Systemic Chemotherapy
Long-term cures are exceedingly rare when patients with organ-limited mCRC are treated with chemotherapy alone. In a retrospective review of 2751 patients with metastatic CRC, during a median follow-up of 10.3 years, only 6 (0.24%) were found to be free of disease after having received chemotherapy alone.[30] It is now well established that a multimodality strategy results in a much higher chance of long-term cure. In patients with organ-limited disease, chemotherapy is administered in three main settings, which include neoadjuvant therapy, conversion therapy, and adjuvant therapy. Neoadjuvant therapy refers to chemotherapy given to patients with potentially resectable disease, while conversion therapy refers to chemotherapy given to patients deemed to have initially unresectable disease. Adjuvant chemotherapy is use of chemotherapy following an R0 surgical resection, with the intent of preventing disease recurrence.
Neoadjuvant Chemotherapy
Up to 20% to 30% of patients with liver-limited mCRC may have potentially resectable disease at the time of initial presentation. However, because a large proportion of patients experience recurrence of their disease either in the liver or systemically, chemotherapy has been integrated in their up-front care to improve upon the potential benefit of surgery.
Several clinical trials have specifically evaluated the role of neoadjuvant therapy for patients with potentially resectable liver metastases. In a single-arm trial involving 20 patients, neoadjuvant therapy with a weekly administration of FOLFOX (fluorouracil [5-FU], leucovorin/folinic acid [LV], and oxaliplatin(Drug information on oxaliplatin) [Eloxatin]) resulted in a partial or complete response in all patients enrolled.[31] A total of 16 patients underwent a potentially curative resection, with 7 developing recurrence during the median follow-up period of 23 months. A phase II trial of neoadjuvant therapy investigated bevacizumab(Drug information on bevacizumab) (Avastin) plus CapOx, the combination of capecitabine(Drug information on capecitabine) (Xeloda) and oxaliplatin.[32] In this study, 56 patients received 6 cycles of therapy prior to surgical resection, and a remarkably high objective response rate of 73% was observed. A total of 52 of the 56 patients were able to undergo an R0 resection, with complete pathologic response occurring in nearly 10% of patients. Given concerns over the potential risks of bleeding or wound-healing complications, bevacizumab was not given with the last cycle of chemotherapy prior to surgery. This study is important as it showed that bevacizumab could be safely administered to patients with no increased risk of intraoperative bleeding or wound-healing complications. Moreover, it was estimated that normal liver regeneration occurred in all but one patient.
The European Organisation for Research and Treatment of Cancer (EORTC) randomized phase III trial 40983 investigated use of perioperative FOLFOX4 chemotherapy in patients with up to four resectable liver metastases. In this study, patients were randomized to surgery alone or to receive 6 cycles of FOLFOX4 before surgery and 6 cycles of FOLFOX4 after surgery.[33] The overall response rate was 43% in patients receiving chemotherapy. Of note, surgery was performed in 83% of patients randomized to chemotherapy and in 84% of patients randomized to surgery alone, providing evidence that use of initial chemotherapy did not compromise the ability of patients to undergo surgical resection. While there was an increased risk of postoperative complications in patients receiving neoadjuvant chemotherapy, these events were reversible and not associated with an increased risk of mortality. When the entire group of randomized patients was considered, a 7.3% increase in progression-free survival (PFS) at 3 years was observed in patients receiving chemotherapy, although this difference did not reach statistical significance. However, in the group of patients who underwent surgical resection, a significant 9.2% improvement in 3-year PFS was, in fact, observed.
Adam et al examined the influence of the response to neoadjuvant chemotherapy on the eventual outcome in patients following surgical resection of multiple liver metastases.[34] In this retrospective analysis of 131 patients, 44% underwent hepatectomy after achieving an objective tumor response, 30% went to surgical resection after tumor stabilization, and 26% were surgically resected after tumor progression. Five-year survival was significantly lower in the group of patients who had evidence of tumor progression, compared with patients who had evidence of tumor response (8% vs 37%). Of note, patients with stable disease on neoadjuvant chemotherapy had only a slightly worse prognosis with respect to 5-year survival, compared with responders (30% vs 37%). Disease-free survival in patients who progressed on neoadjuvant chemotherapy was only 3%, compared with rates of 21% and 20% for patients with tumor response or stable disease, respectively. Based on this study, it is clear that tumor progression before surgery is associated with extremely poor clinical outcome, and in this setting, hepatic resection should be avoided in patients who are deemed to be nonresponders to preoperative chemotherapy.
