Deciding the Duration of Adjuvant Chemotherapy in a Patient With Stage III Colon Cancer: When Can Less Be More?

Figure 1. Disease-Free Survival (DFS) With 3 Months vs 6 Months of Adjuvant Chemotherapy (FOLFOX or CAPOX) for Stage II/III Colon Cancer

Figure 2. In the SCOT Trial, Noninferiority—With Regard to DFS—of a 3-Month Adjuvant Therapy Regimen (Compared With 6 Months) Was Stronger in Patients Who Received CAPOX Than in Those Who Received FOLFOX

The Case

A previously healthy 36-year-old man initially presented to his primary care physician with occasional bloody stools and dull right upper quadrant pain. Blood was sometimes mixed into his stools but was more often seen on the toilet paper after wiping. He attributed his symptoms to hemorrhoids and did not undergo the colonoscopy recommended by his primary care doctor. His pain and hematochezia were improved for some time, but they began to worsen 10 months later. At that time he also developed bloating and a feeling of not evacuating his stool completely. A colonoscopy was performed, which found two colonic polyps. One polyp was a benign adenoma but the other was found to be a 1-cm moderately differentiated adenocarcinoma. CT imaging of the chest, abdomen, and pelvis was negative for metastatic disease. The patient underwent a laparoscopic left hemicolectomy. The surgical pathology showed an adenocarcinoma of the colon with invasion of the subserosa and involvement of 2 out of 26 regional lymph nodes, making his cancer stage IIIB (pT3N1bM0). Standard immunohistochemistry assays showed the tumor to be microsatellite stable. He had no family history of colon, breast, or ovarian cancer. His father died of lung cancer at age 82 but had smoked cigarettes for over 40 years. The patient is married with one child. He works as an attorney and enjoys playing the guitar in his free time. Soon after recovering from surgery, he presented to our oncology clinic for consultation. He is very knowledgeable about his options and has researched his disease thoroughly. He is understandably anxious about his diagnosis. He states that he would like to be treated aggressively.

Which of the following options is the best next step in management?

A. Fluorouracil (5-FU) or capecitabine monotherapy for 3 to 6 months

B. Leucovorin, 5-FU, and oxaliplatin (FOLFOX) for 6 months

C. FOLFOX for 3 months

D. Capecitabine and oxaliplatin (CAPOX) for 6 months

E. CAPOX for 3 months

Discussion

In the United States, colorectal cancer is the third most common cancer and the second leading cause of cancer-related death; it is the fourth leading cause of cancer-related death worldwide.[1,2] While the overall incidence of colon cancer is decreasing, the incidence in young adults (aged 20 to 39 years) is on the rise.[3] Thus, there is a real need for more effective and less toxic treatments to prevent recurrence and prolong survival, given the relatively young age of growing numbers of colorectal cancer patients. Younger patients, like the man in the case presented here, tend to desire longer and more aggressive treatment regimens, although these do not always result in better outcomes.[4,5]

This case involves a 36-year-old man with stage IIIB colon cancer who has received definitive surgery with a left hemicolectomy. The 5-year survival rate of patients with stage IIIB colon cancer treated with surgery and adjuvant chemotherapy is approximately 69%.[1] Stage IIA colon cancer has a 5-year survival rate of 89%; stage IIB, 63%; and stage IIIA, 89%. Such discordant survival rates suggest that the different stages of colon cancer are genetically different diseases-something that has been demonstrated in genetic analyses of colonic tumors.[6]

Efforts to improve survival in higher-risk patients have centered on adjuvant chemotherapy. The first regimen to show a significant benefit was 5-FU with levamisole, given for 1 year after surgery.[7] Subsequent studies showed improved overall survival with the addition of leucovorin to 5-FU and similar efficacy for 6 months vs 12 months of treatment.[8] The MOSAIC trial continued to build on the 5-FU/leucovorin regimen with the addition of oxaliplatin. The trial compared 6 months of FOLFOX against 5-FU and leucovorin alone.[9] Patients who received FOLFOX had significantly longer disease-free survival after 3 years (78.2% vs 72.9%; P = .002). Subgroup analysis showed a greater benefit for patients with stage III disease. Other studies have also shown a benefit from the inclusion of oxaliplatin in the adjuvant regimen.[10,11] Therefore, if the patient's goal is optimal survival regardless of toxicity, 5-FU or capecitabine monotherapy (Answer A) would not be an appropriate regimen for him. Monotherapy would exclude oxaliplatin, which has been shown in several studies to increase the overall survival rate by a few percentage points in cancers like his.[9-11]

While true for all patients, in the case of younger patients who are working full time or who have young children to care for, minimizing infusion time is invaluable. This makes the combination of capecitabine and oxaliplatin (CAPOX) an attractive alternative to FOLFOX. No significant difference in efficacy has been shown between modified FOLFOX6 (mFOLFOX6) and CAPOX, both of which are typically given for 6 months.[12,13] CAPOX consists of oxaliplatin, 130 mg/m² given every 3 weeks, along with oral capecitabine; this is in contrast to mFOLFOX6, which requires infusions every 2 weeks, including an extended 46-hour infusion of 5-FU (along with oxaliplatin, 85 mg/m2). Until recently, most providers would have recommended 6 months of fluoropyrimidine and oxaliplatin to this patient.

