Colon Cancer: Controversies in Surgical/Medical Therapy of Stage 2 Disease
Howard Ross, MD, FACS, FASCRS
Chief,
Director, Crohn’s and
Director, Minimally Invasive Surgery
An important unresolved area in the clinical care of the cancer patient is the use of adjuvant chemotherapy in completely resected, pathological stage 2 disease. Patients with stage 2 colon cancer represent a heterogenous group, including patients with both T3 and T4 depths of invasion. Though chemotherapy for stage 3 disease is considered standard practice, the use of chemotherapy for stage 2 adenocarcinoma of the abdominal colon has been individualized.
Revised Colon Cancer Staging System
The importance of a thorough review of the trials evaluating chemotherapy for stage 2 disease is highlighted by the recent finding that stage IIIa colon cancer patients exhibit statistically significantly better survival than stage IIb. Using nationally representative Surveillance, Epidemiology, and End Results (SEER) data, and the revised American Joint Committee on Cancer (AJCC) sixth edition cancer staging system which increased the stratification within colon cancer stages II and III, patients with Stage IIB (T4N0) exhibited 5 year survival of 72 % while Stage IIIA (T1-2N1) patients had better, 83%, five year survival. That these stage 2B patients fared worse than 3A patients might be related to increased utilization of chemotherapy for stage 3 patients.1 Further, the fact that almost a third of stage 2 patients die of disease illuminates an opportunity to attack micrometastatic disease and yield a benefit from adjuvant therapy (5 year survival for stage 2A disease is 72.2%).
Evolution of chemotherapeutic approach to stage 2 disease.
Chemotherapy was shown to prolong survival of patients who had surgical resection of colon cancer in 1988. The landmark study, (NSABP) Protocol C-01, was a prospective randomized study of 1,166 patients with Dukes B and C carcinoma of the colon. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. The findings from this study were the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.2
The first report suggesting chemotherapy should be restricted to node positive disease was the North Central Cancer Treatment Group (NCCTG) trial in which 401 patients with Dukes' B or C colon cancer were randomly assigned to observation or one year of levamisole with or without 5-FU. Though Levamisole was used and is no longer, a significant survival benefit was only evident in node-positive disease3.
Studies to date have documented the appropriateness of replacing Levamisole with Leukovorin, the efficacy of 6 months length of treatment as compared to a year, and the utility of oxaliplatin in addition to 5 fluorouracil and Leukovorin.4-6 These studies and others have clearly established a significant prolongation of overall survival for stage 3 disease with FOLFOX therapy. Chemotherapy for stage 3 colon cancer represents standard of care in 2009.
The ability of adjuvant therapy to prolong survival for Stage 2 disease is much less clear. The great multitude of studies revealing the efficacy of adjuvant chemotherapy were conducted on patients with both stage 2 and 3 colon cancer. When stage was analyzed on its own however, significant survival benefits often were restricted to patients with lymph nodes that contained cancer (stage 3). Trends toward enhanced survival in stage 2 patients were commonly revealed, pushing investigators to conduct additional investigation.
