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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2702-2706 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8404
Downstaging or Downsizing: Time for a New Staging System in Advanced Colorectal Cancer?Liverpool Supra-Regional Hepatobiliary Centre, University Hospital Aintree, Liverpool, United Kingdom; Hopital Paul Brousse, Villejuif, France; and M.D. Anderson Cancer Center, Houston, TX Ten years ago, the management of advanced colorectal cancer was relatively straightforward. For the fortunate few with liver-only disease who managed to find their way to a liver surgeon and who met the stringent criteria of the day for hepatectomy (one to three unilobar metastases, preferably presenting metachronously, and resectable with a generous margin of healthy liver tissue), there was the chance of surgery with curative intent.1 If they survived the surgery, the patients had a 30% to 40% chance of being alive 5 years later.2 However, these patients accounted for less than 10% of all patients with advanced liver-only disease,1,2 and for patients with nonresectable disease, the chance of being alive 5 years after diagnosis was less than 1%.3 Palliative chemotherapy using fluorouracil and leucovorin achieved a measurable response in barely 20% of patients and improved median survival time from 8 months with best supportive care to little over 12 months.4 At that time, the American Joint Committee on Cancer staging system for advanced colorectal cancer was equally straightforward; all patients with metastatic disease beyond the immediate lymph node basin of the primary tumor had stage IV disease, and their prognosis was grim. The situation in 2006 has changed completely for both resectable and unresectable patients. Over the last 10 years, the definition of resectability has evolved, overcoming the morphologic limitation used in the past as selection criteria. Now the definition of resectability with curative intent is the ability of the surgeon to clear, with negative margin, all measurable disease from the liver while leaving a healthy future remnant liver of 20% of the total liver volume.5-7 Factors that determine the extent of safe liver resection include performance status and concurrent parenchymal liver disease.5-7 Liver resection is now considered selectively in some subsets of patients with limited resectable extrahepatic disease. Hilar lymph node metastases; lung, ovarian, and adrenal metastases; and local or regional recurrence are no longer formal contraindications.8,9 BACKGROUND Historically, relative contraindications to considering liver resection on intention to treat have included synchronous presentation of primary colorectal cancer and liver metastasis, especially with a rectal primary tumor; multiple diffusely distributed liver metastases; large metastases; the presence of extrahepatic disease; and high serum carcinoembryonic antigen (> 200 ng/mL).10,11 Each of these factors on their own does not preclude the offer of surgery, and only when more than three factors coincide does the postsurgical prognosis seem poorer.10,11 However, it must be remembered that these scoring systems were derived in an era before the modern use of effective chemotherapy became adopted widely. Novel surgical strategies, such as preoperative portal vein embolization to increase future remnant liver to an acceptably safe volume or two-stage hepatectomy to allow compensatory hepatic hyperplasia before completion of R0 resection,5-7 have also widened the number of resectable patients, including patients with extensive liver-only disease. These changes in the definition of resectability mean that more than 20% of patients with liver metastases can now be considered for surgery with curative intent at the outset, and the 5-year overall survival rate exceeds 50% in single12-14 and multicenter series.15 Furthermore, long-term survival after resection of pulmonary colorectal metastases mirrors that seen after surgery for liver metastases, with similar prognostic indices to those seen with liver resection.8,16-19 The 2003 French Guidelines on the Management of Colorectal Liver Metastases recognize an important subdivision within patients being considered for liver resection.20 These guidelines stratify operable patients into different classes. Patients who are easily resectable (involvement of up to four of the eight anatomic liver segments and noninvolvement of the vena cava, at least one hepatic vein, and the contralateral portal pedicle) are defined as class 1. Patients whose disease is potentially resectable but involves five to six liver segments and/or contralateral major vascular structures within the liver are defined as class 2.20 These guidelines recommend that class 1 resections should be within the ability of most hepatobiliary surgeons and that class 2 resections should be performed by experienced liver surgeons working within recognized major liver units.20 Whether or not locally destructive therapies using radiofrequency and microwave ablation techniques confer survival benefit remains to be proven.14,21 Modern chemotherapy using cytotoxic agents alone offers extension of median survival time to 2 years in patients with nonresectable disease.22-25 When monoclonal biologic agents are added to cytotoxic chemotherapy, the possible median survival time extends beyond 2 years, and 20% of patients will still be alive 4 years after detection of nonoperable liver disease.26-28 It is conceivable that a median survival time of more than 30 months will be seen in studies presented later this year.29 The biggest breakthrough in the management of advanced colorectal cancer over the last decade has been the ability of medical oncologists, using modern cytotoxic agents, to convert inoperable liver disease to resectable disease.30-63 Resectability rates after chemotherapy vary