Quality of Survival Reporting in Chemotherapy and Surgery Trials in Patients with Metastatic Colorectal Carcinoma

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1 1389 Quality of Survival Reporting in Chemotherapy and Surgery Trials in Patients with Metastatic Colorectal Carcinoma Robert C. G. Martin, M.D. 1,2 Vedra A. Augenstein, M.D. 1,2 Charles R. Scoggins, M.D. 1,2 Kelly M. McMasters, M.D., Ph.D. 1,2 1 Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky. 2 The James Graham Brown Cancer Center, Louisville, Kentucky. BACKGROUND. Patients with metastatic colorectal carcinoma (MCC) to the liver receive conflicting management recommendations because of the lack of prospective randomized controlled trials (RCTs) clarifying the optimal management in this disease. The oabjective of the current study was to evaluate the reporting of prognostic factors in MCC from chemotherapy and surgery trials and evaluate the ability to compare these results across treatments. METHODS. RCTs and retrospective series of greater than 75 MCC patients published between were reviewed to identify 10 critical prognostic elements of overall survival reported in both types of journals. RESULTS. A review 92 RCTs and 116 retrospective reports with 64,898 patients analyzed found 7 (3%) reporting all prognostic factors, with both studies demonstrating no difference in the success of reporting criteria met. The only criterion that was universally reported among both chemotherapy and surgery trials was the mortality rates of the study. All remaining prognostic factors in the evaluation of overall survival were significantly different between both chemotherapy and surgical studies. Considerable variation was observed in the disease-free interval, number of hepatic metastases, size of hepatic metastases, and performance status, and were significantly different among some of the most significant factors for patients evaluating treatment: complication reporting, surgical margin evaluation, and overall response rate. CONCLUSIONS. The reporting of results in MCC in chemotherapy trials and surgical reports is limited to general outcomes, with a paucity of prognostic factors, which hinders any ability to compare results across treatments. A mandatory reporting criteria of all metastatic colorectal trials is imperative to optimally manage these patients in both academic and community centers. Cancer 2006;106: American Cancer Society. Address for reprints: Robert C.G. Martin, M.D., Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, 315 East Broadway, Room 313, Louisville, KY 40202; Fax: (502) ; robert.martin@louisville.edu Received July ; revision received August ; accepted September KEYWORDS: metastatic colorectal carcinoma, surgery, chemotherapy, outcomes. In the U.S., there are approximately 150,000 new cases of colorectal carcinoma diagnosed each year. Of these patients, 25% will present with synchronous liver metastases and another 50% will eventually develop metachronous lesions. 1 Ultimately, 99,000 of all patients with colorectal carcinoma will develop metastasis to the liver and other organs. This large number of patients has made metastatic colorectal carcinoma (MCC) the second leading cause of cancer-related death in North America. 2 Given the magnitude of this problem (approximately 40,000 new patients will present with hepatic colorectal metastases each year), it is crucial that consistent, effective, optimal, and welltolerated treatments be available to all patients regardless of age. Because to our knowledge no mandatory reporting criteria exist for 2006 American Cancer Society DOI /cncr Published online 1 February 2006 in Wiley InterScience (

2 1390 CANCER March 15, 2006 / Volume 106 / Number 6 MCC treatment trials, there is limited ability to compare results of treatment in these studies. Patients with MCC to the liver receive conflicting management recommendations because of the disparate reporting of chemotherapy and surgical studies. Despite a plethora of reports in MCC for both surgery and chemotherapy, there has been only a limited ability to compare these results across established prognostic factors. The oabjective of the current study was to evaluate the reporting of prognostic factors in MCC from chemotherapy and surgery trials and evaluate the ability to compare these results across treatments. MATERIALS AND METHODS A review of the literature was performed to assess the quality of reporting prognostic factors in therapeutic trials for MCC to the liver. We reviewed the English language literature indexed in MEDLINE and the Cochrane Database of Systematic Reviews from Subject terms used were colorectal neoplasms, colonic neoplasms, or rectal neoplasms with the secondary subheading applied, as well as treatment subheadings. The results were combined with retrospective studies, prospective studies, or randomized controlled trials, used as subject terms and as textwords. All prospective randomized studies and large retrospective studies with greater than 75 patients were included in this evaluation. Additional studies were identified