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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 1799-1802 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.185
An Increasingly Common Challenge: Management of the Complete Responder With Multi-Focal Metastatic Colorectal CancerMemorial Sloan-Kettering Cancer Center, New York, NY K.A. is a 61-year-old woman diagnosed with a nonobstructing, moderately differentiated adenocarcinoma of the ascending colon in the spring of 2003. At diagnosis, she had palpable left supraclavicular adenopathy that was biopsied and found to be consistent with metastasis of colonic primary tumor. Contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis revealed wall thickening of the ascending colon as well as diffuse adenopathy in hilar, gastrohepatic, retroperitoneal, para-aortic, mesenteric, and iliac regions. Pretreatment fluorodeoxyglucose positron emission tomography (FDG PET) scan revealed diffuse uptake in these multiple nodal stations but no evidence of pulmonary or hepatic involvement. The patient was a widowed administrator for a nursery school program and had no notable past medical history and an unremarkable family history. When the patient presented for medical oncology opinion in June 2003, she had intermittent, mild, crampy abdominal pain, no melena or bright red blood per rectum, and was able to tolerate a low residue diet. She had experienced an 8-lb unintentional weight loss but denied fevers, chills, or sweats. She was informed that treatment options for stage IV colon cancer are palliative rather than curative, with median survival estimated at 20 months based on recent clinical trials. The FOLFOX6 regimen, consisting of biweekly fluorouracil, leucovorin, and oxaliplatin, was recommended. With initiation of treatment, her abdominal cramping improved, and the left supraclavicular lymph node was no longer palpable after three cycles. Treatment was administered for five cycles, and first interval restaging CT scan indicated dramatic response. Treatment was continued for five more cycles, and the second restaging revealed persistence of the colonic primary and stable adenopathy (Fig 1B).
The patient was able to continue work during treatment and experienced transient neutropenia, fatigue, nausea, and mild neuropathy. Although she tolerated therapy well, because comparison of her first and second interval CT scans suggested that her response to FOLFOX had reached a plateau, she was referred to a colorectal surgeon for consultation regarding the possibility of resection of the primary tumor. To further evaluate the extent of residual tumor, PET scan was obtained and revealed persistent uptake in the ileocecal region (standardized uptake value = 4.0) primary, but no evidence of increased uptake in areas corresponding to the multifocal adenopathy appreciated on the pretreatment PET scan. In January 2004, the patient opted for surgery despite both the surgeon and the oncologist's caution that there is no compelling evidence base to suggest that resection of the primary tumor in this circumstance provides survival advantage. At exploratory laparotomy, stricture of the ascending colon was appreciated, and an extended right hemicolectomy with resection of mesentery and regional lymph nodes was performed. Gross pathologic examination revealed an ulcerated firm lesion in the proximal ascending colon that, under microscopic examination, consisted of transmural fibrosis and inflammation associated with surface ulceration. Sixteen regional lymph nodes were recovered, and all 16 were negative for metastasis. No residual viable tumor was identified in the entire resection specimen (Figs 2C and 2D). Thus, this patient with pathologically confirmed distant disease has a surgically confirmed complete response to 10 cycles of FOLFOX therapy.
COMMENT The case describes a surgically documented complete response of stage IV colon cancer to systemic chemotherapy and underscores several challenges relevant for contemporary management. The first issue raised is the specificity of PET scans for detecting viable tumor. The preoperative PET scan revealed persistent activity in the region of the bowel, yet the surgical specimen obtained within 2 weeks of the scan provided no evidence of residual viable tumor. The physiologic basis of a positive site on an FDG PET scan represents local increase in the glucose metabolism above the background glucose metabolism of surrounding tissues. In this particular circumstance, a bulky tumor treated with chemotherapy had undergone complete regression and total replacement by fibrosis and inflammation, as evidenced by the pathology specimen. The healing process is dynamic and requires energy; the persistent FDG uptake in this case was likely due to the presence of inflammatory cell infiltrates and soft tissue remodeling, all of which require energy. It is well appreciated that the absence of FDG uptake does not necessarily indicate the absence of viable tumor. However, the converse is also true; the presence of increased uptake on PET scan need not necessarily intake the persistence of viable tumor. The need for caution in interpreting PET scans has been previously reported1 but merits emphasis, given the degree to which this imaging strategy is used to make decisions about patients' candidacy for surgery. The second more important issue raised by this case concerns how we identify patients' candidacy for surgery. In the absence of symptoms, patients with multifocal disease do not typically benefit from resection. However, given the dramatic response to systemic therapy, surgical resection was nonetheless performed to remove what was thought to be a persistent primary tumor. The presence of lengthy stricture of the ascending colon also influenced the decision to proceed with resection, but given that the patient had no viable tumor detected after careful