Patients saw 32% improved DF survival over those who didn’t complete full course of treatment

The ability of patients with rectal cancer to complete neoadjuvant chemoradiotherapy as planned—although not adjuvant chemotherapy—was associated with improved disease-free survival (DFS) at 3 years compared with patients who were not able to complete the same pre-operative protocol, a post-hoc analysis of the German CAO/ARO/AIO-04 trial has shown.

In a cohort of 1232 patients treated with neoadjuvant fluorouracil-based chemotherapy with or without the addition of oxaliplatin, those who were able to complete the neoadjuvant course of fluorouracil alone were 32% more likely to be alive and free of disease at 3 years compared with those who nearly completed the same treatment course at a hazard ratio (HR) of 1.32 (95% CI, 0.95-1.83; P=0.009), Markus Diefenhardt, MD, University of Frankfurt, Frankfurt, Germany and colleagues reported in JAMA Oncology.

Compared to patients who received reduced dose neoadjuvant fluorouracil, patients who completed the full neoadjuvant fluorouracil course were 87% more likely to be free of disease at 3 years at a HR of 1.87 (95% CI, 1.14-3.07; P=0.01), researchers added.

For those who received neoadjuvant fluorouracil-oxaliplatin, those who were able to complete the regimen as planned were 50% more likely to be disease-free at 3 years at a HR of 1.50 (95% CI, 0.98-2.29: P=0.06) compared to those who nearly completed the same protocol.

Fluorouracil-oxaliplatin completers were also 72% more likely to be free of disease at 3 years compared to those who received reduced-dose fluorouracil/oxaliplatin at a HR of 1.72 (95% CI, 1.14-2.59; P=0.009), study authors noted.

“To date, the association of adherence to treatment with oncologic outcomes has not been reported in phase 3 trials of rectal cancer, to our knowledge,” investigators pointed out.

“A shift toward total neoadjuvant treatment, rather than aCTh (adjuvant chemotherapy) may increase adherence to systemic treatment and potentially increase DFS,” they suggested.

CAO/ARO/AIO-04 Trial

The CAO/ARO/AIO-04 trial was a prospective, randomized, phase 3 trial carried out between 2006 and 2010.

All patients had T3 to T4 node-positive rectal cancer.

A total of 625 patients, mean age 63 years, received neoadjuvant fluorouracil alone while another 607 patients, mean age also 63 years, received fluorouracil plus oxaliplatin.

Full doses of neoadjuvant radiation therapy plus concurrent fluorouracil were tolerated by 67% of the fluorouracil alone group while 71.5% of patients who received full-dose radiotherapy plus concurrent fluorouracil-oxaliplatin were also able tolerate the regimen as planned.

Most patients subsequently underwent surgery with curative intent and were eligible for adjuvant chemotherapy.

For those treated with fluorouracil adjuvant chemotherapy alone, 57.6% completed the full treatment course compared with only 32% of those who received adjuvant fluorouracil-oxaliplatin.

“Patients were grouped into 3 nCRT (neoadjuvant chemoradiotherapy) adherence groups,” the authors explained: those who received full-dose radiotherapy at 50.4 Gy plus concurrent chemotherapy; those who received 45 Gy or more of radiotherapy and 80% of concurrent chemotherapy (nearly-complete nCRT) and those who received less than 45 Gy of radiotherapy or less than 80% of concurrent neoadjuvant chemotherapy (reduced nCRT).

Adherence to adjuvant chemotherapy was similarly categorized into 3 groups: those who received all cycles without dose reduction; those who received all cycles with dose reductions (near complete) and those who discontinued adjuvant chemotherapy (incomplete).

“After a median follow-up of 50 months (interquartile range, 38-61 months), 3-year DFS was 71.1% in the fluorouracil group and 75.8% in the fluorouracil-oxaliplatin group,” investigators noted.

As the authors also noted, between 60% and 67% of patients who were 70 years of age and older received neoadjuvant treatment with either fluorouracil alone or with the fluorouracil-oxaliplatin combination as did between 62% and 66% of patients who had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2.