Neoadjuvant chemotherapy may be associated with complete disappearance of some or all of the hepatic metastases on imaging studies (approximately 18% of tumors will disappear completely).[35] Pathological complete response is associated with a high rate of long-term cure after surgical resection (5-year survival of 79%).[36] Controversy exists regarding the need to resect patients with complete radiographic responses, to achieve long-term cure. Up to 70% of these sites of complete radiographic response are associated with pathologic complete response or failure to recur at these sites.[36,37] The remaining 30% of patients are at risk of disease recurrence if resection is not performed. Thus, curative therapy should include resection of these regions, although the potential risk of disease recurrence at other sites must also be taken into consideration.
Conversion Therapy
The majority of patients will present with liver metastases from CRC that are unresectable or not optimally resectable based on their size, number, or location at the time of initial assessment. In this setting, conversion therapy is used in appropriately selected patients. The primary focus, therefore, is on achieving downsizing of the metastatic disease that is sufficient to allow surgical resection to be performed, but not with the goal of achieving a complete or even maximal response.
Adam and colleagues in France have had the largest experience in this area to date, and their work has provided important insights into the potential role of conversion therapy.[38-40] In their original series of 701 patients with initially unresectable liver metastases, treatment with oxaliplatin-based chemotherapy resulted in downsizing in nearly 15% of patients, and subsequent surgery. Based on 5-year follow-up after surgery, 22% of patients had no evidence of residual or recurrent disease. When stratified according to the underlying reasons for initial unresectability, the 5-year overall survival (OS) rates were 60% for patients with large tumors, 49% for those with poorly located tumors, and 34% for patients with multinodular tumors. In an expanded series of 1439 patients treated with a broader range of cytotoxic chemotherapy, the conversion rate was 12.5%, with a 5-year survival rate of 33%.
Folprecht and colleagues[41] conducted an interesting analysis of all published/presented clinical trials and retrospective studies of the rate of objective response and the subsequent rate of resection of initially unresectable metastases. They observed a strong correlation (r = 0.96) between response rates and the subsequent resection rate in patients with isolated liver disease. Moreover, their analysis confirmed that patient selection and efficacy of preoperative chemotherapy were strong predictors of potential resectability of liver metastases. Since this analysis, several prospective clinical trials incorporating systemic chemotherapy plus surgery have been performed. In these studies, use of oxaliplatin- vs irinotecan(Drug information on irinotecan)-based chemotherapy has shown similar clinical outcomes.[42,43] Of note, approximately 20% to 30% of patients were able to undergo R0 surgical resection. Two trials have directly compared the clinical efficacy of FOLFOX plus irinotecan (FOLFOXIRI), an aggressive regimen that incorporates the three active cytotoxic agents, against that of FOLFIRI (5-FU, LV, irinotecan). Falcone et al randomized patients with mCRC to receive either FOLFOXIRI or FOLFIRI, and they reported a significant increase in R0 resection for the subgroup of patients with liver-only metastases who were randomized to the FOLFOXIRI arm.[44] The R0 resection rate was 36% in the FOLFOXIRI arm vs 12% in the FOLFIRI arm (P = .017). Despite the increased clinical activity of FOLFOXIRI, patients receiving this regimen experienced a significantly higher incidence of grade 3/4 toxicity in the form of myelosuppression and neurotoxicity. In contrast to the positive findings of the Falcone study, Souglakos et al observed a nonsignificant increase in overall response rate (43% vs 33.6%), conversion rate (10% vs 3.4%), and R0 resection rate (8.8% vs 3.4%).[45] A pooled analysis of the Falcone phase III study and two phase II studies reported an overall response rate of 70% with the FOLFOXIRI regimen and a 19% R0 resection rate. The 5-year disease-free survival (DFS) and OS were 29% and 42%, respectively.[46]
Select Trials Reporting Conversion of Unresectable Metastatic CRC to Resectable Metastatic Disease
Is there an optimal cytotoxic chemotherapy regimen for conversion therapy? To date, there has been a significant absence of randomized trials directly comparing the various chemotherapy regimens in patients with liver-limited disease. In reviewing the literature, it appears that irinotecan- and oxaliplatin-based regimens yield approximately the same rate of conversion, on the order of 20% to 30%. While FOLFOXIRI appears to result in higher conversion rates, in the 40% to 60% range, and higher R0 surgical resections, this treatment regimen is clearly associated with increased toxicity and should be used only in certain select patient populations. Upon review of the recent National Comprehensive Cancer Institute (NCCN) guidelines, several regimens are currently recommended, and they include FOLFIRI, FOLFOX, CapOx, and FOLFOXIRI.[47]
The introduction of targeted therapies with either the antiangiogenic agent bevacizumab or the epidermal growth factor receptor (EGFR) inhibitors cetuximab(Drug information on cetuximab) (Erbitux) and panitumumab (Vectibix) has improved the clinical efficacy of chemotherapy in patients with mCRC. As a result, combination regimens incorporating these agents have now been evaluated in clinical trials for patients with liver-limited metastases.