The QUASAR trial was published in 2007 and specifically sought to determine whether patients with stage 2 disease benefit from adjuvant therapy after resection with regard to survival. In the QUASAR trial 3239 patients (2963 [91%] with stage II [node negative] disease, 2291 [71%] with colon cancer were enrolled between May, 1994, and December, 2003. Patients from 150 centers in 19 countries were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Until 1997, levamisole (12 courses of 450 mg over 3 days repeated every 2 weeks) or placebo was added. After 1997, patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only. The primary outcome was all-cause mortality. Analyses were done by intention to treat. At the time of analysis, 61 (3.8%) patients in the chemotherapy group and 50 (3.1%) in the observation group had missing follow-up. After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumor site, stage, sex, age, or chemotherapy schedule. The authors concluded that chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen translated into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).7
Another important study, though underpowered to reveal small survival differences, was the 2007 work by Shippinger et al. This study, like the QUASAR trial sought to determine the survival advantage of Stage 2 patients who undergo adjuvant chemotherapy. In their work, patients with stage II colon cancer were randomized to either adjuvant chemotherapy with 5-FU/LV (100 mg/m2 LV+450 mg/m2 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were available for analysis. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) had died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumor relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Disease-free survival was not significantly different between the two trial arms though a suggestive slight improvement was realized.8
Prospective randomized trials published in the 1990’s also failed to reveal a survival benefit for stage 2 patients. Moertel et al in the Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer showed a decreased relapse rate without a significant improvement in survival.9 The International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators also failed to show a survival benefit for stage 2 patients.10
Meta-analyses
The ability to pool patient data from a number of well controlled studies can help yield answers to clinical dilemmas when a large number of observations are required because the difference between groups are small. Buyse and Pidois in their work , “Should Dukes B patients receive adjuvant therapy: a statistical perspective” specifically evaluated the number of patients needed to identify a realistic treatment benefit. Buyse suggests that with an absolute risk reduction of 4% for Dukes B patients treated with adjuvant therapy, the number of patients required to study to prove a survival difference at 5 years from surgery would be about 4700. These authors analyzed the studies published to date and concluded that it was likely there is some benefit to adjuvant therapy for the Dukes B patient, however individual studies were too small to identify the difference and meta-analyses were required.11
Mamounas et al performed the first meta-analysis investigating adjuvant therapy for completely resected stage 2 colon cancer. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, the authors examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment. The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV. Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors. These authors then concluded that patients with Dukes' B colon cancer benefited from adjuvant chemotherapy and recommended that Dukes B patients should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.12
In 2004 an Intergroup analysis which included pooled individual data from 3302 patients with stage II or III colon cancer who were enrolled on seven randomized trials comparing LV- or levamisole-modulated 5-FU versus surgery alone was performed. In multivariate analysis adjusted for the three major factors independently influencing prognosis (T-stage, histologic grade, and nodal status), adjuvant chemotherapy was associated with a significant 30 percent relative reduction in the risk of recurrence and a 26 percent reduction in the risk of death overall. For patients with node-negative disease, this relative benefit translated into a statistically significant absolute improvement in five-year DFS that favored chemotherapy (76 versus 72 percent), but there was only a trend toward better OS (81 versus 76 percent). In their multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets including sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Gill et al concluded that patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade.13
