1. Goodwin, Peter M.

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The new adjuvant radiotherapy standard of care for cervical cancer-image-guided intensity-modulated radiotherapy (IG-IMRT)-should cut late gastrointestinal (GI) toxicity rates by 50 percent, according to mature results from the Phase III randomized Postoperative Adjuvant Radiation in Cervical Cancer (PARCER) study. While this newer, more costly form of radiotherapy had already been shown to reduce early toxicity rates to some extent, compared with conventional 3D conformal radiation therapy (3D-CRT), it had not been shown to outperform the older technique either in medium term toxicity or anti-cancer activity.

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The PARCER findings, however, presented originally at the 2020 meeting of the American Society for Radiation Oncology (ASTRO) and now published in the Journal of Clinical Oncology demonstrate a clear superiority for long-term GI toxicity and confirm equivalent anti-neoplastic efficacy (2021; doi: 10.1200/JCO.20.02530).


First author Supriya Chopra, MD, DNB, a radiation oncologist from the Tata Memorial Centre Homi Bhabha National Institute in Kharghar near Mumbai, India, told Oncology Times that, for patients with early cervical cancer in whom surgery was needed, there was now a strong mandate for choosing IG-IMRT adjuvant radiotherapy. "If your patients do undergo surgery and require post-op radiotherapy, then it has to be with image-guided IMRT. It's very clear," she said.


The PARCER study investigators decided to document late toxicities clinically-rather than by questioning patients about a range of quality-of-life issues, which Chopra and colleagues had been concerned would not be sufficiently rigorous for deciding upon any potential change in standard of care.

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"There is a huge social cultural difference in how people report quality of life-because of value systems, first, and [also because] an intervention can have very different reported quality of life across continents," she noted. "So, quality of life is not a very stable endpoint. It may be an important endpoint, but it's not a stable primary endpoint. It is not a robust endpoint."


Chopra described the PARCER trial as a "head-on" study in which the only factor differing between the two groups compared had been the radiotherapy method.


"The only test question was whether patients were treated on a linear accelerator with 3-D conformal radiotherapy versus image-guided IMRT. So, I think it was very balanced and fair. Every other factor was controlled. And yet we saw quite a difference," she said.


Study Details

Patients were stratified for the type of hysterectomy and use of concurrent chemotherapy. The primary endpoint was 3-year late GI toxicity of at least Grade 2. Secondary endpoints were acute toxicity, health-related quality of life, pelvic relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS).


A total of 300 patients were randomized (between 2011 and 2019) with 151 treated with IG-IMRT and 149 receiving conventional 3D-CRT. After a median follow-up of 46 months, the 3-year cumulative incidence of Grade 2 or higher late GI toxicity was 21.1 percent in the IG-IMRT arm of the study and 42.4 among patients treated with 3D-CRT. The cumulative incidence for any late toxicity of Grade 2 or higher was 28.1 percent for IMRT and 48.9 percent for standard conformal radiotherapy.


With IG-IMRT, patients reported less diarrhea, improved appetite, and less severe bowel symptoms. But there was no difference in relapse-free or disease-free survival. The 3-year pelvic RFS and DFS were 81.8 percent in patients treated with IG-IMRT and 84 percent in those receiving 3D-CRT.


Chopra said that the other big trial comparing these two modalities, the NRG study had investigated acute (but not late) toxicity by assessing patient-reported quality-of-life issues (J Clin Oncol 2020; doi: 10.1200/JCO.19.02381). It had found a short-term benefit of IG-IMRT, which had disappeared with longer follow-up.


"So, the question we were asking in our study was very important: Does [IG-IMRT] influence late toxicity? It does [benefit] patients when they are on treatment, but it's an expensive treatment to recommend to all patients. So will it make a difference long term?" In answer to these questions, Chopra said the curves from PARCER started to diverge after 36 months. "So, it's very clear to us that there is a clear difference in late adverse events of cancer survivors with advanced techniques of radiotherapy," she said.


When she was asked how significant these late toxicities were-even though they had not yet shown an impact on survival or recurrence rates-Chopra insisted the huge reduction in late GI toxicity was important.


"I would say it was pretty significant. We studied gastrointestinal side effects-symptoms like abdominal bloating, distension, diarrhea, chronic diarrhea, and in a small proportion of patients, obstructive symptoms. And we know that any GI troubles really impact quality of life of patients," she said.


Chopra welcomed the new standard-of-care guidelines that now recommended IG-IMRT in cervical cancer adjuvant therapy. She said both the NRG and PARCER studies had been important for changing the guideline. "Both these studies taken together provide very robust evidence."


"In our study, we were able to demonstrate that, by keeping cancer control exactly the same, you are able to reduce toxicity. So that is very important," she said. And because there could have been increased risk to other organs by introducing a new technique, the PARCER study had looked at other organs.


"Our secondary outcomes were on other organ toxicities. We evaluated genitourinary toxicity, vaginal, constitutional symptoms, [and] fatigue. But overall, even if you take all toxicities pooled together, the IG-IMRT was superior," she said.


"And what we also observe now-on additional statistical analysis that we've done since the study got published-is it's not only the incidence of adverse events, it's also the duration of adverse events that is even smaller with IG-IMRT," Chopra concluded.


Peter M. Goodwin is a contributing writer.