from oxaliplatin-based chemotherapy.”

First-Line Treatment for Metastatic Disease

An additional study reported at the Best of ASCO colorectal cancer session found that cetuximab (Erbitux) and bevacizumab produced comparable benefits when added to first-line treatment with chemotherapy for patients with metastatic colorectal cancer. Details of that study⁶ were reported in the June 25, 2014, issue of The ASCO Post. ■

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

References

1. Arnold D, Graeven U, Lerchenmuller A, et al: Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): A phase III non-inferiority trial (AIO KRK 0207). ASCO Annual Meeting. Abstract 3503. Presented June 2, 2104.

2. Koopman M, Simkens L, May AM, et al: Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC). ASCO Annual Meeting. Abstract 3504. Presented June 2, 2014.

3. Sargent DJ, Shi Q, Yothers G, et al: Prognostic impact of deficient mismatch repair (dMMR) in 7,803 colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. ASCO Annual Meeting. Abstract 3507. Presented June 2, 2014.

4. Tougeron D, Sickersen G, Lecomie T, et al: Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: An AGEO multicenter study. ASCO Annual Meeting. Abstract 3508. Presented June 2, 2014.

5. Rodel C, Liersch T, Fietkau R, et al: Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: Results of the German CAO/ARO/AIO-04 randomized phase III trial. ASCO Annual Meeting. Abstract 3500. Presented June 2, 2014.

6. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014.