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EDITORIALS |
From the Department of Surgery, City of Hope National Medical Center, Duarte, California.
Correspondence: Address correspondence to: Lawrence D. Wagman, MD, FACS, City of Hope National Medical Center, Department of Surgery, 1500 E. Duarte Rd., Duarte, CA; Fax: 626-301-8865; E-mail: lwagman{at}coh.org
The fine study by Litvak et al.1 appearing in this issue of Annals of Surgical Oncology confirms the assumptions that more is better and further emphasizes that nothing is not enough. Litvak and his coauthors establish that combined therapy with irinotecan given systemically and floxuridine (FUDR) given regionally through an hepatic artery infusion will significantly decrease recurrences and improve progression-free and overall survival in patients with colorectal cancer that has metastasized to the liver and is deemed unresectable but cytoreducible. The end point of the cytoreduction in this study was a complete removal and/or destruction of all hepatic lesions. This is somewhat different from the classic gynecologic oncology definition, developed in ovarian cancer, where no residual deposit >1 cm was considered complete cytoreduction. In fact, what the authors define as cytoreduction serves many as the definition of complete resection/ablation. Thus it might be valuable to view the results of this article as closer to curative resection with and without adjuvant chemotherapy, rather than merely treatment of residual disease after maximal debulking. From this vantage point, the implications of the study are strengthened and the use in directing future randomized trials are more powerful, e.g., systemic adjuvant only versus systemic combined with regional adjuvant. In retrospect, the inclusion in 1996 of irinotecan (CPT-11; Camptosar; Pharmacia & Upjohn Co, Kalamazoo, MI) as the systemic agent was filled with foresight, as this agent is now considered the successful new player in the armamentarium for treatment of metastatic colorectal cancer. Whether this topoisomerase I inhibitor can weather the recent analysis demonstrating an excess in mortality over fluorouracil/leucovorin and stand up to one of the newer agents such as oxaliplatin or capecitabine is certain to be studied carefully. This study successfully establishes the feasibility of aggressive therapy utilizing multiple surgical techniques and dual routes of chemotherapy. Furthermore, the authors’ analyses of the dose of drug delivered compared to the dose planned highlights the significant toxicity associated with each of the agents and their delivery routes—regional and systemic. The team is to be congratulated for completing a large series of advanced surgical procedures followed by complex chemotherapy that requires skill and expertise to administer safely. The challenge of combined systemic and pump therapy delivery is underscored by the need for dose reductions of 50% in 40% of the patients for FUDR and 30% of patients who received irinotecan.
The study cannot, with statistical stringency, compare the two groups because of differences in time periods of study, personnel, and potential selection biases not identified by the established risk criteria associated with curative resections (number of metastases, disease-free interval, stage of initial colorectal cancer, etc.). Table 1 of the article nicely outlines the classic risk factors in each of the groups and details an exceptional equivalence, considering the lack of stratification or randomization. Further information regarding the risk factors is provided in Table 3. Unexpectedly, for any given risk factor, as the negative effect of that risk factor increases, e.g. solitary versus more than four lesions, there is little difference in the median survival in months. The difference between a median survival of 33 versus 27 months after resection and adjuvant therapy for the one versus more than four lesions may be statistically different with a larger sample. However, the absolute difference is small enough to make the treatments reasonable in both risk groups. The selection of two time periods may potentially add bias as the skills of the individuals performing the techniques likely improved, specifically in the application of the ablative techniques and the use of simultaneous intraoperative imaging. This may be balanced by the likelihood of the surgical and medical team becoming better in patient selection while simultaneously more therapeutically aggressive as their skill levels increased. Therefore, as the study proceeded, the authors succeeded in treating a patient population with poorer predicted prognosis and setting a higher "disease severity bar" to leap over.
The authors showed significant improvement in liver and extrahepatic control for the combination therapy. What is particularly interesting is that for liver recurrences, 55% occurred at a different site than that of the cytoreductive surgery in the cytoreduction alone group and 27% at a different site in the combination therapy group. This, again, being statistically significant suggests the importance of the adjuvant, liver-directed therapy in controlling minimal (not imaged or palpated) disease. The reader is led to conclude that any reasonable therapeutic intervention in the presence of known intrahepatic disease must include these two routes of drug administration. One might rationally and legitimately argue that the irinotecan alone could have provided the regional and systemic treatment, whereas the FUDR with its high first pass extraction could not have achieved systemic control. This study supports the contention that patients with treated liver metastases remain at significant risk of recurrence and should therefore be treated with an adjuvant regimen. Given the complexity and toxicity of hepatic artery drug delivery, it is imperative that its worth is proven. Unfortunately, this question of combined (regional and systemic) versus systemic alone remains unanswered. This would lead us to design further studies comparing highly effective, non–cross-resistant systemic therapy versus a combination of systemic therapy and regional therapy.
The information provided regarding the decrease in carcinoembryonic antigen (CEA) levels in Table 4 of the article by Litvak et al.1 evokes some thoughtful interpretation regarding the value of any cytoreductive intervention as a component of therapy. Although patients who achieve partial responses represent successful treatment in medical oncology, this has not been considered a success for surgeons. The demonstrated hypothesis of this article is that the establishment of a surgical complete or partial response, as measured by a decrease in serum CEA postoperatively, is predictive of increased survival compared with those patients who are surgical nonresponders, i.e., no or minimal change in CEA. Thus the logical statement summarizing these findings is as follows: if patients who are surgically debulked are responders and responders do better, then patients who are surgically debulked do better. The proof to the statement is provided in the data on CEA and obliges us to consider changing the treatment paradigm to include the surgical intervention as one course of the total treatment. Assuming that a 60% reduction in CEA is equivalent to a 60% reduction in tumor bulk, one might hypothesize that generating surgical partial responses followed by the best available chemotherapy would have an impact on long-term patient survival. Again, interpreting from these results, if surgeons were able to cytoreduce by >60% as compared with simply beginning therapy with systemic chemotherapy or, as in this case, a combination of systemic chemotherapy and FUDR, statistically significant improvement in patient survival could be expected. The data of Litvak et al. supports this, with survival of 31.7 months for those patients with a surgical CEA reduction of >60% and only 9.8 months when the reduction was <30%.
As the therapeutic interventions leading to cytoreduction become more widely available and with lower morbidity, true benefit to cytoreductive treatments with adjuvant chemotherapy may play a far more important role in this patient population. Reduction in the morbidity and mortality associated with cytoreductive liver surgery and adjuvant chemotherapy may indeed make the treatment both therapeutic and cost effective. This article can lead us out of the nihilistic doldrums and reposition the surgeon for an aggressive, combined approach for single-organ, metastatic disease.
Received for publication December 10, 2001. Accepted for publication January 4, 2002.
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