Salvage surgery can be performed in patients with advanced colorectal cancer when chemotherapy achieves tumor shrinkage [43]. In phase III studies, up to 15 % of the patients can benefit from an R0 resection. These patients have a 5-year survival rate of approximately 25 %. These results approach the results achieved in patients with initially resectable metastases [44].

The frequency of salvage surgery depends on the response rate of chemotherapy and on the geographic localization. Obviously, the higher resection rates are observed in trials performed in the Mediterranean countries. Differences in management, multidisciplinary approach, and surgeon experience explain the observed discrepancy. A positive correlation was found between tumor response and resection rate [45]. We confirmed this paper looking only at randomized studies. In the Mediterranean countries, the response rate to achieve a 10 % R0 resection rate is 54 % (Fig. 16.2).

These findings support the use of regimens achieving a high response rate in patients with metastases localized in operable sites.

Response rate over 50 % in first-line therapy has been reported in several randomized studies. FOLFOX4 achieved 50 % (range in trials 34–58 %) [5, 6, 18, 29, 35, 46], FOLFOX6 54 % (range 46–54 %) [3, 15], FOLFIRI 56 % (range 39–56 %) [3, 15, 19, 34, 46], and FOLFOXIRI 60 % (range 53–60 %) [2, 47]. Targeted therapies combined to chemotherapy slightly increase response rates. In patients with wild-type KRAS, response rate was 57.3 % with both FOLFIRI plus cetuximab and FOLFOX plus cetuximab and 55.0 % with FOLFOX plus panitumumab [27, 34, 39].

Of note, the response rate in the bevacizumab trials is not increased as much as in the cetuximab or panitumumab trials, but it is also known that the classical definition of response does not fully reflect the efficacy of antiangiogenic agents.

Finally, should we use the most active regimen frontline to all patients to increase the resection rate? The benefit of a 10 % increase in response rate, which at best is what can be achieved with targeted therapies combined with the most active regimens, should translate in a 2 % increase in R0 resection and ultimately in less than 1 % cure. On the other hand, 100 % of the patients are exposed to a more toxic regimen. Furthermore, such an attitude may compromise the strategy in case of nonresectable metastases as second-line therapies are driven by the choice of the first-line therapy. The correct answer might be to improve patient and tumor selection using optimal biomarkers and imagery to propose the most active regimen only to patients most likely to benefit from this strategy.

To conclude the first-line strategy and regimens, the most relevant ongoing trials are presented in Table 16.1.

Second-line therapy could be administered in most patients when resistance or toxicity closes the first-line therapy. The second-line treatment could be imposed by the choice of the first-line therapy. The knowledge of the most active second-line administrations must not lead to use a suboptimal first-line regimen.

Exposure to all available agents has been reported which could be more significant than the number of lines [48]. Nevertheless, showed by the date between the percentage of patients who received all the available drugs and the median survival, if all eligible patients receive all the available chemotherapy drugs (80 % if we consider that 20 % would have surgery or be unable to receive all drugs), the median survival would be limited to 22 months. However, the median survival would be over 22 months by using targeted agents in the new strategies or using the oxaliplatin in stop-and-go strategy late. This approach argue against the basic one.

Second-line therapies are effective. Classical doublets are active after LV/5FU or capecitabine ineffectively. After failure of FOLFIRI, FOLFOX is still active, but irinotecan or FOLFIRI appears less active after failure of FOLFOX [3]. New irinotecan-based chemotherapy regimens such as FOLFIRI3, ground on an effective interaction between irinotecan given after 5FU infusion [49], should be more active than FOLFIRI in second-line therapy, but these results have not been demonstrated in randomized trials [50, 51].

Targeted therapies have also improved the effect of second-line therapy. Bevacizumab combination with FOLFOX4 after failure of 5FU/irinotecan has increased response rate, PFS, and overall survival [32]. The survival also is prolonged by continuing bevacizumab after progression on first-line therapy, and this result is provided in prospective trials [52]. PTK-ZK combination with FOLFOX after failure of 5FU/irinotecan has shown prolongation of PFS [53]. Cetuximab combination with irinotecan after failure of 5FU/oxaliplatin has demonstrated prolongation of PFS compared with chemotherapy alone even though the outcomes in the subset of patients who were tested for KRAS were not convincing [54, 55]. The median PFS also were prolonged approximately 2 months in FOLFIRI combination with panitumumab [40]. However, the dimensions of the PFS benefit remain modest and uniformly below 3 months, and the OS benefit is shown only in the bevacizumab trial [30]. Crossover in the chemotherapy-alone arms is an acceptable hypothesis to explain the unconformity between PFS and OS.

Majority of patients are even able and glad to accept therapy after two lines of treatment. The BOND trial in which a significant proportion of patients were not only intractable to irinotecan-based chemotherapy but also to oxaliplatin-based chemotherapy has shown cooperation between irinotecan and cetuximab. The effect of irinotecan plus cetuximab overmatches the effect of monoclonal antibody only [37]. Since it was shown that anti-EGFR monoclonal antibodies, cetuximab and panitumumab, were also active alone in third-line versus best supportive care, results magnified in the patients with wild-type KRAS [36, 38]. It is remarkable that bevacizumab is not active in third-line therapy [33].

When to use cetuximab or panitumumab would be a significant practical question for the most part of patients who have nonresectable neoplasms, even in case of tumor shrinkage. As the only active third-line therapies lie on anti-EGFR monoclonal antibodies, there is no third-line therapy for patients with mutated KRAS tumor, and their administration in first- or second-line therapy in patients with wild-type KRAS tumor has the immediate consequence to preclude patients of receiving a third-line therapy. Without the exact data and prospective trial can clarify this unintelligible question. However, there is a nonquestionable survival advantage in third-line therapy. There is also a lack of survival advantage in second-line therapy in the EPIC trial where 50 % of the control patients administered cetuximab in third-line therapy. There is no survival benefit in first-line therapy in the COIN trial and in the preliminary results of the PRIME trial [27, 39]. The CRYSTAL trial has reported the only significant improvement in overall survival (3.5 months) in a first-line trial.

However, the significant results came from a retrospective analysis of a subset of the patients, and the proportion of patients who have accepted the therapy of cetuximab after the first-line in the experimental group has not been covered. According to these data, introduction of the systematic use of anti-EGFR antibody in first-line therapy in patients with unresectable metastases is not enough.