pathology review, it is unlikely that surgical resection has had any influence on the patient's prognosis. Had there been viable minimal residual disease amenable to complete surgical resection, it is still not clear whether continuation of chemotherapy or surgery was the preferred strategy. The third issue raised by this case concerns the type and duration of chemotherapy treatment in the setting of complete response. Given that even contemporary chemotherapy regimens such as FOLFOX and FOLFIRI (FU, leucovorin, irinotecan) have complete response rates of only 6% to 10%, there are no large case series that guide management in this circumstance.2,3 Based on the principle of colorectal adjuvant therapy, where 6 months of treatment is typically administered after primary surgical resection, this strategy is also sometimes adopted for patients after complete resection of metastatic disease.4 Given the sensitivity of this patient's tumor to FOLFOX, we continued therapy for an additional eight postoperative cycles, which she tolerated well. Restaging with physical examination, blood work, CT, and PET scans in February 2005, 9 months after her last dose of chemotherapy, demonstrates a durable complete response. In the face of the improved chemotherapeutic strategies for colon cancer, evaluation of strategies for management of the complete responder or the patient with major response rendering disease amenable to complete resection may for the first time become a relevant issue for more than the anecdotal patient. Integration of the monoclonal antibodies cetuximab and bevacizumab into the FOLFIRI and FOLFOX regimens may increase the number of patients who become resectable or achieve a complete response still further.5,6 European colleagues who have had oxaliplatin available for a longer period of time have already described an increase in so-called oncosurgery made possible because dramatic responses to systemic therapy render previously unresectable patients candidates for potentially curative surgery.7,8 Clearly, questions about the utility and appropriate timing of surgical resection in the setting of multifocal disease that has responded dramatically to chemotherapy are becoming more salient. Even absent a complete response, if multifocal nodal disease disappears but isolated metastases persist, is an attempt at surgical resection warranted? Should efficacious chemotherapy be discontinued to perform surgery capable of removing all visible disease sites or should chemotherapy be continued until complete response has been achieved? The answer to these questions remains uncertain, and no informative clinical trial data are forthcoming. Multicenter collaboration should be coordinated to compare strategies for consolidating potential cures. A multicenter study addressing the duration of continuing chemotherapy in the setting of initial response was recently reported and highlights the fact that trials addressing such questions are indeed feasible.9 Collaboration to answer questions such as those raised by our patient are necessary to capitalize further on the progress already made. In the meantime, these treatment decisions will continue to be made on a case-by-case basis. The key factors that will inform them are the patient's tolerance of chemotherapy, the response to chemotherapy (eg, is partial response continuing or has response reached a plateau), surgical candidacy based on coexisting conditions, and, of course, the patient's own preferences. Before our patient had surgery, her case was reviewed in multidisciplinary case conference. The proximity of practice sites at a large cancer center enabled the medical and surgical oncologist to meet with the patient simultaneously so as to jointly clarify the goals, risks, and uncertainties of alternative approaches to treatment. This helped to prevent the patient from feeling forced to choose between two different therapeutic modalities, each with attendant uncertainty. This is of course not as easily accomplished in smaller settings and private practice, where the vast majority of cancer care is delivered. Yet in the face of uncertainty, despite the obstacles, dialogue between radiology, medical, and surgical oncologists is especially important. The increasing availability of radiologic imaging studies that can be transmitted electronically and reviewed from desktop computers may facilitate cross-disciplinary dialogue between specialists practicing at remote sites. We continue to offer our patient reassurance that she has no detectable residual disease, but our sense of optimism is not supported by a sizable body of long-term data. It is clear that traditional treatment paradigms are being challenged in an era where we have efficacious systemic therapy and that new trials are necessary to consolidate the progress already achieved. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Bourguet P, Blanc-Vincent MP, Boneu A, et al: Summary of the standards, options and recommendations for the use of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDP-PET scanning) in oncology (2002). Br J Cancer 89:S84-91, 2003 (suppl 1)
2. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004
3. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004
4. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004
5. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004
6. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 7. Adam R: Chemotherapy and surgery: New perspectives on the treatment of unresectable liver metastases. Ann Oncol 14:ii13-16, 2003 (suppl 2)[Abstract] 8. Topham C, Adam R: Oncosurgery: A new reality in metastatic colorectal carcinoma. Semin Oncol 29:3-10, 2002
9. Lal R, Dickson J, Cunningham D, et al: A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol 22:3023-3031, 2004 This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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