from the reference lists of MEDLINE-identified studies. Articles were divided into two groups pertaining to the principal treatment modality: surgery versus systemic therapy. A thorough review of all articles was performed to evaluate the reporting of prognostic factors in patients with MCC treatment related to overall survival or disease-free survival. From this review, 10 proposed prognostic factors were identified as being the most powerful predictors of outcome in these patients (Table 1). The factors examined were: mortality, performance status, complications, carcinoembryonic antigen (CEA) level, disease-free interval, number of liver metastasis, size of liver metastases, lymph node status of the primary tumor, distribution of metastasis in the liver/tumor volume/type of organ metastasis, and surgical margin or response rate, depending on the treatment. The reason the last two factors distribution of metastasis on the liver/tumor volume/ type of organ metastasis and surgical margin/ response rate were combined relates to the lack of consensus regarding the prognostic implications of these factors; therefore, they were combined for this review. TABLE 1 The 10 Prognostic Criteria for Article Evaluation Criteria Mortality Type of organ metastasis Distribution of metastasis Tumor volume Disease-free interval No. of hepatic metastasis Size of hepatic metastasis CEA Lymph node-positive primary tumor Performance status Complications Surgical margin or response rate CEA: carcinoembryonic antigen. Clarification of criteria Death from treatment administered Type of organs with metastasis, or the organs with metastasis, or the extent of organ involvement Time from primary colon tumor to metastasis Self-explanatory Self-explanatory At the time or metastatic disease Yes or no World Health Organization or Karnofsky Type of complications Self-explanatory FIGURE 1. Metastatic colorectal publications in chemotherapy and surgery by year published. RESULTS A total of 208 articles were reviewed, with 64,898 patients analyzed. This review included 92 randomized control trials (RCTs) (75 systemic therapy and 17 surgical therapy trials) involving 15,777 patients (12,784 treated with systemic therapy and 2993 treated with surgery); 116 retrospective reports (13 systemic therapy and 103 surgery trials) involved 49,121 patients (1982 treated with chemotherapy and 47,139 treated with surgery). Publications regarding the management of patients with MCC have continued to expand, with the most rapid growth occurring within the last 10 years (Fig. 1). Surgical reports have significantly increased by each 5-year interval, but have been predominantly retrospective. Although there was an even distribution of reports in both surgery and systemic therapy con-

3 Quality of Reporting in MCC/Martin et al TABLE 2 Articles by Specialty Reporting Overall Survival by Established Prognostic Factors for Chemotherapy and Surgery Prognostic factor reported in overall survival Chemotherapy (n 88) (%) Surgery (n 120) (%) Total (n 208) (%) P Mortality 81 (92) 108 (90) 189 (91) 0.8 Type of organ metastasis/distribution metastasis/tumor volume 75 (85) 119 (99) 195 (93) Disease-free interval 50 (57) 110 (92) 160 (77) No. of hepatic metastasis 13 (15) 101 (84) 114 (55) Size of hepatic metastasis 17 (19) 83 (69) 100 (48) CEA 33 (38) 83 (69) 116 (56) Lymph node-positive primary tumor 38 (43) 88 (73) 126 (61) Performance status 67 (76) 28 (23) 95 (46) Complications 76 (86) 78 (65) 154 (74) Surgical margin or response rate 76 (86) 80 (67) 156 (75) No. of the 10 criteria met (7) 1 (1) 7 (3) (13) 9 (8) 21 (10) (34) 22 (19) 52 (25) (46) 81 (68) 121 (58) CEA: carcinoembryonic antigen. ducted in the U.S., the majority of systemic therapy (76%) and surgery studies (73%) were published in American journals. Articles by specialty reporting overall survival by established prognostic factors had significant variability across chemotherapy and surgery. A review of all 208 reports found 7 (3%) reporting all 10 prognostic factors, with only 29 (14%) reporting 9 prognostic factors. The median score was seven prognostic factors reported and the mean score was six, with the distribution shown in Table 1. RCTs were found to be no more thorough in reporting prognostic factors, but had higher quality reports when compared with retrospective studies (48% vs. 30%; scoring 7 9) for systemic therapy. For surgical trials, the retrospective studies had a higher reporting of prognostic data when compared with the RCTs (74% vs. 50%; scoring 7 9). Specific reporting criteria and the compliance rates are presented in Table 2. The only criterion that was universally reported among both systemic therapy and surgery studies was the mortality rates of the study. The type of organ metastasis/distribution of metastasis/tumor volume criteria was reported in 99% of the surgical reports, which primarily reported the lack of extrahepatic disease. This was significantly different from the chemotherapy studies, which reported a distribution of metastasis in 85% of the reports. All remaining prognostic factors were found