widely, from 6% to 60%, and this wide discrepancy reflects patient selection, study design, and variations in institutional definitions of resectability.30-63 However, it is now clear that resection rates directly reflect response rates to chemotherapy,64 and 5-year survival rates after subsequent liver resection approach the rates seen after primary liver resection in initially resectable disease.32,33 Although there are anecdotal reports of complete pathologic responses to cytotoxic chemotherapy,65,66 such observations have not been reported in any of the large-scale chemotherapy studies referred to earlier. In single-institution reports, the radiologic complete response rate is approximately 7%,67 and mapping of resection should still rely on prechemotherapy (baseline) imaging studies to minimize hepatic recurrence rates in patients who undergo resection after preoperative chemotherapy.68 An additional benefit of neoadjuvant chemotherapy on intention to resect is that response to chemotherapy may well be a surrogate marker for the success of liver surgery. Few patients who experience progression on chemotherapy and yet who still remain resectable are still alive 5 years after hepatectomy.67 When we combine the advances in surgical resection (redefinition of resectability and conversion of inoperable disease to resectable disease using chemotherapy) with the survival benefits seen using modern chemotherapy regimens, the overall 5-year survival rate in advanced colorectal cancer now exceeds 20%. However, these advances have not been reflected in our present approach to staging advanced colorectal cancer. When Cuthbert Dukes wrote his seminal paper on the staging of primary rectal cancer in 1932, he deliberately excluded patients whose cancer had already spread to the liver at the time of diagnosis. To include these patients was pointless because they had incurable disease and would soon inevitably die; therefore, there was no Dukes’ stage D. Even today, patients whose disease has metastasized beyond the lymph node basin of the primary tumor are collectively grouped by the 2002 AJCC Cancer Staging Manual (sixth edition) as having stage IV disease, with no differentiation based on prognosis between site and extent of metastatic disease.69 This restriction probably reflects a continuing reliance on the TNM system of cancer staging introduced by the International Union Against Cancer in 1958 at a time when patients with advanced colorectal cancer had little prospect of surviving more than 6 months from the time of diagnosis. TNM is a staging system used to stratify patients with respect to predicted prognosis and to identify patients at increasing risk of recurrence or with de novo end stage disease and incurable metastatic spread at presentation. If earlier stages (I, II, and III) are useful to indicate appropriate further clinical management (ie, whether or not patients need to be offered adjuvant treatment), the present stage IV reflects the outdated concept of end stage for an ending patient. The present stage IV does not allow clinicians to stratify patients according to prognosis or guide therapeutic decision making and allow comparison of results of radical and nonradical treatments. Moreover, the present definition of M1 seems to be inadequate to encompass patients with delayed appearance of overt metastases because rapidly evolving diagnostic techniques will detect disseminated disease at decreasingly shorter time intervals after apparently curative R0 surgery for primary colorectal cancer. Therefore, the treatment intention for these patients (radical, nonradical, or supportive therapy) will impact strongly on survival of these patients. Presently, stage IV covers a group of patients whose outlook varies from incurable, with a prognosis of maybe only 6 months of survival time, to potentially curable and clearly does not match our current stage-based treatment strategies and outcomes. Furthermore, the new approach of converting incurable nonresectable metastatic disease to resectable disease with potentially curative intent (changing a prognosis of 0% survival at 5 years to > 35% and probable cure) represents a seismic shift in therapeutic strategy for which we currently have no appropriate terminology. Such a strategy is not downstaging within the current terminology because these patients presently remain within a globally encompassing stage IV. The concept of downsizing remains something we might do with our homes in later middle age, after the kids leave home, and has no oncologic equivalent. PROPOSAL These changes call for new thinking in both nomenclature and staging. We now need to differentiate between metastatic disease that is resectable with curative intent and metastatic disease that is not resectable. It may be helpful within the latter group to discriminate between those patients who, in the opinion of an experienced multidisciplinary team, might possibly become resectable after a course of chemotherapy and those patients whose disease remains incurable, even after an apparent complete radiologic response to treatment. Furthermore, it might be helpful to differentiate between liver-only disease, disease involving both liver and extrahepatic sites, and metastatic disease exclusively outside the liver (eg, peritoneal carcinomatosis, disease involving the aortic lymph node chain, and so on). We also need to discriminate between administering chemotherapy in the true neoadjuvant setting, having already predetermined that the patient is resectable at the outset and will be coming to resection with curative intent, and the administration of chemotherapy to patients who have disease that is borderline resectable or whose disease could become resectable if they achieve a partial (or better) response to chemotherapy. Perhaps a better description of the role of such chemotherapy might be neotherapeutic to