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Superiority of Five Year Survival with Chemo-Radiotherapy (CT-RT) vs Radiotherapy in Patients (Pts) with Locally Advanced Nasopharyngeal Cancer (NPC). Intergroup (0099) (SWOG 8892, RTOG 8817, ECOG 2388) Phase III Study: Final Report.

Muhyi Al-Sarraf, et al ASCO 2001

NPC is highly responsive to RT and to CT. The SWOG coordinated an intergroup study comparing concurrent CT-RT followed by CT to RT only in pts with locally advanced NPC (Proc. ASCO 15:313, 1996). With minimum follow-up of five years, the progression-free survival (PFS) was 29% for the intent to treat on RT, and 58% for the CT-RT group (p<.001). The over-all survival(OS) was 37% vs 67% respectively (p.001). The disease related OS was 46% for the RT arm, and 74% for the CT-RT pts. Significant differences were found in OS and PFS between the histological types for all pts treated. The OS for WHO I was 37%, for WHO II was 55%, and for WHO III was 60% (p=.001). We concluded that the combination of CT-RT is superior to RT in pts with locally advanced NPC with respect to PFS and over-all survival.

 


ASCO 2001 Abstract 2532

 
Phase II Study: Concomittant Chemoradiotherapy (CRT) with Paclitaxel & Cisplatin as Primary Therapy for Locoregionally Advanced Nasopharyngeal Carcinoma (NPC).

Savitree Maoleekoonpairoj,et al.

Objectives: To assess the tolerance and efficacy of combination paclitaxel + cisplatin concurrent to radiotherapy in nonmetastatic stage III & IV NPC.
27 patients were enrolled from Jan 1998 to Sept 1999. The schedule of chemotherapy was paclitaxel 45 mg/m2/wk 1 hr infusion weekly x 7 weeks + cisplatin 100 mg/m2 on week 1, 4, & 7, with radiation therapy 1.8-2.0 Gy/fraction, 5fractions /week, a total dose of 70 Gy at primary tumor and 60-66 Gy to regional lymph nodes. Patients characteristics were: median age 43 years (19-66), 16 male and 11 female, histology WHO type 2 = 10 and 3 = 17, performance status 0-1, stage III = 7 (T2N2-6, T3N1-1), stage IV = 20 (T2N3-8, T3N3-1, T4N0-2, T4N1-2, T4N2-2, T4N3-5). Results: all patients were clinically CR after CRT. Grade 3 and 4 oropharyngeal mucositis were seen in 19(70.3%) and 2(7.4%) respectively. 19(70.3%) patients were required nasogastric feeding tube. Hematologic toxicity were anemia (gr1=48%, gr2=37%, gr3=3.7%) and neutropenia (gr1=29.6%, gr2=22%, gr3=7%, gr4=3.7%), none had thrombocytopenia. 4 patients (14.8%) developed gr1 nephrotoxicity. 8(29.6%) patients developed fever from local infection in the oropharynx requiring parenteral antibiotics therapy. All patients received paclitaxel as planned, 7 patients refused the third cycle of cisplatin. The median duration of RT was 57 days (45-72). To date, the median follow-up time is 25.2 months (12.7-33.9), one patient died of local recurrence at 17 months. 3 patients showed distant metastasis at 12,15 and 24 months. The 2 year DFS was 81.5%. Conclusion: CRT as primary therapy leads to high locoregional control of disease especially in patients with very large cervical nodes. The progression free survival and overall survival need longer time to follow up. Role of adjuvant chemotherapy in those patients with initially intensive CRT is ongoing study.

Chemotherapy + Radiotherapy

JCO 16(4):1310-7, 1998 Apr.

SWOG coordinated an Intergroup study with the participation of RTOG, & ECOG. This randomized phase III trial compared chemoradiotherapy vs. XRT alone in patients with nasopharyngeal cancers. Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35-39 fractions. Total dose:70 Gy. The investigational arm received chemotherapy: CISPLATIN 100 mg/m2 on days 1, 22, & 43 during radiotherapy; postradiotherapy, chemotherapy with CISPLATIN 80 mg/m2 on day 1 & fluorouracil 1,000 mg/m2/d on days 1-4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.



