TREATMENT OF NASOPHARYNGEAL CARCINOMA

July 16, 2010 — The standard treatment protocol for advanced nasopharyngeal carcinoma includes adding concurrent adjuvant chemotherapy to radiotherapy. However, a new study has found that although this combination reduced cancer-related mortality, it was associated with a "worrisome increase" in noncancer-related deaths.

The study was published online July 15 in the Journal of the National Cancer Institute.

Adding chemotherapy to radiotherapy significantly reduced the number of deaths attributable to disease progression. But patients receiving combination therapy had a significantly higher incidence of acute toxicities than those receiving radiotherapy alone (83% vs 53%; P < .001).

In addition, there was a 1.7% increase in direct treatment-related mortality in the combination group, and a 4.7% increase in deaths due to "incidental" causes. These included infection, second malignancy, cerebral vascular accident, and suicide.

Thus, even though the addition of chemotherapy significantly reduced mortality attributable to disease progression, the 5-year overall survival was similar in both groups because of an increase in noncancer-related deaths.

Study Lends Support to Standard Treatment

Lead author Anne W.M. Lee, MD, from the Pamela Youde Nethersole Eastern Hospital in Hong Kong, China, pointed out that even though the acute toxicity rate increased significantly by 30%, the great majority of patients recovered uneventfully.

"The increase in late toxicity rate was statistically insignificant," she told Medscape Medical News. "The mortality rate directly due to acute toxicity was 1.2% and to late toxicity was 0.6%."

On the surface, the combination therapy could be accepted as "reasonably tolerable," she pointed out. "However, in addition to these direct treatment-related mortalities, deaths from other causes — including infection, second cancer, and suicide — increased by 4.7%. Whether these can be attributed to subtle damage by chemotherapy cannot be excluded."

"Despite this worrisome concern about a statistically significant increase in deaths due to treatment-related toxicities and other causes that narrow the ultimate gain in overall survival, this study still lends support to continuing the current standard," she said.

"This is because combined treatment can indeed statistically reduce tumor relapse and cancer-specific deaths," said Dr. Lee. "Knowing the suffering associated with disease progression, this achievement is of the highest priority."

However, she emphasized that patients should be duly informed of the associated risk, and clinicians should be alerted to the need for vigilant follow-up. "Future improvements include not only exploration for methods of lowering toxicity, but also for more accurate prognostication so that aggressive treatment can be better tailored to individual patients," said Dr. Lee.

Concurrent adjuvant chemotherapy was added to radiotherapy in the treatment of advanced nasopharyngeal carcinoma on the basis of results from the Intergroup 0099 study, which were published in 1998 ( J Clin Oncol. 1998;16:1310-1317). The results showed an "impressive" increase in both 3-year progression-free survival and overall survival in patients with advanced disease, the Intergroup 0099 authors note. This regimen has since become the standard of care for this population.

Because there are no data on late toxicities, the Hong Kong Nasopharyngeal Cancer Study Group began studies in 1999 to explore long-term efficacy and safety. They believe that this study is the first to use detailed data on late toxicities and causes of death to evaluate the therapeutic index.

Survival Gain Improves Over Time

The study ran from 1999 to 2004, and enrolled 348 patients with advanced nasopharyngeal carcinoma. They were randomized to either radiotherapy alone or to radiotherapy plus cisplatin (100 mg/m2) every 3 weeks for 3 cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m2) plus fluorouracil (1000 mg/m2 per day for 4 days) every 4 weeks for 3 cycles.

One of the primary end points was overall failure-free rate (the time to first failure at any site), which was significantly higher in the combination group than in the radiotherapy group at 5 years (67% vs 55%; P = .014). The authors note that this result appears to be largely due to a significant improvement in the 5-year locoregional failure-free rate with the combination over radiotherapy (88% vs 78%; P = .005).

However, the difference in the 5-year distant failure-free rate did not reach statistical significance (74% vs 68%; P = .320).

The other primary end point, progression-free survival, was also significantly higher at 5 years in the combination group than in the radiotherapy group (62% vs 53%; P = .035).

Despite a significant 14% reduction in deaths from disease progression in the combination group (24% vs 38%; P = .008), the rates of overall survival were nearly identical in both groups during the first 4 years. However, at 5 years, there was a 4% gain in overall survival in the combination group (68% vs 64%). This increased to 7% at 8 years (61% vs 54%; P = .220).

Longer follow-up is needed to confirm this trend, the authors write. "If confirmed, this magnitude of survival gain is still clinically valuable and comparable to the results commonly achieved for other solid cancers."

A Curable Disease

Muhyi Al-Sarraf, MD, lead author of the Intergroup 0099 study, explained that nasopharyngeal cancers are highly sensitive to total radiotherapy, to effective chemotherapy, and to effective concurrent chemoradiotherapy.

Even though patients are usually diagnosed late with locally advanced stage III or IV disease, nasopharyngeal cancer is highly sensitive to treatment, he told Medscape Medical News.

"This is now a curable disease, provided adequate therapy and proper doses with the proper sequence are given," said Dr. Al-Sarraf, professor of medicine and oncology at William Beaumont Hospital in Royal Oak, Michigan. "The cure rate — not just 5-year survival — in 2010 is about 90%."

Dr. Al-Sarraf explained that the standard proper therapy is induction chemotherapy with 3 agents (taxane, cisplatin, fluorouracil) for 3 courses followed by concomitant weekly carboplatin and radiotherapy.

Dr. Al-Sarraf pointed out that modifying the regimen has helped decrease adverse events and improve quality of life. Changing to a single daily fraction of radiotherapy concurrent with chemotherapy is as effective as other schedules and has the fewest local adverse effects, he said.

Concurrent cisplatin and radiotherapy was changed to weekly carboplatin concurrent with and during radiotherapy, which further reduced adverse effects, including nausea and vomiting, hearing loss, renal dysfunction and dehydration, and peripheral neuropathy.

"The modified chemotherapy protocol and the use of carboplatin with radiotherapy is not only the most effective regimen, it is also the safest regimen and offers a better of quality of life," he said.

Detailed Data on Safety

Patients receiving combination therapy in the study had a significantly higher incidence of acute toxicities, with a higher rate of grade 4 events (12% vs 1%). Two patients in the combination group died of sepsis, and there was a significantly higher incidence of radiotherapy-related mucositis (62% vs 48%; P = .02). In addition, the incidence of chemotherapy-related toxicities was 59%.

Although combination therapy had a higher rate of late toxicity during the first 3 years, this had evened out at 5 years (30% vs 24%).

Although there was no statistically significant increase in major late toxicity, the authors write, the increase in noncancer deaths narrowed the resultant gain in overall survival.

The study was funded by grants from charitable organizations, including the Hong Kong Cancer Fund, Ho Hung Chiu Medical Foundation Limited, and the Hong Kong Anti-Cancer Society.

J Natl Cancer Inst. Published online July 15, 2010.