Less is better for neoadjuvant rectal cancer treatment

8 minute read

Skipping preoperative radiation treatment can be better for toxicity and just as good for clinical results.

Some patients with rectal cancer can avoid the toxicity of preoperative radiation therapy without jeopardising their clinical outcomes, according to results of the PROSPECT study presented at the ASCO 2023 meeting in Chicago last week.

The current standard of care treatment for locally advanced rectal cancer cures three in four patients, with very low rates of local recurrence. But “it comes as a cost”, said Dr Deborah Schrag, principal investigator and medical oncologist at the Memorial Sloane Kettering Cancer Centre. That cost included impaired bowel, bladder and sexual function, impaired fertility and marrow reserve, premature menopause, increased risk of pelvic fracture and second malignancy.

This new evidence suggests some patients can avoid exposure to those harms, without risking their recovery. Participants in the PROSPECT trial who had only selective preoperative chemoradiation did not have a worse response to resection, or worse rates of overall survival or disease free (over 98% at five years in both groups) or local recurrence rates than those who received the current standard of care treatment.

What differed between the two groups was toxicity.

The 1128 study participants, enrolled between 2012 and 2018, had a mean age of 57, were clinically staged as T2 node-positive, T3 node positive or T3 node negative, and were eligible for sphincter-sparing surgery.

Of these, 585 were randomised to the FOLFOX group (neoadjuvant chemotherapy with fluorouracil, leucovorin and oxaliplatin). They received six cycles of preoperative FOLFOX and only had radiation therapy if their primary tumour decreased by less than 20%, or if the FOLFOX had to be stopped because of side effects. This was followed by surgery and adjuvant chemotherapy (FOLFOX or CAPOX). The control group received the standard treatment of neoadjuvant pelvic radiation plus sensitising chemotherapy with fluoropyrimidine, surgery, and then adjuvant chemotherapy (FOLFOX or CAPOX).

Patients were followed up for a median of 58 months, with very similar clinical outcomes across both trial arms.

The researchers found that the FOLFOX approach was non-inferior to the standard approach for either survival or disease recurrence.

Five-year disease-free survival was 80.8% in the FOLFOX group and 78.6% in the chemoradiotherapy group. Five-year overall survival was 89.5% in the FOLFOX group and 90.2% in the full treatment arm. Local recurrence at five years was 1.8% and 1.6%. Complete pathological response to resection occurred in 22% and 24%, respectively. Adjuvant chemotherapy was given to 82% and 83% of the groups, for an average of 35 and 27 weeks.

But patients in the FOLFOX group did report more constipation during treatment (27% vs 11%) than those who received the full chemoradiotherapy neoadjuvant treatment, as well as fatigue (42% vs 20%), nausea (21% vs 7%), appetite loss (22% vs 9%) and, importantly, neuropathy (19% vs 5%). Patients in the full treatment arm reported higher rates of diarrhoea (20% vs 6%).

“The observation period is over twice as long in the FOLFOX group [12 weeks, or 22 weeks if also given 5FUCRT, compared to six weeks in the control group].  At 12 months, patient reports of severe adverse symptoms were low, all in the single digit range in both groups,” Dr Schrag pointed out.

The exception was neuropathy, which was reduced to 3% in the FOLFOX group but remained at 8% in the chemoradiation group because the latter received more oxaliplatin postoperatively, Dr Schrag explained.

“We had very high response rates from patients consistently. I think in this trial we established that patients are ready, willing and able to tell us how they function and feel during and throughout treatment. The tool we used is publicly available. It is sponsored by the National Cancer Institute. It is translated into over 35 languages. And I hope it gets used. I think we need to trust our patients,” she said.

The rate of clinician-reported neoadjuvant grade 3 or higher adverse events was 41% in the FOLFOX group and 23% in the chemoradiation group, although this was over FOLFOX’s more than double reporting period.

“Postoperatively, the rate of severe adverse events flipped and was 25% for the FOLFOX group and 39% for the chemoradiation groups,” said Dr Schrag.

Quality of life was measured in a subset of participants and showed a trend favouring the FOLFOX arm but no statistically significant difference. However, bowel function was “significantly better” in the FOLFOX arm prior to surgery, and significantly better sexual function persisted at 12 and 24 months, delegates were told.

Nine out of 10 patients in the FOLFOX group were able to avoid neoadjuvant chemoradiation therapy. Of the 9% who didn’t, none were seen to have a worse outcome as a result of the delay, said Dr Schrag.

Additionally, “there were no baseline characteristics that told us who was destined to end up in that group”, Dr Schrag told the conference.

Dr Schrag told delegates that she hoped the biomarker data from the study, yet to be analysed, would allow for further personalisation of treatment.

