Palliation of Colorectal Cancer: New Possibilities and Challenges

April 30, 2007

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[1] 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.[2] "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 mCRC—typically liver- and/or lung-confined—that 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.[3]

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.[9] 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.[10] 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.[11] 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.[12] A separate analysis of all 74 patients treated with the regimen at the institution was performed.[13] 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.[18]

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.[19] 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.[20]

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.[21] 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.[22]

Conclusions

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

Disclosures:

Dr. Messersmith has received research support from Amgen.

References:

1. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866-4875, 2005.

2. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-2237, 2004.

3. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005.

4. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509-522 (incl discussion), 1996.

5. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999.

6. Adam R: Chemotherapy and surgery: New perspectives on the treatment of unresectable liver metastases. Ann Oncol 14(suppl 2):ii13-16, 2003.

7. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004.

8. Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 16:425-429, 2005.

9. Wein A, Riedel C, Kockerling F, et al: Impact of surgery on survival in palliative patients with metastatic colorectal cancer after first line treatment with weekly 24-hour infusion of high-dose 5-fluorouracil and folinic acid. Ann Oncol 12:1721-1727, 2001.

10. Alberts SR, Horvath WL, Sternfeld WC, et al: Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 23:9243-9249, 2005.

11. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004.

12. Masi G, Allegrini G, Cupini S, et al: First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): Results of a phase II study with a simplified biweekly schedule. Ann Oncol 15:1766-1772, 2004.

13. Masi G, Cupini S, Marcucci L, et al: Treatment with 5-fluorouracil/folinic acid, oxaliplatin, and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 13:58-65, 2006.

14. Quenet F, Nordlinger B, Rivoire M, et al: Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) after chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial (abstract 3613). J Clin Oncol 22(14S):273, 2004.

15. De La Camara J, Rodriguez J, Rotellar F, et al: Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer (abstract 3593). J Clin Oncol 22(14S), 2004.

16. Kooby DA, Fong Y, Suriawinata A, et al: Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 7:1034-1044, 2003.

17. Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004.

18. Vauthey JN, Pawlik TM, Ribero D, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065-2072, 2006.

19. Julie C, Lutz M, Aust D, et al: Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: Results of the EORTC Intergroup phase III study 40983 (abstract 241). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007.

20. Verghese M, Pathak S, Haqqani M, et al: Safety of neoadjuvant oxaliplatin-based chemotherapy (N-FOLFOX) in patients undergoing resection of colorectal liver metastases (R-CLM): Interim results (abstract 290). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007.

21. Karoui M, Penna C, Amin-Hashem M, et al: Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006.

22. Aloia T, Sebagh M, Plasse M, et al: Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 24:4983-4990, 2006.

23. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol 16:301-308, 1998.

24. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000.

25. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.

26. Souglakos J, Androulakis N, Syrigos K, et al: FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 94:798-805, 2006.

27. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.

28. Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004.

29. Feliu J, Salud A, Escudero P, et al: XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer. Br J Cancer 94:969-975, 2006.

30. Hochster HS, Hart LL, Ramakrishnan RK, et al: Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-study (abstract 3510). J Clin Oncol 24(18S):148s, 2006.

31. Gaspar EM, Artigas V, Montserrat E, et al: Single centre study of L-OHP/5-FU/LV before liver surgery in patients with NOT optimally resectable colorectal cancer isolated liver metastases (abstract 1416). Proc Am Soc Clin Oncol 22:353, 2003.

32. Alberts SR, Donohue JH, Mahoney MR, et al: Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited to the liver: A North Central Cancer Treatment Group (NCCTG) phase II study (abstract 1053). Proc Am Soc Clin Oncol 22:263, 2003.

33. Aderka D, Wolf I, Shmueli E, et al: Neoadjuvant bevacizumab (BV)-FOLFIRI regimen for hepatic colorectal (CRC) metastases: Safe and effective and with a better pathological response of metastases in males versus females (abstract 360). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007.