New Adjuvant Therapy for Colon Cancer

New Adjuvant Therapy for Colon Cancer

1055-3207/00 $15.00 + O .O COLORECTAL CANCER NEW ADJUVANT THERAPY FOR COLON CANCER Justified Hope or Commercial Hype Evanthia Galanis, MD, Steven R...

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1055-3207/00 $15.00 + O .O


NEW ADJUVANT THERAPY FOR COLON CANCER Justified Hope or Commercial Hype Evanthia Galanis, MD, Steven R. Alberts, MD, and Michael J. O'Connell, MD

Colorectal cancer is a significant health problem in the United States, with 130,200 new cases and 56,300 deaths occurring in 1999.20Of these, approximately 70% occurred in the colon. The stage of disease at the time of presentation remains the most important prognostic factor for colon cancer patient^.^ Given the excellent prognosis (more than 95% 5-year survival rate) for patients with stage I disease treated with surgery alone, adjuvant therapy is not recommended for this group. In contrast, adjuvant therapy has been shown to improve significantly cure rates for patients with stage I11 (Dukes' C) colon cancer. There is still controversy regarding the role of adjuvant therapy in patients with stage I1 (Dukes' B) disease. STANDARD ADJUVANT THERAPY FOR STAGE Ill DISEASE

The drug 5-fluorouracil (5-FU) has served as the primary agent far the treatment of colon cancer since Heidelberger's report describing the beneficial effects of 5-FU in a small group of patients with advanced colon cancer.53A subsequent trial of 5-FU as adjuvant therapy compared with observation after surgical resection showed a trend toward increased survival in the treated group.15 Given the possible benefits of 5-FU in the adjuvant setting, further clinical trials were performed using 5-FU in combination with other agents. Among them, levamisole (LEV) was chosen because of its immunomodulatory properties. In an English study published in 1987, 141 patients with resected Dukes' A, B, or C colon or rectal cancer were randomized postoperatively to observation, to From the Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9 NUMBER 4. OCTOBER 2000




5-FU alone, or to 5-FU and LEV.52The patients who received the 5-FU and LEV had a significantly longer survival than the patients in either of the other two groups. In a subsequent trial published in 1989, the North Central Cancer Treatment Group (NCCTG) and the Mayo Clinic randomized 401 patients with resected modified Astler-Coller (MAC) stage B,, B,, C,, or C, colon or rectal cancer to observation, LEV, or 5-FU and LEV.21Most (93%)of these patients had colon cancer and nearly half had Dukes' C disease. Significant improvement in disease-free survival was seen in each of the treated groups compared with the observation only group. This led to a national intergroup trial (INT 0035) of 1296 patients with resected Dukes' B, or C colon cancer. Patients with Dukes' B, colon cancer were randomized to either observation or to 12 months of 5-FU and LEV, whereas patients with Dukes' C colon cancer were randomized to observation, 12 months of LEV, or 12 months of 5-FU and LEV? For patients with Dukes' C colon cancer, the combination of 5-FU and LEV resulted in a 41%reduction in the rate of disease recurrence and a 33% reduction in overall death rate compared with the observation group. The use of LEV alone produced no significant benefit. The results within the MAC B, patients were equivocal. The combination of 5-FU and LEV, given over 12 months, was accepted by the National Institutes of Health Consensus Development Panel in 1990 as standard adjuvant therapy for patients with resected Dukes' C colon cancer.44 While the trials of 5-FU and LEV were underway, early studies of the drug leucovorin (CF) combined with 5-FU showed significant benefit in patients with metastatic colorectal c a n ~ e r .CF ~ , stabilizes ~~ the thymidylate synthase/5-FU complex and enhances the cytotoxic effects of 5-FU. Several trials were then underThe ~,~~,~~ taken to assess the efficacy of this combination in the adjuvant ~ e t t i n g . ~ InternationalMulticenter Pooled Analysis of Colon Cancer Trials (IMPACT)study pooled analyzed data from three studies (totalling 1526 patients): 5-FU/CF was compared with follow-up alone. Patients who received 5-FU/CF had a diseasefree survival rate of 62% compared with a rate of 44% in the untreated group after 37 months of f ~ l l o w - u p . ~ ~ The regimen of 5-FU/CF finally was established as standard adjuvant regimen for stage I11 colon cancer when the results of three intergroup studies were presented at the American Society of Clinical Oncology (ASCO) meeting in 1996. The NCCTG and National Cancer Institute of Canada (NCIC) trial compared 5FU/CF (6 months) with 5-FU/CF plus LEV (6 months) with 5-FU/LEV (1 year) and 5-FU/CF plus LEV (1 year). This study of 915 patients showed that 12 months of adjuvant chemotherapy with all three drugs offers no advantage over 6 months. In addition, 6 months of triple therapy produced a significantly superior 5-year overall survival and disease-free survival rate than the combination of 5-FU and LEV for 6 months (75%versus 63% and 70% versus 64%,respecti~ely).~~ The intergroup study 0089 initially presented in 199611and in final form in 199812involved 3759 patients and compared 5-FU/LEV (1 year) with 5-FU/highdose CF weekly (32 weeks), 5-FU/low-dose CF [given for 5 days every 4-5 weeks for six cycles (7-8 months)], and 5-FU/low-dose CF plus LEV (6 cycles, 7-8 months). There was no statistically significant difference in the 5-year disease-free and overall survival between the four arms. There were differences in toxicity profiles between the four regimens, however. With the 5-FU/low-dose CF regimens, there was a significantly higher incidence of stomatitis and neutropenia compared with 5-FU/LEV or the weekly 5-FU/high-dose CF regimen." More patients who received 5 FU/high-dose CF had diarrhea. Updated results of Intergroup 0089 trial were presented at the 1998 ASCO meeting. Although statistically superior in disease-free and overall survival to the standard 12-month 5-FU/LEV regimen, the three-drug combination regimen of