In all controversies, differences of opinion must exist. Figuredo et al found a small benefit in disease free survival to patients with stage 2 disease who underwent adjuvant therapy, but did not find a statistically significant difference in overall survival. In their work, “Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group” Figuredo evaluated 37 trials and 11 meta-analyses and concluded, “in summary, there is no compelling evidence to advise standard use of systemic adjuvant therapy for patients with stage II resected colon cancer. There is probably a small survival benefit for adjuvant treatment that present trials have not detected as significant. The important question is whether this small benefit might prove to be clinically significant for recommendation as standard therapy. In this update of the 1997 Cancer Care Ontario Progam in Evidence Based Care meta-analysis of trials comparing adjuvant therapy to observation, survival data were available for 4,187 patients with stage II disease across18 trials. Using the more conservative random effects model, the mortality RR across the trials was 0.87 (95% CI, 0.75 to 1.01; P .07). This overall result must be interpreted cautiously because this was a selected group of trials using a variety of adjuvant therapies. Of more interest are the pooled results of studies of commonly used adjuvant treatments. Pooling the results of three trials investigating FU plus levamisole led to a mortality RR of 0.90 (95% CI, 0.71 to 1.13; P _ .35). Combining these results with those of the five trials of FU plus folinic acid included in the IMPACT B2 analysis resulted in an RR of 0.86 (95% CI, 0.73 to 1.01; P -.07).14
Toxicities of Adjuvant Therapy and Impact on Quality of Life
The Quasar study group looked specifically at the complications of adjuvant therapy and the impact of chemotherapy on quality of life. The relative risk of death from any cause in patients with stage II cancer was 0·84 (95% CI 0·68–1·00; p=0·046). Serious, unexpected adverse events were rare: (0.5%) patients in the chemotherapy group and (0.25%) of those in the observation group died from non-colorectal cancer causes within 30 weeks of randomization . Only one of these deaths was deemed to be possibly chemotherapy related. Quality-of-life measurements directly related to expected toxicity (diarrhea, nausea, vomiting, mouth pain, fatigue, appetite loss, and social functioning) were worse in those patients in the chemotherapy group than in those in the observation group (p<0.001 for all categories), but only during chemotherapy. Chemotherapy patients with clinician-rated grade 3/4 toxicity reported worse global quality of life than did those with lesser or no toxicity. The only material difference between chemotherapy regimens was between schedules with more grade 3/4 toxicity with the four-weekly than the once-weekly schedule. The proportion of patients with grade 3/4 nausea (6% patients vs 1%), oral adverse events (10% vs 0%), diarrhea (11% vs 5%), neutropenia (7% vs 1%), and any grade 3/4 toxicity (31% vs 10%) was significantly greater with 4-week courses of chemotherapy than with once-weekly delivery (p<0·001 for all adverse events).
Resource usage, other than for chemotherapy administration, did not differ between patients randomized to chemotherapy and observation. A utility score
for QUASAR chemotherapy was not measured directly, but in view of the minor effect of chemotherapy on quality of life, was estimated to be 0.7 during the 6 months of chemotherapy—ie, a loss of about 8 weeks of full health life. To assess cost-effectiveness as cost per quality-adjusted life-year (QALY), the average life-years gained through improved survival with chemotherapy were estimated by use of UK national mortality statistics and the QALYs lost during chemotherapy by assigning a utility score to quantify the reduction in health-related quality of life while undergoing chemotherapy. Sensitivity analyses indicate that the two chief determinants of cost per QALY are the size of survival benefit from chemotherapy and the life expectancy (ie, age) of the patient. For patients under the age of 70 years, there was a net gain of a few months of QALYs even with the lowest estimate of treatment efficacy. By the age of 80 years, only at the highest estimate of treatment efficacy was a small net benefit seen.
Identification of Patients with High Risk Stage 2 Disease
The identification of those stage 2 patients who possess disease which may be associated with diminished survival and might receive the most benefit from adjuvant therapy is important to all physicians who treat colon cancer. The colon and rectal surgery group at Memorial Sloan Kettering Cancer Center assessed the prognostic significance of commonly reported clinicopathologic features of Stage II colon cancer to identify high-risk patients. The authors utilized their prospectively maintained database to identify 448 patients with Stage II colon cancer who had been treated by curative resection alone between 1990 to 2001. With median follow-up of 53 months, 5-year disease-specific survival for this cohort was 91 percent. Univariate and multivariate analyses identified three independent features that significantly affected disease specific survival: tumor Stage T4 (hazard ratio (HR), 2.7; 95 percent confidence interval (CI), 1.1–6.2; P=0.02), preoperative carcinoembryonic antigen >5 ng/ml (HR, 2.1; 95 percent CI, 1.1–4.1; P=0.02), and presence of lymphovascular or perineural invasion (HR, 2.1; 95 percent CI, 1–4.4; P=0.04). Five-year disease specific survival for patients without any of the above poor prognostic features was 95 percent; five-year disease specific survival for patients with one of these poor prognostic features was 85 percent; and five-year disease specific survival for patients with ≥2 poor prognostic features was 57 percent.
