Challenge of Primary Tumor Management in Patients With Stage IV Colorectal Cancer

Optimal first-line therapy of patients who present with primary intact, unresectable stage IV colorectal cancer is controversial. Despite limited data, there are strong biases for either up-front primary tumor resection or for first-line systemic chemotherapy. The argument for up-front primary tumor resection is based on the desire to avoid potential complications of the intact primary tumor (IPT) such as bleeding, obstruction, or tumor perforation. Indeed the concern regarding the risk of primary tumor–related complications during systemic therapy, particularly with bevacizumab, has led both surgical and medical oncologists to advocate primary tumor resection at the time of diagnosis. In fact, the majority of US patients presenting with stage IV disease will still undergo noncurative primary tumor resection. However, during the past decade, several highly active systemic agents, both cytotoxic and biologic, have become available for the treatment of patients with metastatic colorectal cancer. As a result, the median survival duration of patients with unresectable metastatic disease has increased from 9 to 12 months with fluorouracil alone to up to 24 months with sequential modern cytotoxic and biologic treatments. Therefore, it may be generally accepted that, in these patients, systemic chemotherapy with or without primary resection is the essential treatment modality to prolong survival. But these modern agents also have increased activity on the primary tumor and can even induce complete response. Moreover, recent retrospective studies have observed low rates of primary tumor–related complications during treatment in patients with initially asymptomatic disease. Thus the old question of how best to manage the primary tumor continues to be debated. In the article that accompanies this editorial, investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP) have reported the final results of a phase II prospective, single-arm study of primary systemic chemotherapy with fluorouracil, oxaliplatin (mFOLFOX6) and bevacizumab for patients with asymptomatic primary intact unresectable stage IV colorectal cancer (NSABP C-10). The investigators aimed to directly address the concerns for both primary tumor–related complications associated with first-line systemic therapy in patients with asymptomatic disease and the risk of tumor complications with the use of bevacizumab in this setting. A total of 86 patients from 29 different institutions were evaluated with the primary eligibility criteria being that the treating clinician identified the patient to be asymptomatic with respect to his or her primary tumor. After a median follow-up of 20.7 months, the majority of the patients could be successfully managed nonoperatively without the need for primary tumor intervention, meeting the study’s primary end point. Median overall survival was 19.9 months and the overall rate of major morbidity related to the IPT was 16.3% (95% CI, 7.6% to 25.1%) at 24 months. Thustheinvestigatorsconcludedthatfirst-linecombinationtherapy withmFOLFOX6andbevacizumabdidnotresult inanunacceptablerate of primary tumor–related complications and that noncurative resection of the asymptomatic primary tumor in these patients could be avoided. These findings confirm prior retrospective reports demonstrating low rates of intestinal complications with either fluorouracil-based or more modern systemic chemotherapies. In their prospective evaluation, however, the NSABP investigators have further demonstrated the safety of first-line chemotherapy with bevacizumab in patients with intact but asymptomatic tumors. Indeed, 73.3% of the patients still had not required primary tumor resection at the time of death or last follow-up. This timely report has moved clinical treatment decision making forward and provides prospective evidence that routine noncurative resection may be unnecessary. But this relatively small study also highlights the need to address several other unanswered questions. Establishing that the patient is asymptomatic is the key eligibility criteria for this approach. However, perhaps for pragmatic needs of achieving accrual, “asymptomatic” in this study was broadly defined as having “no evidence of bowel obstruction or perforation, and no active bleeding requiring a transfusion.” Ultimately, it was the treating physician at each one of the 29 different institutions who had to adjudicate whether or not a patient who notes no symptoms, tolerates oral intake, and has bowel movements but is obstructed to the passage of an adult colonoscope (or perhaps some other variation on this theme) is labeled as having asymptomatic disease. This key issue of understanding which patients are eligible for this approach can also influence the true incidence of primary tumor–related morbidity (ie, not all patients with asymptomatic disease are the same). Notably, despite the frequency with which patients with stage IV are identified, and despite the relatively broad eligibility criteria, it took the 29 sites more than 3 years to accrue the 86 eligible patients to the study, perhaps reflecting difficulty on the part of the clinicians for deciding that a patient’s disease was indeed asymptomatic. Another unanswered question is when and how should endoluminal surveillance be performed. No endoluminal surveillance strategy was prespecified, and given the number of investigators in the 29 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 26 SEPTEMBER 1