A prospective multicenter trial of dose escalation for weekly gemcitabine concurrent with intensity-modulated radiotherapy following cisplatin and gemcitabine induction chemotherapy in patients with locally advanced nasopharyngeal carcinoma.

person Zeng Qi Cancer Center, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China info_outline Zeng Qi, Bingqin Lin, Fangming Li, Yumeng Liu, Siyang Wang, Feiqiang Deng, Shaona Lei

Authors person Zeng Qi Cancer Center, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China info_outline Zeng Qi, Bingqin Lin, Fangming Li, Yumeng Liu, Siyang Wang, Feiqiang Deng, Shaona Lei Organizations Cancer Center, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China, Department of Oncology, Jiangmen Central Hospital, Jiangmen, China, Zhongshan City People's Hospital, Zhongshan, China Abstract Disclosures Research Funding No funding sources reported Background: Gemcitabine and cisplatin induction chemotherapy, followed by cisplatin-based concurrent chemoradiotherapy, constitutes the standard treatment for locally advanced nasopharyngeal carcinoma (LANPC). However, the substantial cumulative dosage of cisplatin used in this approach renders it intolerable for many patients due to advanced age or compromised renal function. Therefore, identifying alternative chemotherapeutic agents is crucial. Gemcitabine is a potent radiosensitizer with an overall favorable safety profile. Despite extensive research on the maximum tolerated dose (MTD) of concurrent gemcitabine chemotherapy in head and neck cancer, its MTD as a single-agent chemotherapy concurrently administered with intensity-modulated radiotherapy (IMRT) in LANPC remains uncertain. Methods: Patients diagnosed with stage III-IVa nasopharyngeal carcinoma were prospectively enrolled in three hospitals located within the largest NPC endemic area in southern China. After two cycles of cisplatin plus gemcitabine induction chemotherapy, patients underwent combined concurrent radiochemotherapy (70 Gy/6-7 weeks) with weekly gemcitabine. The initial dose level was set at 25mg/m 2 and subsequently escalated in a sequential manner to higher doses of 50mg/m 2 , 100mg/m 2 , 200mg/m 2 , and 300mg/m 2 etc. Our study employed a dose escalation strategy in which the dosage was incremented to the next group only if no more than one out of six patients experienced Dose-Limiting Toxicity (DLT), until DLT occurred in at least two patients. Patients underwent follow-up evaluations every three months. This study is registered with ClinicalTrials.gov under NCT04522050. Results: Between October 2018 and December 2023, a total of 39 Chinese patients were enrolled, 36 (27 males, 9 females) patients were considered evaluable. The incidence of DLT was observed in two out of six patients receiving a dosage level of 300 mg/m², with both cases presenting Grade 3 oral mucositis. Subsequently, the study was replicated using the same dosage level, resulting again in two instances of DLT: one case with Grade 3 radiation dermatitis and another case with oral mucositis. Consequently, a reduced dosage level of 200mg/m² was determined as MTD. No significant hematological toxicity or serious gastrointestinal adverse events were observed. Tumor response evaluation by MRI after twelve weeks of IMRT showed a complete response rate of 100%. To date, only two cases (5.56%) have been reported exhibiting tumor recurrence. Conclusions: The MTD for weekly gemcitabine with IMRT following induction chemotherapy in LANPC is determined to be 200 mg/m 2 . The DLT associated with this treatment regimen primarily consists of radiation dermatitis and/or oral mucositis. Clinical trial information: NCT04522050.

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