Docetaxel (Page 11 of 12)

14.6 Head and Neck Cancer

Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of another formulation of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.

The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 21 and Figures 8 and 9.
Table 21 — Efficacy of Docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINT Docetaxel+ Cisplatin+ Fluorouracil n=177 Cisplatin+ Fluorouracil n=181
A Hazard ratio of < 1 favors Docetaxel+Cisplatin+Fluorouracil
*
Stratified log-rank test based on primary tumor site
Stratified log-rank test, not adjusted for multiple comparisons
Chi square test, not adjusted for multiple comparisons

Median progression free survival (months) (95%CI)

11.4 (10.1 to 14.0)

8.3 (7.4 to 9.1)

Adjusted Hazard ratio (95%CI) *p-value

0.71 (0.56 to 0.91) 0.0077

Median survival (months) (95%CI)

18.6 (15.7 to 24.0)

14.2 (11.5 to 18.7)

Hazard ratio (95%CI) p-value

0.71 (0.56 to 0.90) 0.0055

Best overall response (CR + PR) to chemotherapy (%) (95%CI)

67.8 (60.4 to 74.6)

53.6 (46.0 to 61.0)

p-value

0.006

Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI)

72.3 (65.1 to 78.8)

58.6 (51.0 to 65.8)

p-value

0.006

Figure 8 — TAX323 Progression-Free Survival K-M Curve

Docetaxel Injection
(click image for full-size original)

Figure 9 — TAX323 Overall Survival K-M Curve

Docetaxel Injection
(click image for full-size original)

Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of another formulation of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m 2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m 2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 to 0.90]. Overall survival results are presented in Table 22 and Figure 10.

Table 22 — Efficacy of Docetaxel in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINT Docetaxel + Cisplatin+ Fluorouracil n=255 Cisplatin+ Fluorouracil n=246
A Hazard ratio of < 1 favors docetaxel + cisplatin + fluorouracil
NE — not estimable
*
un-adjusted log-rank test

Median overall survival (months) (95% CI)

70.6 (49.0 to NE)

30.1 (20.9 to 51.5)

Hazard ratio: (95% CI) *p-value

0.70 (0.54 to 0.90) 0.0058

Figure 10 — TAX324 Overall Survival K-M Curve

Docetaxel Injection
(click image for full-size original)

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