Adjuvant Chemotherapy
To date, only a limited number of clinical trials have investigated the role of adjuvant chemotherapy following surgical resection of organ-limited metastases. Two randomized phase III trials were conducted to determine the potential role of adjuvant chemotherapy with 5-FU/ LV vs surgery alone.[58,59] Both trials showed a nonsignificant trend for improvement in DFS. Unfortunately, both studies closed prematurely due to slow patient enrollment. As a result, neither study had sufficient statistical power to demonstrate the predefined difference in OS. A pooled analysis of the individual data from these two trials was subsequently conducted by Mitry et al to improve the statistical power of the survival analysis. This analysis showed a marginally significant trend toward improved progression-free survival for patients receiving chemotherapy (27.9 vs 18.8 months).[60] This study is important as it provides proof of concept for the potential role of adjuvant chemotherapy in patients who have undergone curative resection of liver or lung metastatic disease. Unfortunately, a randomized phase III trial was unable to document the benefit of the FOLFIRI regimen as adjuvant therapy following surgical resection of liver metastases when compared with infusional 5-FU/LV.[61]
What should the recommendations be for adjuvant chemotherapy following surgical resection? Although definitive clinical data are lacking, the current approach would be to offer adjuvant therapy with an oxaliplatin(Drug information on oxaliplatin)-based regimen, whether it be FOLFOX or XELOX, for a defined 3- to 4-month period. As is the case for the adjuvant treatment of early-stage colon cancer, there is presently no role for a biologic agent, such as bevacizumab(Drug information on bevacizumab) or the anti-EGFR antibodies cetuximab(Drug information on cetuximab) and panitumumab, in oxaliplatin-based chemotherapy. Further support for this approach comes from the recently published NCCN clinical practice guidelines for adjuvant therapy of resected metastatic disease, which recommend a shortened course of cytotoxic chemotherapy, as would be offered for patients with resected stage III colon cancer. [47]
Limitations of Chemotherapy
Comparison of Survival of a Group of Patients With Colorectal Metastases to the Liver and a Second Group With Carcinomatosis
The role of chemotherapy is to enhance the outcomes of surgery and/or permit potentially curative resection to be performed. Unfortunately, chemotherapy has potential disadvantages, which relate to direct toxic effects on the liver, leading to an increased risk of potential postoperative complications. There is now a large body of evidence showing that systemic chemotherapy can result in nonalcoholic fatty liver disease and sinusoidal injury. The chemotherapy-associated liver disease ranges from steatosis to steatohepatitis (CASH).[62] Steatosis resulting from chemotherapy and/or any other etiology has been shown to lead to a higher rate of complications following hepatic resection. However, the development of CASH appears to hold greater significance.[63] Of note, CASH appears to be more closely associated with the use of irinotecan(Drug information on irinotecan)-based chemotherapy and to occur more commonly in patients with higher body mass index.[64] The development of CASH has been associated with a higher postoperative mortality rate related primarily to postoperative liver failure. In one series, the 90-day mortality rate in patients with steatohepatitis was 14.7% vs 1.6% for those who did not have steatohepatitis.[65] In contrast to treatment with irinotecan, oxaliplatin-based chemotherapy has been typically associated with liver sinusoidal injury.[62,65,66] In more severe cases, perisinusoidal fibrosis, sinusoidal obstruction, and portal hypertension have been observed. In contrast to CASH, the development of sinusoidal dilation has not been associated with an increased risk of perioperative morbidity and mortality.[67,68]
Peritoneal Carcinomatosis
While this review has focused on liver-limited metastatic disease, cures have also been reported after pulmonary metastasectomy, isolated nodal recurrences, and ovarian metastases.[69-71] While these are highly selected cases, they are worthy of consideration for patients with favorable tumor biology and/or for those who are responsive to chemotherapy. A growing field of interest has been the surgical management of peritoneal metastases from CRC, using cytoreductive surgery and intraoperative chemoperfusion with mitomycin(Drug information on mitomycin) C or oxaliplatin, combined with hyperthermia (HIPEC).[72,73] This interest stems from early randomized trials with this treatment strategy in gastric cancer and a randomized trial in mCRC from the Netherlands.[74,75] This mCRC carcinomatosis trial demonstrated an improvement in median survival in patients receiving intraoperative HIPEC, compared with systemic 5-FU/LV (22.3 months vs 12.6 months). Patients whose tumors could be completely resected from the peritoneum followed by HIPEC had an actuarial 3-year survival of 95%. A follow-up report on this trial demonstrated an overall actual 5-year survival of 45% in the HIPEC arm for patients with all disease resected.[76] A recent report from France noted a 5-year survival of 26% in patients receiving HIPEC with oxaliplatin for colorectal peritoneal carcinomatosis.[77] A number of series have compared surgical cytoreduction and HIPEC for peritoneal carcinomatosis vs surgical resection of hepatic metastases from mCRC, demonstrating similar survival curves (Figure 1).[78-80] This finding suggests that an aggressive combined-modality approach for peritoneal carcinomatosis may have a defined cure rate. Presently, most centers combine surgical cytoreduction and HIPEC with neoadjuvant and postoperative adjuvant systemic chemotherapy, such as has been described for liver-limited metastatic disease.
Therapeutic Agents
Mentioned in This Article
Bevacizumab (Avastin)
Capecitabine(Drug information on capecitabine) (Xeloda)
Cetuximab (Erbitux)
5-Fluorouracil (5-FU)
Irinotecan
Leucovorin (folinic acid)
Mitomycin C
Oxaliplatin (Eloxatin)
Panitumumab (Vectibix)
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
Conclusions
When limited to a specific organ site, mCRC is potentially curable. To date, nearly all of the clinical studies have focused on liver-limited disease, but similar results are now being reported for patients with disease limited to the lungs, ovaries, and peritoneum. It is clear that a multidisciplinary team-based approach is required for the optimal care of this particular subset of patients. The development of an individual treatment plan comes from a careful discussion and ongoing communication among a multidisciplinary team of specialists, including surgeons, medical oncologists, and radiologists. With the appropriate integration of chemotherapy plus biological agents and surgery, up to 30% to 40% of patients with organ-limited metastatic disease can be cured. While the costs of the three biological agents—cetuximab, panitumumab, and bevacizumab—are not insignificant, the clinical evidence is now well-established that their incorporation with cytotoxic chemotherapy regimens in the neoadjuvant and conversion settings has greatly facilitated curative resection of liver-limited metastatic disease. However, further improvements are needed to enhance the clinical outcome of the remaining 60% to 70% of patients. Further refinements in whole-body and hepatic imaging should provide for a more accurate selection of the subset of patients who would benefit most from resection and would identify the presence of minimal residual disease following surgery. Finally, clinical trials are needed to develop novel cytotoxic agents and biologic/targeted agents that can be used in both the preoperative and postoperative settings to reduce the risk of local and systemic recurrence.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