The authors concluded that, the presence of multiple adverse prognostic factors allows identification a high-risk subgroup. Use of commonly reported clinicopathologic features accurately stratifies Stage II colon cancer by disease-specific survival. They believe that those identified as high-risk patients can be considered for adjuvant chemotherapy and/or enrollment in investigational trials.15
Lymph Node Harvest and Survival in Stage 2 disease
The question of what is the optimum number of lymph nodes from a colon resection to ensure accuracy of staging has been extensively studied and debated. Chang et al. performed a thoughtful analysis of studies identified from major databases to assess the association between lymph node evaluation and oncologic outcomes in patients with colon cancer. Specifically Medline, Scopus, Cochrane, and the National Guidelines Clearinghouse databases were searched from January 1, 1990, through June 30, 2006, for studies in which survival data as a function of number of lymph nodes evaluated were available. These studies were evaluated for methodologic quality, design, and data source. A total of 61,371 patients were included. Seventeen studies from nine countries were eligible for systematic review, including two secondary analyses of multicenter randomized trials of adjuvant chemotherapy for colon cancer, five population-based observational studies, and 10 single-institution retrospective cohort studies. Despite heterogeneity in methodology and differences in threshold numbers of lymph nodes evaluated (range = 6 – 40 lymph nodes), 16 of 17 studies reported that increased survival of patients with stage II colon cancer was associated with increased numbers of lymph nodes evaluated. (Four of six studies with data from stage III patients also reported a positive association with survival among patients with stage III colon cancer). In their discussion, these authors pointed out limitations in the literature and noted that the heterogeneity of the quality of reported series and the type of comparisons performed within each individual study limit comparisons among reported series and do not permit the quantitative evaluation of aggregate data or the determination of a clear cutoff value of the number of lymph nodes evaluated that is associated with improved survival. Because all of the studies were observational (a randomized controlled trial to compare different numbers of lymph nodes evaluated is not possible until all of the determinants of lymph node numbers can be controlled), a causal relationship between the number of lymph nodes evaluated and colon cancer survival could not be definitively established. Although the association between lymph node recovery and colon cancer outcomes was clear, it was difficult to assess the strength of this association because it is not possible to separate the effect of improved staging accuracy from the survival advantage resulting from more lymph nodes being recovered from a tumor’s drainage distribution.
With regard to stage 2 disease, accurate lymph node staging of patients is a prognostic factor, and it affects subsequent treatment. The need for complete identification of a tumor’s draining lymph nodes was demonstrated by studies in which the proportion of patients with at least one positive lymph node has been shown to increase as the total number of lymph nodes recovered increases. However, several reports show diminishing returns for improved staging accuracy beyond examination of 12 – 17 lymph nodes. Studies from the NCDB, SEER and the secondary analysis of Intergroup 0089 separately evaluated N0 patients with more than 20 lymph nodes evaluated. The analysis in the INTACC trial used 18 or more lymph nodes as the highest category for the number of lymph nodes recovered. In these trials, even at the highest strata of the number of lymph nodes evaluated, increased survival was associated with increased numbers of lymph nodes evaluated.16
Molecular Staging
Dissatisfaction with the ability to predict which stage 2 colon cancer patients will ultimately develop metastatic disease has led to a search for molecular markers that can more accurately assess occult metastases in regional lymph nodes in patients with pN0 colorectal cancer and improve risk stratification in this clinically heterogeneous population. Molecular staging could overcome limitations in the detection of occult lymph node metastases by incorporating all available tissue into analyses and increasing detection sensitivity through quantifiable disease-specific molecular markers Guanylyl Cyclase C (GCC) is a protein expressed by normal intestinal and colorectal cancer cells, but not by extra-intestinal tissues, and may be suited for the detection of metastatic colon tumor cells in lymph nodes. Waldman et al examined the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase–polymerase chain reaction, with recurrence and survival in patients with colorectal cancer. These authors conducted aprospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals). 2570 fresh lymph nodes measuring 5 mm or larger were evaluated for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months (range, 2-63 months) for disease recurrence or death. Time to recurrence and disease free survival relative to expression of GUCY2C in lymph nodes was recorded. Thirty-two patients (12.5%) had lymph nodes negative for GUCY2C (pN0 [mol−]), and all but 2 remained free of disease during follow-up (recurrence rate, 6.3%; 95% confidence interval [CI], 0.8%-20.8%). Conversely, 225 patients (87.5%) had lymph nodes positive for GUCY2C (pN0 [mol+]), and 47 developed recurrent disease (20.9%;95%CI, 15.8%-26.8%) (P=.006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 (mol+) exhibited earlier time to recurrence (adjusted hazard ratio, 4.66; 95% CI, 1.11-19.57; P=.04) and reduced disease-free survival (adjusted hazard ratio, 3.27; 95% CI, 1.15- 9.29; P=.03). Waldman and his group concluded thatExpression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer.