to be significantly different between both systemic therapy and surgical studies. Considerable variation was noted with regard to the disease-free interval, number of hepatic metastases, size of the hepatic metastases, and performance status. Systemic therapy and surgical therapy studies were found to be significantly different among some of the most significant factors for patients evaluating treatment: complication reporting, surgical margin evaluation, and overall response rate. There was an even distribution between systemic therapy and surgical trials with regard to the number of criteria met among all studies. There was a slight increase in the number of surgical trials meeting seven to nine of the criteria; however, this was related primarily to the vast majority of surgical trials being performed in a retrospective manner. Even with a majority of chemotherapeutic trials being performed in a prospective, randomized control fashion, only 46% of these studies met the established 7 9 criteria. The reporting of prognostic factors for both surgical and systemic therapy trials is both widely varied and inconsistent. Of the 120 surgical trials reviewed, 77 (64%) presented survival as a 5-year survival rate, with 57 surgical trials (48%) presenting outcome as median survival, and 36 (30%) presenting outcome as both the 5-year survival rate and median survival. In contrast, a review of the systemic therapy trials demonstrated only 12 studies presenting outcome as either 1-year (n 1), 2-year (n 6), and 5-year (n 5) survival rates. A significantly greater number of systemic therapy trials (n 58 trials) presented outcome as a median overall survival. It is interesting to note that only 51 of the prospective RCTs in the chemo-

4 1392 CANCER March 15, 2006 / Volume 106 / Number 6 therapeutic management of MCC presented any form of survival outcome and this most commonly was presented as a median survival. Consistent limitations in systemic therapy trial reporting were evident across many of the known powerful predictors of outcome in MCC, including number of hepatic metastases, size of the hepatic metastases, CEA level, lymph node-positive primary colon tumor, and disease-free interval. Similarly, the surgical trials were consistently poor in reporting overall performance status of a patient, the degree or severity of complications, and the surgical margin status in patients who have undergone resection. The significant limitations in surgical trial reporting for both performance status and the severity of complications will continue to limit the ability of surgical trials to be compared with their chemotherapeutic studies. Less than 10% of all surgical trials evaluated reported the severity of complications, and in a majority of these studies they were labeled as either minor or major without any consistent definition for these descriptions. The consistent inability to utilize well-established and consistent grading scales will only further limit the ability of surgical trials to demonstrate the reported benefits of quality of life-improving surgical therapy in patients with MCC. DISCUSSION Colorectal carcinoma remains in the top 3 cancers in terms of both incidence and mortality for both men and women, with greater than 300,000 deaths reported to occur per year. This incidence and mortality has remained consistent among both developed and developing countries, as recently presented in the Global Cancer Statistics of With the continued resistance to widespread colorectal carcinoma screening, even in developed countries, this incidence (and therefore subsequent mortality) will continue to remain a significant health problem and management dilemma among oncology specialties. The liver remains the most common site of metastatic disease from the colon because of the dominant portal venous flow from the entire colon and a majority of the rectum. Because of this dominant flow, the liver has the ability to be the predominate focus for all metabolites from digestion and micrometastatic disease from the colon. Historic data have demonstrated that in autopsy studies 38% of patients who die of MCC may have the liver as the only site of metastatic disease. 4 These data suggest that if metastatic disease in the liver can be controlled by surgical resection or other means, survival may be improved. In fact, large, nonrandomized studies of surgical resection of colorectal metastases to the liver have demonstrated long-term survival in a significant fraction of patients. Over the last 30 years, aggressive management for colorectal hepatic metastases has allowed effective long-term palliation, prolonged survival, and, in some cases, cure. To our knowledge, there currently is no consensus regarding the optimal treatment of patients with colorectal metastases to the liver. Many physicians believe that MCC to the liver represents disseminated systemic disease, is incurable, and is not amenable to effective surgical treatment. Recently, because of clinical trials demonstrating a modest improvement in median survival with more aggressive chemotherapy regimens, some have called for chemotherapy to be the standard therapy for all patients with colorectal metastasis. 