Concomitant Radiotherapy and Chemotherapy for Early-Stage Nasopharyngeal Carcinoma

JCO 18(10):2040, 2000 

Chemotherapy consisted of Cisplatin and fluorouracil (5-FU). CISPLATIN 100 mg/m2 bolus injection was delivered on day 1, & 5FU 1,000 mg/m2 was administered by 24-hour continuous infusion daily on days 1 - 5 for 5 days. 60% of the drug doses were given to the patients when CT was administered concomitantly with radiation. 4 courses of chemotherapy were delivered: 2 simultaneously with XRT on weeks 1 & 6 and an additional 2 courses monthly after the completion of radiotherapy.

Results: Patients who were treated with XRT alone primarily had stage I disease, whereas none of those who were treated with CCRT had stage I disease (11 of 12 patients v none of 32 patients;P = .001). The locoregional control rate at 3 years for the radiotherapy group was 91.7% (median follow-up period, 34 months) and was 100% for the CCRT group (median follow-up period, 44 months) (P = .10). The 3-year disease-free survival rate in the radiotherapy group was 91.7% and was 96.9% in the CCRT group (P = .66).







Anthony Tc Chan, et al. ASCO 2000



A Phase III Randomized Trial Comparing Concurrent Chemotherapy-Radiotherapy with Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma.



In this randomized phase III trial we compared concurrent chemotherapy-RT (CRT) to RT alone in NPC patients with Ho's N2, N3 staging or any N stage with a nodal diameter of 4 cm. Between April 1994 - June 1999 321 eligible patients were randomized to receive cisplatin 40 mg/m2 weekly up to 8 weeks concurrently with radical RT or RT alone. For both arms, the dose of radical RT to nasopharynx (NP) & upper neck by conventional fractionation were 66 Gy & 58 Gy respectively. Booster external RT was given to tumors with parapharyngeal infiltration and to residual nodes. Intracavitary brachytherapy was given to residual disease in the NP. Patients with distant metastases or inadequate bone marrow. renal and liver functions were excluded. The baseline patient characteristics including age, sex and Ho's staging were comparable in both arms. 92.5% of patients had WHO types II and III histology. An intention-to-treat principle was applied to the progression free survival (PFS) analysis with 80% power to detect a hazards ratio of 1.77 using a 2-sided 5% level test. There was no treatment related death in the CRT arm and one patient died of aspiration pneumonia during treatment in the RT alone arm. Systemic toxicities in file CRT arm consisted of nausea, vomiting and myelosuppression, while the local toxicities were similar in both arms. 79% of the patients in the CRT arm received at least 4 cycles of cisplatin. The 2 year PFS was 78% in the CRT arm and 62% in the RT alone arm. There was a significant difference in PFS favoring the CRT arm (p = 0.0127, unadjusted log-rank test) with an estimated hazards ratio of 1.74 (95% CI 1.12 to 2.71). Treatment remains significant in a Cox regression analysis after adjusted for significant prognostic variables including Ho's N stage and sex. This study demonstrated that a CRT regimen of weekly cisplatin 40mg/m2 with radical RT is well tolerated and resulted in a benefit which would have an effect on patient management in a population with a high incidence of NPC.




Improved Local Control and Survival with Concomitant Boost Radiation Therapy (CBRT) and Chemotherapy (CT) for Nasopharyngeal Carcinoma (NPC).
Suzanne L Woldenet al.