5-FU, low-dose CF, and LEV was not superior to 5-FU/low-dose CF alone.I2In addition, there was no significant difference between 1year of 5-FU/LEV and the shorter 5-FU/CF regimens. The results of Intergroup 0089 indicated that LEV is not a mandatory component of 5-FU-based adjuvant chemotherapy. Equivalent treatment effect was seen with the 5-FU/CF regimens, although chemotherapy was given roughly for half the duration of the standard 5-FU/LEV regimen. The National Surgical Adjuvant Breast and Bowel Project (NSABP)C-04 study57 compared 5-FU/LEV (1 year) with 5-FU/high-dose CF weekly (48 weeks) and 5-FU/high-dose CF weekly plus LEV (1year). This study established that 5-FU/ high-dose CF for 48 weeks was at least as effective as the standard of 12 months of 5-FU/LEV. Based on the results of the three studies described previously, 6 months of adjuvant therapy with 5-FU/CF should represent the standard adjuvant treatment for patients with resected high-risk colon cancer. The two regimens of 5-FU at 425 mg/m2/day and low-dose CF at 20 mg/m2/day daily for five days every 4 to 5 weeks for six cycles or 5-FU at 500 mg/m2/day and high-dose CF at 500 mg/m2/ day for 6 weeks in eight-week cycles for four cycles appeared to be equivalent. 5FU/LEV appears to be equally effective, provided that 12 months of treatment are administered. This regimen is no longer commonly used in clinical practice primarily because of the longer duration of treatment required. ADJUVANT THERAPY FOR STAGE II COLON CANCER

There is controversy regarding the role of adjuvant therapy for patients with stage I1 disease. With surgery alone, the 5-year survival rate in these patients can be 70% to 80%. Adjuvant treatment in this population should be effective and have low toxicity in order to be justifiable, given the relatively good prognosis with surgery alone. Recently, the International Multicenter Pooled Analysis of B2 Colon Cancer Trials (IMPACT-B,) Group reported a pooled analysis of 1016 stage B2 patients treated in five trials between 1982 and 1989.5-FU/CF appeared to produce a 17% reduction (when compared with a no-treatment control) in the rate of first posttreatment events (recurrences, second tumors, or deaths from any cause) and a 14% reduction in the all-cause mortality rate. Events in this patient population were relatively rare, however, with only 211 observed relapses and 218 deaths in the 1016 patients in the analysis. As a result, this reduction in event rates translated into only a small improvement in 5-year event-free survival (73%versus 76%)and survival (80% versus 83%) for patients on the 5-FU/CF treatment arms. The differences were not statistically significant, although a trend was apparent when one-sided tests were used ( P = 0.61 and P = 0.057 for event-free and overall survival, respectively). Increasing age and poorly differentiated tumors were significant indicators for poor prognosis (P < 0.02).Based on these data, the IMPACTB2 investigators concluded that no postoperative treatment should be the control group of choice in randomized trials for patients with Dukes' B (stage 11) colon cancer.18 NSABP published the pooled analysis of four trials (C-01, C-02, C-03, and C-04) including a total of 1565 patients with Dukes' B disease and 2255 patients with Dukes' C disease. In two of the four studies (C-03, C-041, the experimental arm was compared with another arm that also contained treatment. In the other two (C-01, C-02), MeCCNU/vincristine/5-FU (MOF) and portal vein infusion, respectively, were compared with no treatment. When data from all four trials were examined retrospectively in a combined analysis, the reduction in death rate was



