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Induction chemotherapy extends failure-free survival in locoregionally advanced nasopharyngeal carcinoma
The addition of induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma, according to multicenter, randomized, controlled phase 3 trial results published in The Lancet Oncology.
Concurrent chemoradiotherapy is the standard treatment for locoregionally advanced nasopharyngeal carcinoma; however, distant metastasis is the main source of treatment failure.
The addition of induction chemotherapy demonstrated early eradication of micrometastases in previous studies; however, it did not reduce distant metastases or prolong survival.
“One explanation is that a truly effective induction chemotherapy regimen has not yet been identified,” Ying Sun, MD, from the department of radiation oncology at Sun Yat-sen University Cancer Center, and colleagues wrote.
The combination of docetaxel, cisplatin and fluorouracil (TPF) has shown promising results with manageable toxicity as induction chemotherapy for nasopharyngeal carcinoma, however survival data are lacking.
Therefore, Sun and colleagues evaluated the addition of TPF induction chemotherapy to chemoradiotherapy in 480 patients with previously untreated, stage III to IVB nasopharyngeal carcinoma aged 18 to 59 years. Researchers randomly assigned patients to receive concurrent chemoradiotherapy alone (n = 241) or with TPF induction chemotherapy (n = 239).
Induction chemotherapy consisted of three cycles of IV docetaxel (60 mg/m² on day 1), IV cisplatin (60 mg/m² on day 1) and continuous IV fluorouracil (600 mg/m² per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy, which included three cycles of 100 mg/m² cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy.
After a median follow-up of 45 months, more patients treated with TPF induction chemotherapy plus concurrent chemoradiotherapy were failure free at 3 years (80% vs. 72%; HR = 0.68; 95% CI, 0.48-0.97) and alive at 3 years (92% vs. 86%; HR = 0.59; 95% CI, 0.36-0.95). Further, more patients in the induction chemotherapy arm did not experience distant failure at 3 years (90% vs. 83%; HR = 0.59; 95 CI, 0.37-0.96) and were alive without locoregional failure at 3 years (92% vs. 89%; HR = 0.64; 95% CI, 0.36-1.13).
More patients treated with induction chemotherapy experienced grade 3 or grade 4 neutropenia (42% vs. 7%), leucopenia (41% vs. 17%) and stomatitis (41% vs. 35%).
Additional follow-up is needed to assess long-term efficacy and toxicity of TPF induction chemotherapy, Sun and colleagues wrote.
Future trials designed to evaluate TPF plus cisplatin-based concurrent chemoradiotherapy compared with concurrent chemoradiotherapy followed by adjuvant chemotherapy also are necessary, Michael T. Spiotto, MD, PhD, assistant professor of radiation and cellular oncology at University of Chicago Medical Center, wrote an accompanying editorial.
Such a study could validate induction chemotherapy or reaffirm the use of adjuvant chemotherapy; however, the addition of cisplatin-based concurrent chemotherapy may be limited for other head and neck squamous cell cancers.
“Nevertheless, this study is an important step for redefining treatment guidelines in nasopharyngeal cancers,” Spiotto wrote. – by Kristie L. Kahl
Disclosures: The researchers and Spiotto report no relevant financial disclosures.
Perspective
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Nasopharyngeal carcinoma is a rare tumor — the overall incidence is less than one per 100,00 person-years — with an increased prevalence in Asia, and especially southern China. Because this tumor is rare, there are few approved treatments and novel clinical trials.
In 1998, Al-Sarraf and colleagues published a landmark paper describing the use of chemoradiotherapy with high-dose cisplatin followed by adjuvant chemotherapy with cisplatin and 5-fluorouracil. This regimen showed a statistically significant improvement in PFS and OS compared with radiation alone and became the standard of care. However, it was difficult to administer the adjuvant chemotherapy and, in 2012, Chen and colleagues showed no difference in failure-free survival between chemoradiotherapy with or without adjuvant chemotherapy in Chinese patients.
The concept of high-dose induction chemotherapy was validated by Posner and colleagues in 2007 with docetaxel, cisplatin and 5-FU. Not only was the regimen tolerable, but it also allowed patients to receive subsequent chemoradiation. Clinically, more physicians were utilizing induction chemotherapy in patients with nasopharynx cancers.
Sun and colleagues developed a phase 3 study examining the use of induction chemotherapy with standard chemoradiation in nasopharyngeal cancers. Compared with the Posner regimen, Sun and colleagues elegantly dose-reduced the overall chemotherapy, creating more tolerability — decreased stomatitis and myelosuppression — with no apparent decrease in efficacy. The study showed a statistically significant improvement in failure-free survival and it asserted that induction chemotherapy would not decrease dose delivery during chemoradiation.
Just as in head and neck squamous cancers, induction therapy is now an important component of treatment for patients with nasopharynx cancers. Although this report does not create a de facto standard of care, it does provide a chemotherapy regimen that we feel will be a preferred option for clinicians and in a tumor type in which no single standard of care exists. Induction chemotherapy allows systemic treatment to begin quickly, preventing possible delay of therapy due to inability to schedule timely chemoradiation. By administering full-dose induction chemotherapy, one may reduce the risk for distant failure. More mature data from the study will be needed to fully assess recurrence and OS. However, this study provides strong rationale for integration of induction chemotherapy in patients with nasopharynx cancers and establishes a reasonable platform for future testing of biologic agents in this rare tumor type.
Sun and colleagues provided us a new regimen that has results that are comparable to the Al-Sarraf regimen and validates the use of induction chemotherapy in nasopharyngeal cancer. We will eagerly await updates from this trial, but for now, we will begin adopting this regimen in our nasopharyngeal patients.
Al-Sarraf M, et al. J Clin Oncol. 1998;16:1310-1317.
Chang ET and Adami H. Cancer Epidemiol Biomarkers Prev. 2006;15:1765-1777.
Chen L, et al. Lancet. 2012;doi:10.1016/S1470-2045(11)70320-5.
Posner MR, et al. N Engl J Med. 2007;357:1705-1715.