“We are going to be performing correlative analyses and trying to identify the molecular signatures that predict for responsiveness to chemotherapy, or the molecular signatures that predict for responsiveness to chemoradiation, or conversely, resistance,” Professor Schrag said.

Newer treatments have been developed since this study was undertaken in 2012, including the use of immune-ablative therapy for patients whose tumours have microsatellite instability, shorter courses of adjuvant FOLFOX, short course radiation, total neoadjuvant therapy, FOLFIRINOX and non-operative management.

Considering a higher threshold of primary tumour reduction of 40% could be useful when thinking about non-operative management for a patient, suggested Netherlands Cancer Institute radiation oncologist Professor Corrie Marijnen, who followed Dr Schrag on the ASCO stage to provide comment on the trial.

“Being a radiation oncologist and then discuss[ing] a trial that wants to omit radiation oncology is quite a challenge,” Professor Marijnen told those assembled.

“I still believe in radiotherapy. And I think if you’re going for non-operative management, and you’re not so worried about distal metastasis, I think very localised treatment with radiotherapy, with our modern techniques, with the contact therapy, that has just been published, can achieve very good response rates there.”

The difference between early/intermediate tumours and mid/high rectal tumours was important for clinicians to consider, Professor Marijnen noted.

“For more advanced tumours, if you want to achieve a full, complete response, only FOLFOX may not be enough,” she told delegates.

“For early/intermediate and mid/high rectal cancers, FOLFOX followed by selective chemoradiotherapy can definitely replace the standard of neoadjuvant chemoradiotherapy. And I think that the largest benefit in doing so is that we will see less long-term, radiotherapy-related toxicity.”

The scales tipped in favour of the non-radiation treatment when radiotherapy-induced toxicity was considered, she said.

“It’s a no brainer, that if you don’t give radiotherapy, you won’t have toxicity. So probably, well, very likely, in the chemoradiotherapy arm there will be an increase of faecal incontinence, sexual dysfunction and infertility.”

Ultimately, choice of treatment could depend on patient preferences, she suggested.

Patients have a different threshold for deciding to undergo radiotherapy than clinicians do, with the former giving the green light at anywhere from 0-11% benefit in local control, while doctors pushed the button at 5% according to research previously undertaken by Professor Marijnen and her colleagues.

“When I started, rectal cancer was fairly simple, and it’s getting more complex because there’s a completely different approach: if you’re going to operate on your patient or if you have a patient in front of you that wants non-operative management. It is definitely more and more a shared decision-making process, I think, and to do that is rather difficult as well,” said Professor Marijnen.

Also playing a role in the decision would be whether a patient truly had “locally advanced” disease, because definitions of “locally advanced” vary, Professor Marijnen pointed out. By European standards, the majority of study participants would fall into the early and intermediate grade of tumours, a group that would not be recommended for adjuvant treatment, she said.

In the US, however, neoadjuvant treatment is recommended for nearly all patients.

And in Australia, we generally follow the US model, colorectal surgeon Professor Paul McMurrick told Oncology Republic, with most patients with a T2 node-positive or T3 node-positive or node-negative rectal cancer discussed at a multidisciplinary meeting and offered preoperative neoadjuvant chemoradiation using 5FU-based chemotherapy.

There were certainly advantages to removing radiation from the equation, said Professor McMurrick. The functional side effects of radiation therapy were significant, affecting pelvic nerve and organ function, fertility, and there were additional risks associated with subsequent reconstructive surgery, some of which would take place less frequently without radiation.

Furthermore, radiation therapy would still be on the table for patients who developed other pelvic cancers in the future, which might not be the case if they had already used that option, he added.

However, the exclusion of patients from the trial who had an abdominoperineal resection, a group of patients who were at higher risk of local relapse, was notable, said Professor McMurrick.

“We know [that] somewhere between 8% and probably 15% of patients who have a rectal cancer won’t be reconstructed. they’re going to have an abdominoperineal resection with a permanent stoma. If the tumour is well down in the lower third and there’s deemed not to be an acceptable margin between the tumour and the sphincter mechanism, then sometimes they can’t be reconstructed,” he explained.

Nor did the trial include bulky tumours that touch the pelvic side wall, “and again, they’re the most problematic of all these tumours,” he said.

Inclusion of these groups in further trials was important to apply this information more broadly, said Professor McMurrick.

“I’ll be very interested to hear the doubtless robust discussions [about these results] at our upcoming multidisciplinary meeting,” he said.

“We have a very well-attended MDM that involves surgeons, oncologists and radiation therapists and I’ll be very interested to hear the perspective of each of them.”

NEJM 2023, online 4 June

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