The addition of the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab to either FOLFOX or to capecitabine and oxaliplatin (XELOX/CapOx) vs the cytotoxic chemotherapy regimens alone was investigated in a randomized phase III trial in advanced mCRC.[48] Unfortunately, there was only a slightly higher incidence of R0 surgical resection with bevacizumab (8.4%) vs chemotherapy alone (6.1%).
The anti-EGFR antibodies cetuximab and panitumumab have been approved for use in patients with mCRC.[49] Subsequent studies have shown that these agents are active only in patients with wild-type KRAS tumors. KRAS mutations occur in up to 30% to 40% of patients with CRC, and they typically involve codon 12 or 13. In general, KRAS mutations lead to resistance to antibody therapy. However, recent studies have suggested that the G13D mutation in codon 13 may still allow for sensitivity to anti-EGFR antibody therapy, in sharp contrast to mutations in codon 12.
Retrospective analyses of clinical trials in mCRC have provided insights into the potential role of cetuximab in the treatment of liver-limited disease. In a phase II trial of FOLFOX plus cetuximab, 37 of the 43 patients enrolled had liver involvement, and in 17 of these patients, the liver was the only site of metastatic disease.[50] An objective response was seen in 34 of the 37 patients; 10 of these patients underwent surgical resection of their metastases, including 8 patients with liver metastases. In a series of 151 patients with unresectable mCRC liver metastases refractory to systemic chemotherapy, the addition of cetuximab to combination chemotherapy allowed 27 patients to undergo surgical resection, and of this group, 25 underwent potentially curative hepatectomy.[51] Of note, this group included a majority of patients who were deemed to have either technically unresectable or marginally resectable disease. Moreover, the incorporation of cetuximab with chemotherapy conferred significant clinical benefit, with median progression-free survival (PFS) and OS of 13 and 20 months, respectively.
Several single-arm phase II trials have investigated the combination of cetuximab with either irinotecan- or oxaliplatin-based regimens. Min et al reported a radiologic response rate of 39%, with 30% of patients treated with FOLFIRI plus cetuximab able to undergo resection of their liver metastases.[52] Nearly identical results were observed with the combination of FOLFOX and cetuximab, which yielded an R0 resection rate of 29%.[53]
Two recent randomized studies have investigated the safety and efficacy of cetuximab in combination with either FOLFIRI[54] or FOLFOX.[55] The addition of cetuximab to FOLFIRI significantly increased the overall response rate (59% vs 43%; P = .004) in patients with wild-type KRAS when compared with FOLFIRI alone, and this resulted in a higher number of patients able to undergo R0 surgical resection (4.3% vs 1.5%). An exploratory analysis revealed a two-fold higher rate of R0 surgical resection in patients with liver-limited disease (9.8% vs 4.5%).[54] Similar findings were reported by Bokemeyer et al[55] with the combination of cetuximab plus FOLFOX4. The overall response rate increased from 37% to 61% in patients with wild-type KRAS and in those treated with the combination vs FOLFOX4 alone. This improvement in response rate in patients treated with the combination was associated with an increase in the R0 resection rate from 2.4% to 4.7%.
A trial of 114 patients with initially nonresectable liver-limited metastases randomized patients to receive cetuximab in combination with either FOLFOX6 or FOLFIRI. R0 resection rates of 38% and 30% were observed, respectively, with an overall R0 resection rate of 34%.[56] In a retrospective analysis of response according to KRAS status with the two arms of the trial combined, the clinical response rate in patients with wild-type KRAS was 70% compared with 41% for those with mutant KRAS. This study provides further evidence of the strong association between high tumor response rate and increased rate of liver metastasectomy.
PRIME (the Panitumumab Ran-domized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) was designed to evaluate the efficacy and safety of panitumumab plus FOLFOX4 vs FOLFOX4 alone as initial treatment for mCRC. The addition of panitumumab to FOLFOX4 chemotherapy significantly improved the overall response rate (57% vs 48%; P = .02) and median PFS in patients with wild-type KRAS tumors (9.6 vs 8.0 months; P = 0.01), which translated into a nonsignificant increase in median OS from 19.7 to 23.9 months.
In terms of surgical resection, metastasectomy of any site was attempted in 10.5% of patients treated with the combination regimen as opposed to 9.4% of patients treated with chemotherapy alone. However, the R0 resection rate was higher in patients with wild-type KRAS tumors and liver-limited disease (28% vs 18%) who were treated with panitumumab plus FOLFOX4. At the time of the most recent analysis, median OS had not been reached in patients who underwent R0 liver resection, in contrast to a median OS of 23.6 months in those who were unable to undergo complete surgical resection.[57]
