'Big Jump' in Survival in Advanced Nasopharyngeal Cancer

Adding induction chemotherapy to standard concurrent chemoradiotherapy boosted overall survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, but at a cost of higher rates of acute grade 3 or 4 toxicities, in a phase 3 study conducted in China.

"The increase from 90.3% to 94.6% in overall survival is a big jump. It means the new treatment lowered the risk of death by about 50% " Jun Ma, MD, of the Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Quangzhou, China, told Medscape Medical News.

As for side effects, "most acute side effects were temporary and reversible [and] would not significantly impair the patient's quality of life. The incidence of late side effects was not increased with the induction chemotherapy, with the exception of mild peripheral neuropathy," Ma said.

Approached for comment, Marcelo Bonomi, MD, of the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital, Columbus, said the study has already changed practice at his institution, where use of induction chemotherapy is now standard in these patients.

The absolute benefit in overall survival is "huge," and acute toxicity is the "price to pay" for improved overall survival, Bonomi told Medscape Medical News.

The study was published online September 19 in the New England Journal of Medicine and was presented earlier this year at the annual meeting of the American Society of Clinical Oncology.

Clear-cut Survival Advantage

The authors explain that, at presentation, 70% of patients with nasopharyngeal carcinoma have locoregionally advanced disease and an unfavorable prognosis. Chemoradiotherapy with a platinum-based agent is the backbone of therapy in this group.

In their study, the investigators explored adding induction chemotherapy with gemcitabine and cisplatin, which had already shown promising efficacy in phase 2 trials.

Theirs was a phase 3 study, conducted in 480 patients with previously untreated, locoregionally advanced, nonmetastatic stage III–IVB nasopharyngeal carcinoma.

Roughly half of the patients were randomly allocated to receive induction chemotherapy with gemcitabine (1 g/m² on days 1 and 8) plus cisplatin (80 mg/m² on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg/m² every 3 weeks for three cycles plus intensity-modulated radiotherapy).

The patients in the other group were treated with chemoradiotherapy alone.

At a median follow-up of 42.7 months, the primary endpoint of 3-year recurrence-free survival was 85.3% with induction chemotherapy vs 76.5% with chemoradiotherapy alone (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 – 0.77; P = .001).

Overall survival at 3 years (a secondary endpoint) also clearly favored induction chemotherapy (94.6% vs 90.3%; stratified HR for death, 0.43; 95% CI, 0.24 – 0.77).

The survival advantage with induction chemotherapy is "pretty clear-cut and may become even larger with time. That is, the survival advantage at 3 years may not tell the full story," James Fetten, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News.

"What makes intuitive sense about this strategy is that people die of distant metastasis in this disease, not from recurrence locally," said Fetten, who was approached for comment.

"Giving chemotherapy initially, as early as possible, not only controls the local disease, it addresses the most feared complication, which is microscopic distant disease," he said. He noted that this is already "done for other locally advanced cancers, like breast cancer."

Not All Side Effects Created Equal

Virtually all patients (96.7%) completed three cycles of induction chemotherapy, despite acute toxicities. The incidence of acute adverse events of grade 3 or 4 was 75.7% with induction chemotherapy vs 55.7% without, with a higher incidence of grade 3/4 neutropenia (28.0% vs 10.5%), thrombocytopenia (11.3% vs 1.3%), anemia (9.6% vs 0.8%), nausea (23.0% vs 13.9%), and vomiting (22.6% vs 13.9%).

The incidence of late toxic effects was similar in the treatment groups, with the exception of grade 1 or 2 peripheral neuropathy, the incidence of which was higher in the induction chemotherapy group than in the standard-therapy group (8.8% vs 1.7%).

"As for side effects," said Ma, "it would be important to tell patients that not all serious (grade 3 or 4) side effects are created equal. For example, the major increased acute side effects in our trial was hematological, including neutropenia, thrombocytopenia, and anemia. Most of these side effects were discovered by laboratory tests only, and most patients have no symptoms.

"What's more important to patients' long-term quality of life is late side effects, which are likely to be persistent or even permanent. We are glad to see that the incidence of late side effects was not increased with the induction chemotherapy, with the exception of mild peripheral neuropathy," said Ma.

Summing up, Ma said this trial establishes induction chemotherapy plus concurrent chemoradiotherapy as the "standard of care" in locally advanced nasopharyngeal carcinoma. "It has already changed practice in many cancer centers," she added.

Funding for the study was provided through grants from the Innovation Team Development Plan of the Ministry of Education, the Natural Science Foundation of Guangdong Province, and other health and science organizations. Ma, Fetten, and Bonomi have disclosed no relevant financial relationships.

N Engl J Med. 2019;38:1124-1135. Abstract

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