30% for Dukes' B patients versus 18% for Dukes' C patients and occurred irrespective of the presence or absence of adverse prognostic factors. The NSABP analysis was set up to answer a different question compared with the one that IMPACT-B, investigators attempted to answer: for clinical trials including both Dukes' B and C patients, is there a different treatment effect within these stages of disease? The NSABP investigators concluded that patients with Dukes' B colon cancer derived at least similar benefit from adjuvant chemotherapy as patients with Dukes' C colon cancer and should be presented with this treatment option.z4 Given the fact that the individual trials on which the analysis was based were not set up to compare treatment effect within stage, however, this retrospective analysis is suggestive rather than conclusive. Factors with possible prognostic significance in patients with colorectal cancer , ~ ~ molecular markers such as absence of expression of the include p l ~ i d yother deleted in colorectal cancer (DCC) overexpression of thyrnidylate synand the p53/BAX pathway.45Although intriguing as possible prognostic tha~e,'~ markers in colorectal cancer and predictive markers for response to 5-FU chemotherapy, their value as specific prognostic factors in patients with stage I1 disease must be explored further. Other clinical factors that may be helpful in decision making include T4 disease (adherence, invasion, or perforation of the primary tumor), intestinal obstruction as a presenting symptom, perineural invasion, venous or lymphatic invasion, and poorly differentiated histol~gy.~Z Overall, we believe that adjuvant therapy in patients with stage I1 colon cancer outside the clinical trial setting represents an individualized decision that must be reached after assessment of the potential negative prognostic factors that would increase the risk of tumor relapse, the patient's general status of health and age, and enthusiasm regarding the small anticipated benefits and potential side effects. In our institution, we usually offer adjuvant chemotherapy off study to patients with grade 4 tumors, aneuploid tumors, tumors with cell proliferation index (G2M + S phase) higher than 20%, and patients with T4, NO, MO disease. FUTURE DIRECTIONS

It is important that in the new generation of trials for adjuvant treatment of colon cancer, additional parameters such as quality of life during treatment are taken into consideration.This allows a more complete comparison between otherwise equally effective treatments. In addition, these studies can provide an excellent venue for the evaluation of the prognostic significance of molecular markers. Chemotherapy

Recent developments include oral fluorinated pyrimidines and the thyrnidylate synthase inhibitor raltitrexed (Tomudex). In addition, two agents with different mechanisms of action, the topoisomerase-I inhibitor, irinotecan, and the platinum analog, oxaliplatin, recently have been added to our armamentarium against colon cancer. Oral Fluoropyrimidines

These agents offer the convenience of orally administered therapy and potentially fewer toxic effects and expense than conventional intravenous regimens.One extensively studied oral fluorinated pyrimidine is UFT. It is a combination of oral uracil with the 5-FU prodrug, tegafur, in a 4:l molar ratio.6



In a phase I11 study of 816 patients with metastatic disease, UFT plus oral CF resulted in a similar response rate and survival compared with a standard intravenous 5-FU/CF regimen. The use of UF'T was associated with a statistically significant decrease in grade IV hematologic toxicities and mucositis, however.30 Based on these results, UFT plus leucovorin (ORZEL) is currently under review for approval by the Food and Drug Administration for the treatment of patients with metastatic colon cancer. In contrast, in the adjuvant setting, data on oral fluoropyrimidines are rare.27,38 The NSABP C-06 trial, which recently completed accrual in the United States, was designed to assess the value of UFT in the adjuvant setting. Patients with stage I1 or I11 colon cancer were randomized to receive oral UFT plus oral CF versus intravenous 5-FU plus intravenous CF using a weekly regimen. Evaluation of the prognostic significance of several biomarkers alone or in combination including DNA mismatch repair genes, p53, deleted in colon cancer gene, proliferation status and thymidylate synthase also will be performed. Finally, there will be evaluation and comparison of quality of life in the two study groups. Two other fluorinated pyrimidines are currently in clinical trials and likely will be included in future adjuvant studies. One of these compounds is the combination of 5-FU and the DPD inhibitor 776C85.40776C87 (emiluracil) is an irreversible inhibitor of DPD, which makes small oral doses of 5-FU clinically effective. Of note, the pharmacokinetics of 5-FU/776C85 and the other oral fluorinated pyrimidines are similar to those of continuous infusion; their comparison with intravenous bolus or continuous infusion 5-FU regimens is of particular interest. The second compound is capecitabine, a novel oral tumor-activated fluoropyrimidine carbamate. Tumor selective enzymatic activation of capecitabine by thymidine phosphorylase and carboxyl esterase results in higher 5-FU concentration in tumors compared with plasma and riormal tissues and may increase the therapeutic index. In patients with metastatic disease, capecitabine led to a higher response rate compared with a bolus 5-FU/CF regimen and a more favorable toxicity profile. No difference in progression-free survival was seen, however.48 Capecitabine has been approved for treatment of metalstatic disease and its role in the adjuvant setting remains to be determined. Raltitrexed

