Adherence to Pre-Op Tx Tied to Better DFS in Rectal Cancer


Rectal cancer patients who successfully completed their neoadjuvant chemoradiotherapy regimen saw improved disease-free survival (DFS), a post-hoc analysis of a large phase III trial found.

In the CAO/ARO/AIO-04 trial, the 3-year DFS was 71.1% for patients assigned to neoadjuvant fluorouracil-based chemoradiotherapy and 75.8% for those who also received oxaliplatin, at a median follow-up of 50 months, reported Markus Diefenhardt, MD, of the University of Frankfurt, Germany, and colleagues in JAMA Oncology.

But regardless of which treatment arm patients were assigned to, treatment completion compared with “near completion” was associated with improved DFS:

  • Without oxaliplatin (HR 1.325, 95% CI 0.959-1.832, P=0.09)
  • With oxaliplatin (HR 1.501, 95% CI 0.980-2.299, P=0.06)

And the difference in DFS becomes statistically significant when comparing patients who completed treatment with those who had “reduced” treatment:

  • Without oxaliplatin (HR 1.877, 95% CI 1.147-3.072, P=0.01)
  • With oxaliplatin (HR 1.724, 95% CI 1.144-2.596, P=0.009)

CAO/ARO/AIO-04 included patients from 80 centers who received neoadjuvant fluorouracil-based chemoradiotherapy with (n=607) or without (n=625) oxaliplatin. Treatment completion was defined as the full 50.4 Gy dose of radiotherapy and concurrent chemotherapy. The protocol defined near-completion as those who received 45 Gy or more of radiotherapy and 80% of concurrent chemotherapy, and reduced treatment as those who received 45 Gy of radiotherapy or less than 80% of concurrent chemotherapy.

“The findings emphasize the need for appropriate trial design with optimized nCRT [neoadjuvant chemoradiotherapy] dose and schedule and supportive strategies to facilitate good adherence and precision delivery, especially for intensified nCRT,” Diefenhardt and colleagues wrote.

However, in an accompanying editorial, Robert Madoff, MD, and Emil Lou, MD, PhD, both of the University of Minnesota in Minneapolis, questioned if this broad recommendation aligns with the current paradigms of rectal cancer treatment, which they wrote have evolved since the launch of this study.

“There are competing goals and values in modern rectal cancer therapy. For example, while neoadjuvant radiotherapy and chemoradiotherapy decrease the risk of local recurrence, they do not improve overall survival,” Madoff and Lou wrote. “In addition, this risk reduction is not without cost because the compromise to quality of life from radiotherapy-associated adverse events, such as sexual dysfunction, bowel dysfunction, and pelvic fractures, must not be underestimated.”

As such, there is interest in radiotherapy-free regimens that are now under study, they wrote.

At the same time, the move toward increased organ preservation works against the goal of eliminating radiotherapy from neoadjuvant treatment, as patients who achieve a clinical complete response to neoadjuvant treatment can be managed with a “watch and wait” strategy.

Regardless, Madoff and Lou said that the post-hoc design of the analysis means its conclusions can only be hypothesis-generating. Additionally, they wrote that “there is a real possibility that the patients who are not considered adherent differed from the patients who were adherent,” with the nonadherent patients possibly being more frail, having depression, or other comorbidities.

The phase III study also compared adjuvant treatment with fluorouracil-based chemotherapy with or without oxaliplatin. In contrast to neoadjuvant treatment, completion of adjuvant treatment was not associated with DFS in either study arm, which the researchers said demonstrated that “the role of adjuvant chemotherapy for patients with rectal cancer remains opaque.”

Even among those patients who completed neoadjuvant treatment, completion of adjuvant treatment was not associated with an improved DFS compared with patients with incomplete treatment, they found.


Diefenhardt reported no conflicts of interest. One co-author reported grant support or fees from Amgen, AstraZeneca, Bristol-Myers Squib, Merck, Merck Sharp & Donne, Roche, Sanofi, and Servier.

Madoff and Lou had no conflicts of interest.

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