5 This statement is made even though the median overall survival is only slightly better than 1 year. Even recognizing this limitation, many physicians do not believe that MCC to the liver represents a surgically correctable disease. The primary basis for this belief has been that surgical resection of liver metastasis has not been proven by a randomized trial comparing surgery alone with chemotherapy alone. However, even with the greater that 10,000 patients who have undergone hepatic resection for colorectal metastasis, some physicians still appear surprised that some patients who undergo surgical resection od not develop disease recurrence 5 In the study by Nordlinger and Rougier, this sentiment was followed by the statement that there appears to be no explanation for why some patients with disseminated disease survive for longer than 5 years after local treatment only, without evidence of disease recurrence. 5 This skepticism regarding the benefit of surgical therapy continues and is the main reason why curative surgery has been offered to only a small number of patients with what are considered to be good preoperative prognostic factors. Author Bias Author bias, both surgical and chemotherapeutic, remains one of the strongest factors affecting treatment decisions for patients with MCC. This review demonstrates the continued limitations in all reports of the treatment for MCC. The limited data reported only continue to perpetuate the belief that patients treated with either surgery or chemotherapy are different and each specialty is treating a different type of MCC. The continued paucity of prognostic factor data presented in MCC literature based on prognostic factors will only continue this bias. The term unresectable is reported frequently in the MCC literature regarding disease in the liver. Without a true definition of unresectable, this term has no

5 Quality of Reporting in MCC/Martin et al meaning or permanence across all treating physicians. It is imperative that researchers provide information to the readers regarding the patient population and the breadth of reasons precluding surgical treatment. Most physicians in oncology, either surgical or medical, would agree that patients with a small single lesion in the liver would have a better prognosis than those who have multiple, larger lesions. However, to our knowledge, these data are rarely presented in systemic therapy trials, and only data regarding aggregate survival or response rate are reported. The number, size, overall volume, and distribution of the metastases remain key to instituting management strategies and thereby improving patient outcome across all oncology specialties. Because a majority of patients with MCC are treated outside an academic institution, author/physician bias only continues to play a stronger role in treatment decisions. Because a majority of community physicians obtain the latest treatment options from journals and conferences, a more complete and reproducible reporting of survival data must be presented, taking into account all pertinent prognostic factors, so that patient-specific treatment options can be discussed more thoroughly. Most oncologists, both surgical and medical, will agree that there are multiple presentations of MCC, and treatment options are weighed based on these variations. Therefore, why do we continue to report only general, vague, nonpatientspecific data for the practicing physician to offer to his/her patient? The surgical literature continues to demonstrate consistent author bias, with its refusal to adopt any form of complication severity scale or quality of life evaluation after surgical therapy. The well-established medical oncology complication scale has been effectively utilized for many years. However, the strongest author/physician bias remains the belief that a complication related to chemotherapy that requires surgical intervention is a ECOG Common Toxicity Criteria Grade 4 complication. This belief will only continue to hinder the reported benefits of surgical therapy, through the inability of the surgical literature to demonstrate quality of life improvement or dispel the belief that surgery is equivalent to the most severe chemotherapeutic toxicity. Only the consistent reporting of at least performance status both preoperatively and postoperatively will continue to dispel these beliefs in the medical oncology field. Prognostic Factors In the absence of prospective RCTs comparing chemotherapy to surgical therapy, one might use metaanalysis or a cohort comparison of the patients reported in the literature. However, this review demonstrated the near-impossible task of directly comparing surgical and chemotherapy studies. In general, the factors omitted in most reports are those pertaining to the number of hepatic metastasis and their size, the lymph node status of the primary tumor, patient performance status, and CEA level. CEA is often mentioned, but the actual levels are reported in