Raltitrexed (Tomudex) is a quinazoline derivative that is a potent inhibitor of thymidylate synthase. Tomudex is given as a single bolus injection every 3 weeks. Three phase I11 trials comparing raltitrexed with standard chemotherapy (5-FU plus CF) in metastatic disease have been completed. One study showed a shorter median survival for the raltitrexed arm (9.7 versus 12.7 months);' whereas the other two trials showed similar objective tumor response and median s~rvival.'3,~~ Although raltitrexed appears to be better tolerated compared with the bolus 5-FU regimens in terms of myelotoxicity and mucositis and is simpler to administer, a recent study showed raltitrexed to be inferior compared with a continuous infusion 5-FU regimen in terms of treatment-related deaths and quality of life. A recent European/ Japanese Intergroup Trial (EORTC-40962)is currently comparing 5-FU/CF with raltitrexed in the adjuvant treatment of stage I11 colon cancer. lrinotecan

The topoisomerase I inhibitor, irinotecan (CPT-111, has activity in patients with 5-FU refractory as well as chemotherapy naive advanced colorectal cancer.



Two phase I11 trials comparing CPT-11 to either supportive care3 or a 5-FU regimen36demonstrated a survival benefit for CPT-11 in patients with 5-FU refractory disease. In addition, in the metastatic disease setting, first-line treatment with CPT11 and 5-FU/CF led to a higher response rate compared with 5-FU/CF or CPT11 alone (49% versus 27% versus 29%) and longer time to treatment failure (5 months versus 3.8 months versus 3.1 months). The overall survival was not significantly different, however.39The role of CPT-11 in the adjuvant setting will be investigated in a current US intergroup study. In this study, a weekly 5-FU/highdose CF regimen is compared with a weekly 5-FU/CF/CPT-11 regimen. Oxaliplatin

Oxaliplatin is a new platinum derivative that has demonstrated activity as a single agent in the treatment of 5-FU refractory advanced colorectal carcinoma. Although its basic mechanism of action is similar to that of cisplatin, oxaliplatin has some unique characteristics as it pertains both to activity and toxicity profile. In vitro studies have shown that the combination of oxaliplatin plus 5-FU has important synergistic antiproliferative activity. Recent clinical trials have confirmed this laboratory finding. Single agent oxaliplatin demonstrated a 10%response rate in patients with 5-FU refractory disease and 27% response rate when used as first-line treatment. When combined with 5-FU/CF, the efficacy of oxaliplatin increases to 30% and 50%,respective1y.m In vitro studies with the combination of oxaliplatin and SN-38, which is the active metabolite of CPT-11, have shown a strong cytotoxic synergy in the human colon cancer cell line, HLT-29, regardless of the sequence of admini~tration.~~ The phase I1 dose of the oxaliplatin plus CPT-11 combination has been established. Despite the fact that response was not the primary endpoint, significant evidence of antitumor activity was observed in this group of mostly 5-FU refractory colon cancer patients. Among 24 such patients, there were 7 (29%)with partial responses and 9 (38%) with ~tabilization.~~ The role of oxaliplatin and CPT-11 as part of combination regimens as first-line therapy of patients with metastatic colorectal cancer is currently under investigation as part of a current intergroup (N9741). Despite the fact that no data on CPT-11 or oxaliplatin in the adjuvant setting are currently available, the data discussed previously for patients with metastatic disease have guided the development of the new generation of adjuvant studies in stage I1 and I11 colon cancer. Promising Chemotherapy Agents Under Development

Agents that target the cell cycle are currently in early stages of clinical development. Among them, agents with potential promise in the treatment of colon cancer include farnesyl transferase inhibitors: the mTOR inhibitor (rapamycin analog) CCI-779,7 and the cyclin-dependent kinase inhibitor flavopirid~l.~~ Finally, other new agents that could be theoretically important in the adjuvant setting because they can block angiogenesis and tumor invasion include angiogenesis inhibitors such as angiostatin and endostatinS7and matrix metalloproteinase inhibitor~.~~,~~ Portal Vein Infusion