In an effort to reduce toxicity and cost, recent studies performed as part of a planned global collaboration have compared adjuvant chemotherapy for 3 months vs 6 months in patients with high-risk colon cancer. The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration is a combined analysis of six prospective randomized trials comparing adjuvant chemotherapy with FOLFOX or CAPOX for 3 months vs 6 months. While varying slightly in overall design, each of the trials was required to include patients with stage III colon cancer and to use 3-year disease-free survival as the primary endpoint. Although the final results have not been published yet, the preliminary data were presented at the 2017 American Society of Clinical Oncology Annual Meeting (Figure).[14] At a median follow-up of 39 months, based on the preselected statistical design, noninferiority of 3 months of adjuvant chemotherapy–as compared with 6 months–was not shown for the overall cohort. However, these results sparked a heated debate, since the absolute difference between the two treatment durations was small. The 3-year disease-free survival rate for the 3-month arm was 74.6%, compared with 75.5% in the 6-month arm (hazard ratio, 1.07; 95% CI, 1.00–1.15), raising the question of clinical vs statistical differences. Even though the predefined goal for statistical noninferiority was not met, is the absolute difference of 0.9% worth an additional 3 months of chemotherapy?

Interestingly, noninferiority was established for 3 months (as compared with 6 months [Answer D]) in the subgroups of patients who received CAPOX and of those with T1-3N1 disease. The preliminary results also demonstrated a significantly higher rate of grade 3 neurotoxicity in the 6-month arm compared with the 3-month arm (16% vs 3% with FOLFOX; 9% vs 3% with CAPOX; P < .0001).While we await the final results of the IDEA trials (some have still not reached maturity), the duration of adjuvant therapy for patients with high-risk colon cancer warrants discussion between physicians and their patients. In patients with T1-3N1 disease, we believe that treatment for 3 months should be the preferred regimen. The shorter duration of therapy is less expensive, less toxic, more convenient, and by most any assessment is equally effective. FOLFOX (Answers B and C) requires more frequent infusions than CAPOX. Moreover, in preliminary data from the SCOT trial (part of the IDEA consortium), noninferiority was stronger in the patients who received CAPOX than in those who received FOLFOX.[15]

Therefore, for this 36-year-old man with T3N1b resected colon adenocarcinoma, 3 months of adjuvant CAPOX (Answer E) is the best next step in management. Treating him for 3 months instead of 6 months would minimize toxicity, especially cumulative neurotoxicity, and would have a clinically equivalent effect on prolonging his disease-free survival. Because patients in the IDEA trials were not randomly assigned to receive CAPOX or FOLFOX, we cannot definitively say that one regimen is superior to the other. Still, CAPOX did show stronger noninferiority in the SCOT trial, and the dosing of CAPOX would be more convenient for this patient, who continues to work.[15]

How do these results alter guidelines for other common colorectal cancers? It is unlikely that similar studies will be done in patients for whom the benefit of adjuvant oxaliplatin is unclear, such as patients above the age of 70, those with stage II colon cancer, and those with rectal cancers. However, we would support discussing the results of the IDEA trials with these patients and at least consider the possibility of a shorter treatment course after weighing the risks and benefits for each individual.

Outcome of This Case

Our patient underwent 3 months of adjuvant chemotherapy with CAPOX. He was anxious about the shorter course but tolerated treatment aside from some mild neuropathy. He was able to continue playing guitar and kept working during the 3-month treatment course. His posttreatment CT scans were unremarkable; he will be due for a follow-up colonoscopy 1 year after his surgery date. He was enrolled in a survivorship clinic and will have frequent monitoring of his carcinoembryonic antigen level, along with yearly imaging, for at least 5 years to watch for disease recurrence. He was encouraged to exercise regularly and to begin taking aspirin and vitamin D to reduce his risk of developing a new colon cancer.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.

If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.

References:

1. American Cancer Society. Cancer facts & figures 2016. Atlanta, GA: American Cancer Society; 2016.

2. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1:505-27.

3. Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974–2013. J Natl Cancer Inst. 2017 Aug 1. [Epub ahead of print]

4. Abdelsattar ZM, Wong SL, Regenbogen SE, et al. Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening. Cancer. 2016;122:929-34.

5. Kneuertz PJ, Chang JG, Hu CY, et al. Overtreatment of young adults with colon cancer: more intense treatments with unmatched survival gains. JAMA Surg. 2015;150:402-9.

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7. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352-8.

8. O'Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol. 1998;16:295-300.

9. André T, Boni C, Mounedji-Bouniaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

10. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109-16.

11. Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29:3768-74.

12. Blanc J-F. Capecitabine as adjuvant treatment for stage III colon cancer. Gastroenterol Clin Biol. 2006;30:169-70.

13. Pectasides D, Karavasilis V, Papaxoinis G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015;15:384.

14. Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration. J Clin Oncol. 2017;35(18 suppl):abstr LBA1.

15. Iveson T, Kerr R, Saunders MP, et al. Final DFS results of the SCOT study: an international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer. J Clin Oncol. 2017;35(15 suppl):abstr 3502.