Effect of extended preoperative chemotherapy on pathologic response and pathologic livery insufficiency after hepatic resection of colorectal liver metastases
Reviewer: Christine Hill, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 7, 2009
Presenter: D. Zorzi, MD Anderson Cancer Center, Houston, TX
Recent advances in detection and treatment of liver metastasis from colon cancer have resulted in improved outcomes for patients in this disease setting.
Most patients are treated with multimodality treatment, and chemotherapy is often given neoadjuvantly, prior to resection of primary disease and/ or liver metastases.
The effectiveness of this approach has not been investigated in the setting of a randomized clinical trial, and the optimal combination of drugs, as well as duration of pre-operative treatment, are largely unknown.
This trial was undertaken to evaluate the role of FOLFOX chemotherapy (5FU and oxaliplatin) with and without bevacizumab, specifically with regard to pathologic response and hepatotoxicity, following resection of colorectal liver metastases.
A total of 219 patients were evaluated retrospectively.
All had pathologically proven diagnosis of colorectal cancer, with liver metastasis.
All received FOLFOX chemotherapy with or without bevacizumab prior to undergoing resection of colorectal liver metastases.
Patients were analyzed in two groups according to duration of chemotherapy:
Short group: 1-8 cycles of chemotherapy (N = 157)
Long group: ? 9 cycles of chemotherapy (N = 62).
Frequency of pathologic complete or major response (< 50% viable tumor cells) were compared between the two groups.
Hepatotoxicity, defined by sinusoidal injury or post-operative liver injury (bilirubin
> 7 mg/dL) was also compared.
Clinical and disease variables did not differ significantly between the two groups.
The proportion of patients achieving complete or major pathologic response did not differ between the two groups (57% versus 55% in short and long groups, respectively, p = 0.738).
Significantly higher rates of complete or major response were observed in patients who received FOLFOX + bevacizumab as compared to FOLFOX alone, regardless of treatment length:
Of patients receiving 1-8 cycles of FOLFOX chemotherapy, 5% achieved complete pathologic response, and 43% major pathologic response. This was compared to 9% complete response and 58% major response for patients receiving 1-8 cycles of FOLFOX + bevacizumab (p = 0.00017).
Of patients receiving ? 9 cycles of FOLFOX chemotherapy, 10% achieved complete response and 30% major response, as compared to 9% complete response and 68% major response in patients receiving ? 9 cycles of FOLFOX + bevacizumab (p = 0.0011).
Incidence of sinusoidal injury was higher in the long chemotherapy group (42% versus 26% in the short group, p = 0.017).
Incidence of post-operative liver insufficiency, as defined by bilirubin peak > 7 mg/dL, was also higher in patients receiving ? 9 cycles of chemotherapy (11% versus 4% in the shorter group, p = 0.035).
On multivariate analysis, ? 9 cycles of chemotherapy was the only independent prognostic factor in determining risk of post-operative liver insufficiency (Odds ratio 3.90, p = 0.031).
The authors conclude that extended pre-operative chemotherapy increases the risk of hepatotoxicity after hepatic resection for liver metastases from colorectal cancer.
They conclude that the addition of bevacizumab to FOLFOX appears to have impact on pathologic response, while duration of chemotherapy does not appear to impact pathologic response.
The study presented here represents an interesting contribution to the literature, particularly regarding subject matter that is not well-studied.
From the data presented here, duration of chemotherapy for more than 8 cycles does not appear to procure benefit above 1-8 cycles, and may impose greater risk for liver toxicity for patients with liver metastasis from colorectal cancer.
Additionally, addition of bevacizumab to FOLFOX chemotherapy may provide increased pathologic response as compared to FOLFOX alone.
The authors’ conclusions regarding both pathologic response and liver toxicity are certainly of interest; however, the study presented here is limited by several aspects:
The retrospective nature of the data presented here introduces bias, and several factors regarding patient care may have impacted the management decisions.
The authors provided little information regarding factors impacting the reasons why patients did or did not receive bevacizumab as part of chemotherapy, as well as the length of chemotherapy. Patient and/ or disease factors may have played into these decisions, and may bias the authors’ conclusions.
For example, oncologists may have chosen to administer chemotherapy for a longer duration, thus delaying surgery for patients seemingly less suitable for resection than other patients. These differences may have contributed to the variations in post-operative liver toxicity. Although performance status and age were similar between the two groups, nuances in decision making are not always translatable to such objective factors.
In addition to these factors, the impact of the authors’ observations on survival is not presented as part of this study, and would be most interesting. The authors do not comment on how the liver toxicity mentioned contributed to overall survival and quality of life. In addition, pathologic response to chemotherapy does not universally predict improved survival, although it likely does portend greater disease responsiveness to therapy, which may translate to improved survival. Along these lines, radiologic response to chemotherapy has recently been demonstrated to predict survival for colorectal cancer patients with liver metastases (Small, J Surg Onc, 2008).
Despite these limitations, the study presented here is important in decision-making with regard to this subset of patients with colorectal cancer. Further investigation in the form of a randomized trial would certainly be of interest, and the data presented here is important in and of itself in the absence of randomized data.
Jul 31, 2014 - In patients with colorectal liver metastases, chemotherapy with cetuximab was associated with high rates of tumor response and resection of metastases, according to research published online Nov. 25 in The Lancet Oncology.