For women with high-risk endometrial cancer, adjuvant chemotherapy given during and after external-beam radiotherapy provides an absolute 11% improvement in failure-free survival, although not overall survival, in women with stage III disease, the final analysis of the international PORTEC-3 trial indicates.
However, the same adjuvant protocol does not benefit women with stage I or II endometrial cancer compared to radiotherapy alone, investigators report.
In addition, the severity and duration of the toxicity associated with chemoradiotherapy, together with the protracted treatment course, suggest that the new approach should be carefully discussed with cancer patients who have stage III, high-risk endometrial cancer before launching into the arduous protocol, lead author Stephanie de Boer, MD, Leiden University Medical Center, the Netherlands, and colleagues emphasize.
"Analysed by stage, patients with stage III endometrial cancer who have the highest frequency of recurrence also had the greatest absolute benefit from the combined treatment," the investigators observe.
"[I]n view of the higher risk of recurrence among women with stage III disease, this chemoradiotherapy schedule should be considered to maximise failure-free survival, and benefits and risks should be individually discussed," they conclude.
The study was published online February 12 in Lancet Oncology.
In an accompanying editorial, Sean Dowdy, MD, and Gretchen Glaser, MD, both of the Mayo Clinic in Rochester, Minnesota, disagree with the authors' cautious interpretation of PORTEC-3 findings, stating that "the significant improvement in failure-free survival seen in patients with stage III disease seems to justify the accompanying toxicity."
The editorialists point out that women aged 70 years or older derived the greatest benefit from chemoradiotherapy, as determined on the basis of multivariate analysis. Given this, "providers should council elderly patients of this potential benefit of chemoradiotherapy," they comment.
This is important, because in the United States, patients aged 70 years are half as likely as younger patients to receive adjuvant chemotherapy or radiotherapy after surgery, the editorialists point out.
On the other hand, Dowdy emphasized that the fact that older women with stage III disease appear to benefit the most from the chemoradiotherapy approach does not mean younger women won't also benefit from the same treatment, provided they have stage III disease.
"We should not opt to give less treatment simply because of age," he emphasized in an email to Medscape Medical News.
"Chemoradiation offers significant benefit for women under the age of 70, and I would consider it standard of care for any patient with stage III disease," he clarified.
Study Details
In the PORTEC-3 study, 660 patients were randomly assigned to receive either chemoradiotherapy or radiotherapy alone. The median age in both groups was 62 years.
"External beam pelvic radiotherapy was given in both treatment groups to a total dose of 48.6 Gy in 1.8 Gy fractions, 5 days a week," the investigators report.
Patients who received additional chemotherapy received two cycles of IV cisplatin at a dose of 50 mg/m2 in the first and the fourth week of external-beam pelvic radiotherapy, followed by four cycles of IV carboplatin, AUC5, plus paclitaxel 175 mg/m2 at 21-day intervals.
"The coprimary endpoints were overall survival and failure-free survival," the study authors state. Failure-free survival was defined as relapse or death related to either endometrial cancer or its treatment.
At 5 years, overall, 81.8% of patients in the chemoradiotherapy group were alive, compared with 76.7% for the radiotherapy-alone group (P = .109).
The 5-year failure-free survival rate was 75.5% for the chemoradiotherapy arm, compared to 68.6% for the radiotherapy-alone group (P = .022).
Vaginal and pelvic control rates were high in both treatment arms.
"In subgroup analysis, women with stage III endometrial cancer had significantly lower overall survival and failure-free survival than those with stage I-II disease," the researchers report.
On the other hand, differences between the coprimary endpoints, determined on the basis of treatment allocation, were most pronounced among women with stage III disease.
Table. 5-Year Outcomes by Disease Stage for Each Treatment Group
| Chemoradiotherapy, Stage III | Radiotherapy-Alone, Stage III | Adjusted P Value | Chemoradiotherapy, Stage I-II | Radiotherapy-Alone Stage I-II | Adjusted P Value | |
|---|---|---|---|---|---|---|
| Overall survival | 78.7% | 69.8% | .074 | NA | NA | NA |
| Failure-free survival | 69.3% | 58.0% | .014 | 80.8% | 76.6% | .47 |
Toxicity Profile
Toxicity was significantly greater with chemoradiotherapy than it was with radiotherapy alone.
Of women in the chemoradiotherapy group, 93% experienced adverse events (AEs) of grade 2 or worse, compared with 43% in the radiotherapy group. Of women treated with chemoradiotherapy, 60% experienced AEs of grade 3 or worse, compared to only 12% in the radiotherapy group (P < .0001). Most of the AEs were hematologic in nature.
From 12 months onward, both groups experienced equal rates of AEs of grade 3 or worse. There were no treatment-related deaths.
"The most significant and clinically relevant difference between the arms was found for grade 2 or worse sensory neuropathy," the investigators note.
Neuropathy persisted long after treatment had been completed. One quarter of patients in the chemoradiotherapy arm reported either "quite a bit" or "very much" tingling or numbness at 2 years, compared with only 6% of those in the radiotherapy group.
Of women in the adjuvant chemotherapy group, 8% reported neuropathy of grade 2 or worse at 3 years, compared to only one woman (1%) in the radiatotherapy-alone arm (P < .0001).
"Because pelvic control was high with radiotherapy alone, this chemoradiotherapy schedule cannot be recommended as a new standard for patients with stage I-II endometrial cancer," the PORTEC-3 study authors caution.
"Women with high-risk endometrial cancer should be individually counselled about this combined treatment," they conclude.
Editorialists Dowdy and Glaser agree that the "small magnitude of benefit" seen with the addition of chemotherapy for patients with stage I or stage II disease "does not seem to justify the accompanying increase in adverse events, impairment in long-term quality of life, and longer treatment duration."
The study was funded by the Dutch Cancer Society, Cancer Research UK, the National Health and Medical Research Council Project, Cancer Australia, L'Agenzia Italiana del Farmaco, and the Canadian Cancer Society Research Institute. The authors, Dr Dowdy, and Dr Glaser have disclosed no relevant financial relationships.
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