DISCUSSION


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Many mCRC patients still have good performance status to tolerate further treatment after standard first-line and second-line therapies, but the alternative third- or later-line therapeutic regimens are limited, and the efficacy has been discouraging. Regorafenib was accepted as the third-line therapy based on better survival than BSC, as it showed a discouraging result, with a PFS of 1.9 months and an OS of 6.4 months.2 Famitinib and TAS-102 also did not show better efficacy, with a PFS of 2 months and an OS of 6–9 months.5,6 Compared with the low ORR (1%–2.2%) and small survival benefit in these three RCTs, our study showed a higher response rate with a PR of 20%, a longer median PFS of 5.98 months and a median OS of 14.77 months.

Prior to our study, several small-sample studies including 19–100 patients explored the role of bevacizumab plus chemotherapy as third- or later-line therapy in mCRC patients who progressed after all standard treatments. The ORR was from 0% to 28.5% (median, 9%), the PFS was from 3.5 to 8.9 months (median, 3.9 months), and the OS was from 7.7 to 13.8 months (median, 9.5 months). The details are shown in Table 4.1117 Together with those studies, our data suggest that adding bevacizumab to third- or later-line therapy in mCRC patients may lead to tumor control and improved survival. The following reasons may contribute to the potential advantages of bevacizumab in third- or later-line therapy. First, bevacizumab not only inhibits neoangiogenesis, but also normalizes the surviving tumor blood vessels. The later effect results in the accumulation of cytotoxic agents in the tumor, which may enhance the efficacy of chemotherapy. Second, bevacizumab adding a survival advantage as a part of cross-line treatment might imply treatment failure mainly due to resistance to cytotoxic agents but not to anti-angiogenesis drugs.9,10 Moreover, the success of bevacizumab in first- and second-line treatment7,8 and the success of regorafenib and famitinib in later-line therapy2,5suggest that anti-angiogenesis may play a role throughout the whole course of treatment. After an indirect comparison of later-line treatments, the promising survival benefit of bevacizumab compared with regorafenib or famitinib suggested not only that head-to-head RCTs comparing the monoclonal antibodies and TKIs are urgently needed, but also that anti-angiogenesis should be combined with chemotherapy, rather than utilized alone, in patients with a good PS in the later-line setting.

(To view a larger version of Table 4, click here.)

In the subgroup analysis, patients with a primary colon tumor may have had a longer OS than those with a primary rectal tumor, which is in accordance with the regorafenib data from the CORRECT trial.2 In our study, PFS before the beginning of salvage therapy, pretreatment target drugs, cycles of bevacizumab, chemotherapy regimen, and performance status in salvage therapy were similar in patients with different primary tumor sites. A subgroup analysis from a Phase III trial (FIRE-3), which compared head-to-head bevacizumab with cetuximab in first-line therapy, showed that a primary rectal tumor might benefit from a cetuximab-containing regimen.4 In summary, these studies suggested that a benefit from the target drugs was associated with the primary tumor site. Presently, the reason that primary colon cancer benefits from anti-VEGFR pathway therapy more than primary rectal cancer has not been elucidated. It was reported that VEGF-A, the target of bevacizumab, is present in higher levels in left-sided colon and rectal cancers than in right-sided colon cancers.18,19

It has been reported that pretreatment LDH levels can predict the efficacy of first-line bevacizumab-based therapy in mCRC patients.20,21 Our data did not show that patients with a pretreatment high LDH level have a longer OS when treated with third- or later-line bevacizumab-containing therapy. However, the response rate was 42.9% (6/14) in pretreatment high-LDH-level patients, which was higher than the 4.8% (1/21) response rate in pretreatment low-LDH-level patients. Theoretically, LDH can increase the accumulation of lactate in tumors and create an acidic tumor microenvironment, which enhances pericyte deficiency, neovascularization, and sensitivity to antiangiogenesis agents.22,23 Our study could not predict a role for LDH in third- or later-line therapy. This might be explained by the limitation of the small sample and retrospective nature of our study. A larger sample and a prospective study are needed to further answer this question.

The toxicity profile of bevacizumab plus chemotherapy seemed to be similar to those observed in previous studies,1117 which included chemotherapy-related and bevacizumab-related toxicities. The common adverse events related to chemotherapy were leucopenia, anemia, fatigue, and nausea/vomiting. The common adverse events related to bevacizumab were hypertension, bleeding, and proteinuria. These toxicities were tolerable, and no dosage was adjusted or therapy was interrupted by the toxicity. Two patients discontinued therapy because of the intolerance of thrombocytopenia and diarrhea. No gastrointestinal perforations and embolisms occurred, most likely due to the small number of patients. No patients discontinued therapy because of bevacizumab-associated toxicities.

Several limitations hampered the generalization of the present results to all patients with heavily treated mCRC; these limitations can be partly attributable to the study’s retrospective nature. First, selection bias cannot be excluded because only medically fit patients with very a good performance status might have been treated with bevacizumab-containing third- or later-line therapy. This is suggested by the inclusion of only one patient with an ECOG performance status of 2 in the whole cohort of bevacizumab-treated patients, which might have led to a more favorable OS estimate in these patients. Second, the small cohort in this study may also affect the objectivity of our data. Third, the PFS evaluation could have been biased by the fact that neither independent monitoring nor a centralized review of the radiological responses was performed in our study. Fourth, this study had no data on chemotherapy alone. Nevertheless, our data were equal to or a little better than previous similar data, which were superior to the results of chemotherapy alone in the third- or later-line therapy.2,5 Finally, there were insufficient data on toxicity, particularly on peripheral neuropathy associated with oxaliplatin, not necessarily indicating the absence of peripheral neuropathy associated with oxaliplatin, but rather the lack of detailed medical records.

CONCLUSION

To the best of our knowledge, this was the first study to explore the role of bevacizumab-containing regimens as third- or later-line therapy in Chinese patients with heavily treated mCRC. Our data showed that adding bevacizumab to third- or later-line therapy may lead to tumor control and improved survival in mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens as third- or later-line therapy. Further studies are needed to validate these findings.

Acknowledgments

This study was supported by grants from Science and Technology Planning Project of Guangdong Province, People’s Republic of China (2011B061300069) and National Natural Science Foundation of China (81272641, 81071872 and 81572409).


Disclosure

The authors report no conflicts of interest in this work.


Qiong Yang,1–4,* Chenxi Yin,1,3,4,* Fangxin Liao,1,3,4 Yuanyuan Huang,1,3,4 Wenzhuo He,1,3,4 Chang Jiang,1,3,4 Guifang Guo,1,3,4 Bei Zhang,1,3,4 Liangping Xia1,3,4

1VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China; 3State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 4Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work


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Source: OncoTargets and Therapy.
Originally published September 1, 2015.