differentiate the intention of this treatment from true neoadjuvant chemotherapy? Such a treatment strategy needs to be clearly defined to the patient at the outset, with clear end points after a predetermined number of chemotherapy cycles and being mindful of the effects of long-term chemotherapy in causing hepatic fibrosis and steatosis.70,71 Thus, should we consider a new staging system for colorectal cancer that has spread beyond the N2 lymph node station of the primary tumor? The new stage IV would be stratified into the following two main groups according to resectability for cure: stage IVR for patients with resectable disease and stage IVU for patients with unresectable disease. Stage IVR would be further divided into IVRa (resectable liver only), IVRb (resectable extrahepatic only), and IVRc (resectable hepatic and extrahepatic). Unresectability should only be assessed by an experienced site-specific surgical oncologist at the time of detection. Stage IVU could be further divided into IVUa (unresectable liver only), IVUb (unresectable extrahepatic only), and IVUc (unresectable hepatic and extrahepatic). Clearly, there is much to discuss within these early proposals. If, as some authors suggest,16-19 prognosis after resection of pulmonary metastases is similar, number for number, to that seen after resection of liver metastases, then maybe resectable single-site lung and liver disease should be grouped together in stage IVRa? The proposals outlined earlier should be subjected to expert surgical review and be tested robustly in real life because there could be fears that nonexpert surgeons and nonsurgeons might be tempted to stage such patients before referral to a specialist center. If these proposals were to be adopted, unless they were rigorously tested beforehand, there is a real danger that staging decisions by nonexperts could lead to inaccurate reflection of the patient population in any summary statistics. Another area of contention that will need to be addressed is that of overall number of metastases. There are those who contend that the overall number of metastases is as important as their site in resectable metastatic disease.8 Number of metastases has long been regarded as a prognostic factor,10,11 and so in stage IVRa patients, we would expect poorer outcomes after resection of four metastases versus one metastasis, or in stage IVRb patients, we would expect a better outcome in patients with one resectable extrahepatic tumor compared with three resectable extrahepatic tumors. Furthermore, in the unresectable stage IVU patients, stage IVUb may represent one or more than one extrahepatic site. Any formal adoption process of these proposals should consider the practical workability of further prognostic substratification that reflects real differences in prognosis after surgical resection. The aforementioned French classification is not included in the new stage IV for two reasons; the feasibility of a liver resection (easy or difficult) does not imply a strict correlation with prognosis, and in patients with marginally resectable tumors (class 2), the opinion of an expert surgeon, as suggested by the 2003 French guidelines, will classify the patients as IVR or IVU. Such a restratification should alert physicians to the possibility of curative treatment strategies in advanced disease. In addition, adoption of this system would provide clear indications of the type of therapy (surgery for stage IVR and chemotherapy or other therapy for stage IVU). Moreover, if the intent of treatment is to convert patients from stage IVU to IVR, then the term downstaging acquires a new meaning and is now formally correct. This approach might be considered analogous to the current staging of advanced ovarian cancer,69 in which relatively large-volume but localized pelvic peritoneal disease amenable to surgical resection remains within stage III, rather than being classified as stage IV (distant metastatic disease). The new staging system would represent a basis for more direct comparison of results from different institutions and would allow further stratification for subset analyses within future trials of new treatment strategies. Advanced colorectal cancer is rapidly evolving from an acute terminal illness into a chronic and manageable condition. The increasing evidence of chemotherapy response that is sufficient to render previously nonresectable disease now resectable with curative intent opens up the possibility that achieving resectability could become a recognized end point for future clinical trials in medical oncology. Although this new classification proposal would need to be validated prospectively, we believe that there is sufficient evidence to support its adoption since prognosis (within stage IV) is now clearly different between these two groups in relation to resectability and also to sites (single and multiple) of metastatic disease. Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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Author Contributions
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J Clin Oncol 23:1799-1802, 2005 67. Adam R, Pascal G, Castaing D, et al: Tumor progression while on chemotherapy: A contraindication to liver resection for multiple colorectal metastases. Ann Surg 240:1052-1061, 2004[CrossRef][Medline] 68. Vauthey J-N, Abdalla EK: Unresectable hepatic colorectal metastases: Need for new surgical strategies. Ann Surg Oncol 13:5-6, 2006 69. American Joint Committee on Cancer: AJCC Cancer Staging Manual (ed 6). New York, NY, Springer Verlag, 2002 70. Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004 71. Bilchik AJ, Poston GJ, Curley SA, et al: Neoadjuvant chemotherapy for metastatic colon cancer: A cautionary note. J Clin Oncol 23:9073-9078, 2005 This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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