It was interesting to note that current standard of care includes adjuvant chemotherapy for patients with stage III pN1 disease, a cohort with a recurrence rate in this study identical to patients with pN0 (mol+). In the discussion of their paper, these authors commented that molecular staging represents one component of a comprehensive diagnostic, prognostic, and predictive strategy to personalize management strategies for individual patients. It provides adjunctive clinicopathological information that supplements, but does not replace, complimentary anatomical, microscopic, and morphological staging modalities. 17
Lurje et al utilized Interleukin 1 beta (IL1B) and interleukin 1 receptor antagonist (IL1RN) in an effort to identify a molecular marker for tumor recurrence in stage II colon cancer patients. Interleukin 1 beta (IL1B) and interleukin 1 receptor antagonist (IL1RN)have been shown to play a critical role in the early onset of tumor-associated angiogenesis. In their study, eight functionally significant polymorphisms within six genes of the angiogenesis pathway [IL1B, IL1RN, vascular endothelial growth factor A (VEGFA), VEGF receptor 2, interleukin-8, cyclooxygenase-2] were tested to evaluate if they will predict the risk of tumor recurrence in stage II colon cancer patients treated with 5-fluorouracil based adjuvant chemotherapy. Blood samples were obtained from 109 patients with stage II colon cancer at the University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism protocols. Patients harboring the IL1RN/IL1B 1-T-C (IL-1RN variable number tandem repeats (VNTR)/IL1B C+3954T/C-511T) haplotype were at greatest risk of developing tumor recurrence [relative risk (RR): 2.72, 95% confidence interval (CI): 1.22-6.08] (adjusted P=0.015). In addition, IL1B +3954 any T (RR: 2.78, 95% CI: 0.99-7.83) (adjusted P=0.043), IL1RN VNTR (RR: 6.09, 95% CI: 1.11-33.4) (adjusted P=0.038), and VEGFA -634 any C (RR: 2.91, 95% CI: 1.13-7.48) (adjusted P=0.026) were shown to be adverse prognostic markers, in both univariate and multivariable analyses. These authors concluded that polymorphisms in IL1B, IL1RN, and VEGFA as well as IL1B/IL1RN haplotype analysis may serve as molecular markers for tumor recurrence in stage II colon cancer, and analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.18
References
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16. Chang GJ , Rodriguez-Bigas MA, Skibber JM , Moyer VA Lymph Node Evaluation and Survival After Curative Resection of Colon Cancer: Systematic Review J Natl Cancer Inst 2007;99: 433 – 41.
17. Waldman SA, Hyslop T, Schulz S, Barkun A, Nielsen K, Haaf J, Bonaccorso C, Li Y, Weinberg DS. Association of GUCY2C Expression in Lymph NodesWith Time to Recurrence and Disease-Free Survival in pN0 Colorectal Cancer
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18. Lurje G, Hendifar AE, Schultheis AM, Pohl A, Husain H, Yang D, Manegold PC, Ning Y, Zhang W, Lenz HJ. Polymorphisms in interleukin 1 beta and interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer. Pharmacogenet Genomics. 2009 Feb;19(2):95-102.