only 51% of systemic therapy and 68% of surgery articles. Pretherapy values have been shown to be correlated with the extent of disease, resectability, and overall prognosis. Posttherapy levels also have been found to be integral in monitoring progression of disease, especially recurrence after resection. Because the importance of CEA levels correlating with therapy remains somewhat controversial, the guide for reporting should be simple: if CEA values exist for a group of patients, they should be reported. None of the systemic therapy studies reviewed herein reported survival for patients specifically with metastatic disease confined to the liver, even though it is recognized that this is the most frequent site, and often the only, site of metastasis. To our knowledge, all the studies regarding the use of chemotherapy in Phase III prospective randomized trials or in Phase II studies have reported outcome as either response rates or overall survival of the entire patient cohort. None of these reports have published survival data based on well-known and accepted prognostic factors in patients with MCC. Numerous surgical studies have demonstrated significant prognostic factors in managing MCC. 6 8 These factors (i.e., size of the lesion being 5 cm, more than 1 hepatic lesion, a CEA level 200 g/dl, a disease-free interval of 12 months, and a lymph node-positive primary tumor) and others have all been reported with varying survival statistics, demonstrating these factors to be highly predictive of a patient s overall outcome. Unfortunately, to our knowledge, none of these factors have been presented in some of the most important medical oncology reports in the last 3-4 years with the advent of both irinotecan 9 11 and oxaliplatin. 12,13 One of the main reasons stated for this is that the patients enrolled in these medical oncology reports had unresectable disease. However, when the entry criteria are evaluated, greater than 50% of these patients had disease contained in the liver, had a single hepatic metastasis, or an excellent performance status (either World Health Organization criteria 0 or 1). These continued differences in reporting have only made the management of patients with MCC more confusing. Response Rates Other limitations in the evaluation of the efficacy of chemotherapy in MCC were recently discussed at the

6 1394 CANCER March 15, 2006 / Volume 106 / Number 6 American Society of Clinical Oncology Congress in This report correctly stated that the way the clinical oncology society assesses the efficacy of treatment for hepatic tumors is, in general, questionable. There are now several reports in which the standard radiologic criterion for the assessment of response does not truly evaluate the biologic activity of these tumors. The conventional radiologic assessment of response does not necessarily reflect the true extent of the tumor-cell kill. Tumor size or volume has been found to be highly unreliable when compared with the utilization of tumor markers These reports alone call into question the notion that chemotherapy should be the first-line therapy in patients with MCC when the results are based primarily on response rates. Prospective Randomized Controlled Trial, the Answer? A logical solution to the optimal management of the patient with MCC would be a comparison of patients with similar predictive factors who were randomized to either surgery alone or chemotherapy alone. This trial, which in fact could help to clarify many of these ongoing debates, likely could never be completed because of physician bias. The goal of nearly all MCC trials is the prolongation of survival. From small research laboratories to major cancer centers, information regarding MCC is accumulating without a standardized framework. Invariably, this results in conflicting management recommendations and general inconsistency regarding the treatment of individual patients. By following mandatory reporting criteria for reports on MCC to the liver, incorporating the 10 prognostic factors outlined herein, researchers will create an efficient method of communication. As a result, the management of patients will be standardized according to the most successful therapeutic methods and patient care will be simplified, as well as made more fair. Potential benefits of this standardization system are enormous and will assist physicians in both academic and community centers and help improve the treatment of all patients with MCC to the liver. Ultimately, the management of patients with MCC to the liver requires a multidisciplinary approach. Most patients treated with surgical resection or ablation of liver metastases will experience disease recurrence, often at extrahepatic sites, and require systemic therapy. Durable complete response to systemic therapy is a rare event, and many patients initially treated with chemotherapy may be good candidates for surgical resection or ablation. The optimal timing and sequence of systemic and surgical therapy remains to be established in future clinical trials. 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