Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.
Drs. Grothey and Marshall have provided an excellent review of the latest developments in palliative treatment of patients with metastatic colorectal cancer (mCRC) and associated issues. Although widely metastatic disease remains incurable, outcome for mCRC patients has improved dramatically with new agents such as oxaliplatin (Eloxatin), irinotecan (Camptosar), capecitabine (Xeloda), bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix). Medical oncologists treating mCRC are increasingly challenged with the task of integrating these drug regimens into clinical practice to provide the optimal care for their patients.
Choosing a Regimen
In a palliative setting, the question of whether to begin with irinotecan-based regimens or oxaliplatin-based combinations is frequently raised. The authors seem to recommend oxaliplatin-based first-line therapy, likely on the basis of the N9741 study in which FOLFOX (infusional fluorouracil [5-FU], leucovorin, oxaliplatin) outperformed IFL (bolus irinotecan, 5-FU, leucovorin) as well as several adjuvant trials. However, the bolus vs infusional 5-FU schedules in N9741, and limited availability of second-line therapy for subjects in the IFL arm, limit the interpretation of this finding.
Our own view is that there are no major differences in outcome whether one starts with oxaliplatin-based or irinotecan-based chemotherapy for mCRC. This is borne out by several randomized trials including a randomized phase III trial in the first-line setting and a sequencing study in which survival for patients who received FOLFIRI followed by FOLFOX was similar to those receiving the regimens in reverse sequence. "Stop-and-go" strategies have also been successfully explored with both regimens, as the authors note.
We agree with Drs. Grothey and Marshall that the choice of chemotherapy regimen in mCRC depends on the treatment goal for each patient. Surgery, be it resection of the primary cancer or metastectomy, remains the only modality for cure in colorectal cancer. The unfortunate patients with unresectable disease should receive optimal palliative therapy that provides the best prolongation of survival with the fewest side effects.
What about patients with mCRCtypically liver- and/or lung-confinedthat may be resectable if shrinkage is obtained? In this subset of patients, the goals of therapy may change depending on response to chemotherapy. These patients should be identified early, discussed in a multidisciplinary fashion, and treated aggressively with appropriate neo-adjuvant chemotherapy.
Neoadjuvant Therapy for Initially Unresectable mCRC
Tumor response rate has nearly tripled over the past decade with contemporary colorectal chemotherapy (see Table 1). In addition, tumor shrinkage has been correlated with successful liver metastectomy in a retrospective analysis of published trials, and can help in selecting the optimal neoadjuvant regimen(s) in mCRC patients with potentially resectable metastases.
Extensive experience with neoadjuvant chemotherapy has been reported in a cohort study of 701 patients with initially unresectable colorectal liver metastases who received chronomodulated intravenous 5-FU, leucovorin, and oxaliplatin.[4-6] The criteria for resectability were not predefined; patients were considered unresectable if their liver lesions were large, multinodular, or "ill located," or if the patients had extrahepatic disease. A total of 95 patients (13.5%) became resectable on reevaluation and underwent liver metastatectomy with curative intent. Approximately 35% of patients who had curative resection were alive at 5 years, and about half developed recurrence later. Survival was better in patients with "large" liver metastasis, followed by "ill location," multinodular disease, and extrahepatic disease, with 5-year survival rates of 60%, 49%, 34%, and 18%, respectively.
The efficacy of systemic chemotherapy in downstaging patients' colorectal metastases to allow successful resection was investigated in a secondary analysis of the phase III Intergroup N9741 trial.[7,8] The study randomized 795 mCRC patients to received IFL, FOLFOX, or IROX (irinotecan/oxaliplatin). It is important to note that this trial was not designed to evaluate the efficacy of these regimens as neoadjuvant therapy. The authors identified 450 mCRC patients who may have potentially benefited from resection of mestastases and reported successful secondary metastatectomy in 24 (5%). Twenty (92%) of the resected patients received oxaliplatin-based therapy. The median survival was about 42.4 months for resected patients, compared to about 20 months in unresected patients.
Prospective Trials Supporting Use of Neoadjuvant Chemotherapy
A number of small prospective trials have been initiated to evaluate the role of neoadjuvant chemotherapy in patients with initially unresectable colorectal metastases (see Table 2). Wein et al examined the efficacy of preoperative high-dose infusional 5-FU and leucovorin in 53 patients with primary unresectable CRC metastases. Twenty-two patients (41%) had responsive disease (complete plus partial responses) and six patients (11%) underwent curative resection of the metastases. Median survival of all patients was 17 months, which was comparable to historical data, and 4 of 6 resected patients (8%) were disease-free at 3 years.
