Young Age and Aggressive Treatment in Colon Cancer

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JAMA Surgery

Overtreatment of Young Adults With Colon Cancer: More Intense Treatments With Unmatched Survival Gains

Peter J. Kneuertz, MD; George J. Chang, MD, MS; Chung-Yuan Hu, MPH, PhD; Miguel A. Rodriguez-Bigas, MD; Cathy Eng, MD; Eduardo Vilar, MD, PhD; John M. Skibber, MD; Barry W. Feig, MD; Janice N. Cormier, MD, MPH; Y. Nancy You, MD, MHSc

Importance Colon cancer is increasing among adults younger than 50 years. However, the prognosis of young-onset colon cancer remains poorly defined given significant age-related demographic, disease, and treatment differences.

Objective To define stage-specific treatments and prognosis of colon cancer diagnosed in young adults (ages 18-49 years) vs older adults (ages 65-75 years) outside of the clinical trial setting while accounting for real-world age-related variations in patient, tumor, and treatment factors.

Design, Setting, and Participants A nationwide cohort study was conducted among US hospitals accredited by the American College of Surgeons Commission on Cancer. Participants were 13 102 patients diagnosed as having young-onset colon adenocarcinoma aged 18 to 49 years and 37 007 patients diagnosed as having later-onset colon adenocarcinoma aged 65 to 75 years treated between January 1, 2003, and December 31, 2005, and reported to the National Cancer Data Base.

Exposures Patients who underwent surgical resection and postoperative systemic chemotherapy of curative intent.

Main Outcomes and Measures The primary end point was stage-specific relative survival, an objective measure of survival among patients with cancer, adjusting for baseline mortality rates and independent of the data on cause of death. The secondary end point was stage-specific likelihood of receiving postoperative systemic chemotherapy.

Results Most young-onset colon cancer was initially seen at advanced stages (61.8% had stage III or IV). After adjusting for patient-related and tumor-related factors, young patients were more likely to receive systemic chemotherapy, particularly multiagent regimens, at all stages relative to those with later-onset disease. These odds ratios were 2.88 (95% CI, 2.21-3.77) for stage I, 3.93 (95% CI, 3.58-4.31) for stage II, 2.42 (95% CI, 2.18-2.68) for stage III, and 2.74 (95% CI, 2.44-3.07) for stage IV. The significantly more intense treatments received by younger patients were unmatched by any survival gain, which was nil for stage II (relative risk, 0.90; 95% CI, 0.69-1.17) and marginal for stage III (relative risk, 0.89; 95% CI, 0.81-0.97) and stage IV (relative risk, 0.84; 95% CI, 0.79-0.90).

Conclusions and Relevance Young adults with colon cancer received significantly more postoperative systemic chemotherapy at all stages, but they experienced only minimal gain in adjusted survival compared with their older counterparts who received less treatment. This mismatch suggests that attention should be given to long-term cancer survivorship in young adults with colon cancer because they likely face survivorship needs that are distinct from those of their older counterparts.

Julia R. Berian, MD1,2; Al B. Benson III, MD3; Heidi Nelson, MD4

The downward trend in colorectal cancer (CRC) incidence and mortality over the past several decades1 has not held true for young patients. Currently, CRC incidence in patients younger than 50 years continues to increase, most markedly among those younger than 35 years by approximately 2% per year. This trend was identified in a recent analysis that estimated patients younger than screening age (ie, age 50 years) will comprise 10.9% of colon and 22.9% of rectal cancers by 2030, compared with 4.8% and 9.5% in 2010, respectively.2 Young-onset CRC is characterized by more advanced stages, poor tumor differentiation, mucinous carcinoma, more distal location, and even a particular profile of biomarkers.3 Although more aggressive disease usually results in worse outcomes, disease-specific and overall survival for patients with young-onset CRC consistently matches or surpasses that of older patients, stage-for-stage.3 Given this seemingly conflicting information, optimal treatment for these young patients remains unclear.