Regional chemotherapy and, in particular, portal vein infusion chemotherapy have been advocated because of the high rate of relapses within the liver and the fact that micrometastases appear to receive their primary blood suppIy from the



portal vein. Portal vein infusion of chemotherapy has the advantage of providing high concentrations of 5-FU to the liver. Because of the metabolism of 5-FU in the liver, a lower concentration of the drug is subsequently achieved in the rest of systemic circulation. In the NSABP C-02 trial, 1158 patients with Dukes' A, B, and C colon cancer were randomized to either no adjuvant chemotherapy or to 5-FU (600 mg/m2/ day for 7 days) administered as a continuous intraportal infusion together with heparin. Patients randomized to portal chemotherapy had a small but significantly better overall survival and disease-free survival compared with a control group, ~ ~ results .~~ but there was no difference in the development of liver m e t a ~ t a s i s .The were similar for the Swiss Group for Clinical Research study7 and for a more recent metaanalysis that included 4000 patients in 10 studies.22Despite improvement in overall survival, the number of liver metastases was not reduced. This result suggests that the portal vein infusion of 5-FU may mediate any effect on survival through a systemic mechanism. In contrast, an international phase 111 study with European and Japanese participation (1235patients) failed to show any difference in disease-free or overall survival.3sCurrently, portal vein infusion therapy is still an experimental approach and cannot be considered in the routine adjuvant treatment of patients with colon cancer.


Different immunotherapy approaches including autologous tumor vacc i n e ~ ' ~ ,and ' ~ , the ~ ~ addition of interferon to 5-FU/CFs5have yielded poor results in most clinical trials. Promising results recently were obtained in the adjuvant setting with an autologous tumor cell-BCG vaccine, however.s0In this prospective randomized phase 111 study, 254 patients with stage I1 or 111 colon cancer were assigned to three weekly vaccinations with a booster vaccination at 6 months versus no treatment. Patients with stage I1 disease had a 61% decrease in their risk of recurrence and significantly longer recurrence-free survival ( P = 0.032). There was also a trend toward improved overall survival. No benefit was detected for stage I11 patients. The benefit shown in this study, although statistically significant, is derived from a subset analysis in a relatively small number of patients and clearly must be confirmed before this approach being incorporated into clinical vractice. I Promising clinical results in immunotherapy of colorectal cancer in the adjuvant setting also have been obtained with monoclonal antibodies. Different antigens, such as carcinoembryonic antigen (CEA), 17-lA, and TAG 72, have been identified on the surface of colorectal cancer cells, but the largest clinical experience relates to the murine monoclonal antibody 17-1A. In a phase I11 study, 189 patients with stage 111colorectal cancer were randomized to receive either surgery alone or five injections of the 17-1A immediately after surgery.34At a median follow-up of 5 years, patients who received treatment had a 30% improvement in death rate and 27% improvement in the recurrence rate. The treatment was well tolerated with only four mild anaphylactic reactions observed out of 371 infusions. Several confirmatory trials are currently ongoing. The US Intergroup is investigating the role of 17-1A in patients with stage I1 colon cancer. This trial is randomizing patients to surgery alone or five injections of 17-1A over a 4-month period of time. In addition, a phase I11 randomized study of adjuvant 17-1A plus 5-FU/ LV versus 5-FU/LV alone for surgically resected stage I11 adenocarcinoma of the colon is currently ongoing in the United States. The effect of chemotherapy on the efficacy of the monoclonal antibody is to be determined. Other monoclonal anti~




bodies such as antiidiotypic monoclonal antibodies against a highly specific CEA epitope BB1, BIBH1, and A33/1131 are currently in early stages of clinical development. Ongoing immunotherapy efforts include use of vaccine therapy with tumorspecific mutated ras peptides, vaccination with the carcinoid embryonic antigen peptide 1 (CAP), and recombinant CEA vaccinia virus vaccine with postvaccination CEA peptide challenge. In summary, in recent years new chemotherapy/immunotherapy agents have emerged in the study of the adjuvant treatment of colon cancer. Better tolerated oral fluoropyrimidine regimens may be able to decrease the toxicity associated with adjuvant treatment of colon cancer without decreasing its efficacy as indirectly indicated by the results in metastatic disease. Active agents with different mechanisms of action and without cross resistance in 5-FU refractory patients such as CPT-11 and oxaliplatin may improve further the efficacy of adjuvant chemotherapy and are under active investigation. Finally, the role of monoclonal antibodies such as 17-1A and tumor vaccines in this setting remains to be better defined.

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