“Thus, age and performance status did not prohibit administration of oxaliplatin,” they emphasized.

“These data reflect the importance of optimal dosing and supportive strategies to facilitate adherence to nCRT, especially among older patients and those with poor performance status,” they stated.

In an invited commentary, editorialists Robert Madoff, MD, and Emil Lou, MD, PhD, both from the University of Minnesota Medical School in Minneapolis, Minnesota, pointed out that “dramatic improvements” have been made in the treatment of locally advanced rectal cancer over the past 4 decades.

“The wide-spread adoption of precise anatomical surgery (total mesorectal excision) has been associated with decreased local recurrence rates, previously a major problem,” as they noted.

Similarly, neoadjuvant radiotherapy, given either alone or together with sensitizing chemotherapy, has further reduced the risk of local recurrence as has delaying surgery so as to allow the tumor to regress with or without chemotherapy.

Nevertheless, “[t]here are competing goals and values in modern rectal cancer therapy,” as Madoff and Lou pointed out.

For example, neoadjuvant radiotherapy and chemotherapy may decrease the risk of local recurrence but the combination does not improve overall survival.

“[T]his 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 factures, must not be underestimated,” they cautioned.

Concerns about radiotherapy-associated adverse events (AEs) have, in fact, prompted interest in pursuing radiotherapy-free regimens and instead treating patients to combination neoadjuvant chemotherapy alone, a concept current being studied in the PROSPECT trial, as the editorialists pointed out.

At the same time, eliminating radiotherapy from the rectal cancer protocol conflicts with the desirable goal of organ preservation.

“There is growing evidence that patients with a clinical complete response can be safely managed with close observation,” Madoff and Lou observed.

“This trend calls for more aggressive neoadjuvant therapy which, in combination with longer intervals to surgery, has been shown to lead to higher complete response rates,” they noted.

Indeed, there are multiple advantages to taking the total neoadjuvant therapy approach.

These advantages include the earlier provision of systemic therapy with the goal of treating micrometastatic disease before it develops into clinical metastasis.

Total neoadjuvant therapy may also improve adherence to chemotherapy over that usually achieved in the postoperative setting where many patients either don’t start treatment at all or if they do, most receive reduced doses of chemotherapy, as the editorialists observed.

The same approach may also improve pathologic complete responses compared with either neoadjuvant radiotherapy or chemoradiotherapy alone.

“Diefenhardt and colleagues have made a potentially important observation that emphasizes the importance or treatment adherence (or, more accurately, the ability of an individual to complete treatment as originally planned),” Madoff and Lou stated.

On the other hand, the editorialists cautioned that the current study is a post-hoc analysis of a completed trial, not a planned comparison.

There is also a “real possibility” that patients who were not adherent to the protocol in the current analysis differed from those who were adherent in terms of frailty rates, depression or other specific comorbidities that could have contributed to the observed differences in DFS rates, independent of the adherence issue, the editorialists observed.

Furthermore, “the lack of improvement in overall survival is a serious concern,” Madoff and Lou emphasized.

The editorialists further questioned what the authors meant when they recommended that oncologists “optimize” the dose and schedule of neoadjuvant therapy, pointing out that if it means planned dose reductions or prolonged times of administration, “how different is this as a practical matter from similar reductions made ad hoc to address poor patient tolerance?” they asked.

  1. Rectal cancer patients who could tolerate full-dose neoadjuvant radiation and concurrent chemotherapy were more likely to be free of disease at 3 years than patients who had to have doses of either protocol reduced to improve tolerance.

  2. The same beneficial effect on disease-free survival was not seen between those who completed full-dose adjuvant chemotherapy and those who needed a dose reduction.

Pam Harrison, Contributing Writer, BreakingMED™

Diefenhardt had no conflicts of interest to declare though several other co-authors did which are listed in the publication.

Neither Madoff nor Lou had any conflicts of interest to declare.

Cat ID: 23

Topic ID: 78,23,730,16,23,192,925