In JAMA Surgery, Kneuertz et al4 provided insight into treatment patterns and prognosis in young adults with colon cancer. The authors confirmed that younger age at onset was associated with advanced presentation and worse histologic features. Younger patients—regardless of stage—were significantly more likely to be treated with chemotherapy, often multiagent regimens, than older patients. Not routinely recommended for early-stage disease, adjuvant chemotherapy resulted in little survival gain for these patients compared with the older group. This assessment of care suggests that, despite best intentions, treatment did little to improve the health of this population but rather was associated with increased risk for adverse outcomes and increased cost of care.

Improving care for young patients with colon cancer requires that patterns of overtreatment be remedied. In light of these findings, it is important to address (1) overtreatment in young patients when clear evidence exists and (2) the challenge of treating patients when the evidence is mixed. Several steps are suggested to improve understanding and care for this population in the future.

Despite evidence-based guidelines (NCCN category 2A),5 patients with early-stage colon cancer underwent treatment that was probably not beneficial. The 6% of stage I patients who received adjuvant chemotherapy were not receiving standard treatment. These treatment decisions might have resulted from physician-initiated efforts to aggressively treat these patients simply based on their younger age. Alternately, patients may have pressed their physicians for more intensive treatment, despite minimal gains. Large observational data sets cannot offer insight into treatment rationales. Behavioral science has only begun to illuminate the decision-making processes, incentives, motivation, and communication patterns that go into the shared treatment choice of physician and patient.

When the evidence to support a treatment is not clear, decisions become more complex. Chemotherapy for stage II colon cancer is controversial; however, it is recommended for cases with high-risk features, such as poorly differentiated histology, lymphovascular invasion, and bowel obstruction. Even though “high-risk” features may assist prognostication, they are not sufficient to identify patients who have disease that will or will not recur, nor do they predict response to adjuvant therapy. Patients with stage II disease generally have high survival rates, almost approximating survival in the age-matched general population.6 Whether young or old, survival gains from adjuvant chemotherapy are modest for stage II disease,7calling into question the relative benefit of the additional therapy given to the patients in the study by Kneuertz et al.4

Future therapy decisions might be guided by molecular markers. Tumors with mismatch repair deficiency (dMMR), found among sporadic and inherited cases, are characterized by high microsatellite instability (MSI-H) or deficiency in certain gene products (MLH1 or MSH2). Patients with these deficiencies do not benefit from fluorouracil-based chemotherapy, and stage II patients with tumors having dMMR may even have poorer survival when treated with adjuvant therapy than with surgery alone.8 In addition, MSI-H status has relatively good prognosis, so chemotherapy is generally discouraged. Although testing for MSI status is not uniformly performed, NCCN guidelines recommend that testing be considered among stage II patients if chemotherapy is presented as an option.5 New biomarkers and multigene assays must aim to accurately estimate the potential benefit of chemotherapy.

Progress in treating patients with young-onset colon cancer will require better data, a patient-centered approach, and a clear feedback cycle back to physicians. The population of patients with young-onset CRC is not only increasing but may be distinct from the population of patients with CRC occurring at older ages. More research is needed to explain the increasing incidence of young-onset CRC, associated risk factors, and the differential treatment response compared with that of older patients. Tissue banking and new techniques in genetic and molecular analysis provide an opportunity to identify key missing information in the basic biology of these tumors. Future efforts should also include a patient-centered approach, evaluating patient perceptions of treatments, associated risks, priorities, and the process of shared decision making. If overtreatment is verified in additional studies, feedback should be provided to hospitals and clinicians regarding their performance in delivering appropriate care. Use of chemotherapy for stage III colon cancer is a quality metric. Early-stage disease, too, may require a quality metric defining appropriate treatment. To accomplish this, however, there must be agreement regarding appropriate use of chemotherapy for early-stage CRC among young patients.

Young patients with CRC may be receiving overly aggressive adjuvant therapy. For patients with stage I CRC, average-risk stage II, and MSI-H, adjuvant treatment is not currently recommended. For patients with high-risk features, a balanced risk-benefit discussion with patients is critical. Clinicians must educate patients about treatment options and their benefits and risks. This discussion should be objective, based on evidence, and not influenced by the perception that young patients have worse disease warranting more aggressive treatment.

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