Albeit hotly debated, oxaliplatin-containing regimens may be slightly more active than others in shrinking colorectal metastases for patients with metastectomy as a treatment goal. Alberts et al reported a phase II trial conducted by the North Central Cancer Treatment Group, in which 42 patients with unresectable liver-only colorectal metastases received FOLFOX4. Twenty-five patients (60%) had tumor shrinkage and 17 (40%) underwent resection after a median of 6 months of chemotherapy. Median survival was 26 months, and 11 had recurrence at median follow-up of 22 months.
Pozzo et al reported a phase II trial evaluating the efficacy of a neoadjuvant irinotecan-containing regimen in 40 mCRC patients with initially unresectable liver metastases. Resectability of the liver disease was determined by tumor location, number, size, postoperative liver reserve, and presence of extrahepatic disease. Nineteen patients (48%) responded and 13 (32.5%) underwent curative-intent metastatectomy following chemotherapy. All patients were alive at a median follow-up of 19 months, and median time to progression was 14.3 months.
The combination of irinotecan and oxaliplatin together with 5-FU/leucovorin has also been investigated. Twenty-three (72%) of 32 mCRC patients achieved tumor response with palliative FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan) in a phase II trial. A separate analysis of all 74 patients treated with the regimen at the institution was performed. In this secondary analysis, 53 patients (72%) achieved an objective response. Of these 53 patients, 30 (41%) had sufficient tumor shrinkage to be considered for secondary metastatectomy. Eventually, 25% of the patients underwent surgical resection. Median survival was 36.8 months, compared to 22.2 months in the other 34 chemotherapy-responsive patients who did not have resection.
Two prospective trials are in progress to evaluate the efficacy of this combination in a neoadjuvant approach.[14,15] Interim results were reported in abstract form, and over half of the patients with initially unresectable disease were rendered resectable following therapy. Survival of patients who had secondary metastectomy after receiving the regimen remains unknown.
Impact of Neoadjuvant Therapy on Postsurgical Outcome
Resectability of colorectal liver metastases seems to have improved with the introduction of increasingly active regimens. However, there is also an increasing wariness about the safety of neoadjuvant combination chemotherapy. Liver injury, including steatosis, steatohepatitis, and vascular damage, has been found in patients treated with mCRC chemotherapy regimens.[16,17] However, the impact of neoadjuvant chemotherapy on postoperative liver function and survival rates remains unknown. Vauthey et al performed a retrospective analysis of 406 patients with colorectal liver metastases who underwent surgical resection after preoperative chemotherapy. They reported increased 90-day postoperative mortality in patients who developed steatohepatitis compared to those without.
In contrast, subanalysis of the prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) Intergroup 40983 trial reported that neoadjuvant FOLFOX4 significantly increased the risk of liver damage but had no substantial impact on surgical complication. The EORTC trial randomized 364 patients with potentially resectable CRC liver metastases to receive perioperative FOLFOX and surgery, or surgery alone. Separately, Verghese et al reported no clinically significant deleterious effects of preoperative FOLFOX on liver function and surgical outcome in patients with resected colorectal liver metastases.
The postsurgical morbidity may be more related to the amount of neoadjuvant chemotherapy mCRC patients receive than the type of regimen. Karoui et al reported increased postoperative morbidity and liver injury following prolonged preoperative chemotherapy in patients with hepatic colorectal metastases. The preoperative chemotherapy did not increase operative mortality in this series. Aloia et al similarly reported increased hepatic vascular damage with FOLFOX, and the risk of postoperative morbidity was related to the duration of neoadjuvant chemotherapy.
New possibilities and challenges arise with the continual introduction of more efficacious chemotherapeutic agents in mCRC. Cure is increasingly possible for a subset of patients with initially unresectable metastatic disease treated with preoperative chemotherapy. Admittedly, neoadjuvant colorectal cancer therapy is still in its early phase of development. Several ongoing prospective phase II/III trials will help select the optimal regimen(s) for further testing. At the same time, the potential adverse impact of these agents on postsurgical outcome needs to be studied carefully.
Wen W. Ma, MD
Wells A. Messersmith, MD
Dr. Messersmith has received research support from Amgen.
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