Publication Year: 2000 ASCO 1638

RTOG 9003 showed that CBRT without CT produced superior local control compared to standard fractionation radiotherapy (SFRT) for advanced head and neck squamous cell carcinoma, but NPC was excluded. Intergroup 0099 showed that the addition of CT to SFRT improved outcome for patients (pts) with advanced NPC. To exploit both therapeutic variables, we have treated 49 pts with advanced NPC from 1988-present, using 70Gy CBRT (1.8Gy/day, weeks 1-6; 1.6Gy 2nd daily fraction weeks 5-6) with 2 cycles of concurrent cisplatin 100mg/m2 days 1 and 22. Thirty-seven pts received up to 3 planned cycles of cisplatin-based adjuvant CT. Patient characteristics: 82% male; median age 47 years; 53% WHO II, 43% WHO III histology; T4 31%, N2/3 57%, Stage IV 47% (1997 AJCC). The CBRT-CT group is compared to a nonrandomized cohort of 51 patients treated with 70Gy SFRT (1.8Gy/day) without CT from 1988-1995. The groups are well matched for prognostic factors except stage, for which the SFRT group was less advanced (p=0.01): T4 16%, N2-3 25%, Stage IV 22% (1997 AJCC). Median follow-up intervals were 25 and 44 months for the groups, respectively. The two-year actuarial locoregional control, progression free survival, and survival were 89% vs 76% (p=0.04), 80% vs 60% (p=0.02), and 97% vs 80% (p=0.03) in the CBRT-CT vs SFRT patients, respectively. The results for CBRT-CT compare favorably to those obtained in the combined modality arm of Intergroup 0099 in a similarly advanced group (90% vs 91% Stage IV by 1992 AJCC criteria, respectively). Grade III/IV mucositis was the most common acute toxicity during CBRT-CT; 41% required temporary feeding tubes. There were no treatment related deaths. Based on these preliminary results, CBRT with CT improves local control and survival for pts with advanced NPC compared to SFRT alone and deserves comparison to other combined modality regimens.




Concurrent Chemoradiation in Advanced Stage Nasopharyngeal Cancer (NPC).

Apichai Leelasiri et al
Publication Year: 2001 ASCO 2540


NPC is common in Southeast Asia especially Thailand. Because of silent anatomy, early diagnosis is difficult and most patients (pts) present with advanced stage. Chemoradiation (CRT) has been shown to be more effective than radiation alone in treatment of NPC. This study was done during 7/95-9/99 to explore the efficacy of CRT in advanced satge NPC, also the side effects and overall survival. There were 30 new pts with NPC stage III (4 pts) and IV with no distant metastasis (26 pts), M:F 21:9. Median age was 46 years (range, 21-67). The main presenting symptoms were epistaxia (21 pts), or bloody expectoration, cervical adenopathy (18 pts) and eustachian tube obstruction (17 pts). The median duration of symptoms was 5 months (range, 1-24). The pathology revealed differentiated squamous cell carcinoma (SCC) 1 pt, nonkeratinizing SCC 19 pts and undifferentiated carcinoma 9 pts. Pretreatment baseline included CBC, blood chemistries, chest x-ray, CT/MRI nasopharynx, bone scan and U/S abdomen. Treatments consist of carboplatin AUC 6 IV drip 1 hour day 1 with 5 FU 800 mg/m2/day CIV 24 hours day 1-4 and radiation 6,600 cGy starting day 1. Chemotherapy was repeated every 4 weeks for total 5 cycles. With median follow-up 27.6 months, overall response was 86.7% with 23 pts had complete response (CR) and 3 pts partial response (PR). Median overall survival does not reach. At the time of analysis (11/00), 18 pts are alive in CR, 4 pts alive with diaease, 4 pts are dead and 4 pts lost to follow-up. For the side effects, there were 5,13,10 pts had mucositis grade 1,2,3. Seven,14,2,2 pts had leukopenia grade 1,2,3,4. Eight,0,3 pts had thrombocytopenia grade 1,2,3. Sixteen,10,1,1 pts had anemia grade 1,2,3,4. All pts who completed treatment have been suffering from dry mouth. From this study, concurrent CRT is very effective in advanced stage NPC in Thai pts with substantial side effects.


Phase II Study: Concomittant Chemoradiotherapy (CRT) with Paclitaxel and Cisplatin as Primary Therapy for Locoregionally Advanced Nasopharyngeal Carcinoma (NPC).

Savitree Maoleekoonpairoj et al.



Objectives: To assess the tolerance and efficacy of combination paclitaxel and cisplatin concurrent to radiotherapy in nonmetastatic stage III and IV NPC. Method: 27 patients were enrolled in this phase II study from Jan 1998 to Sept 1999. The schedule of chemotherapy was paclitaxel 45 mg/m2/wk one hour infusion weekly x 7 weeks and cisplatin 100 mg/m2 on week 1, 4, and 7, with radiation therapy 1.8-2.0 Gy/fraction, 5fractions /week, a total dose of 70 Gy at primary tumor and 60-66 Gy to regional lymph nodes. Patients characteristics were: median age 43 years (19-66), 16 male and 11 female, histology WHO type 2 = 10 and 3 = 17, performance status 0-1, stage III = 7 (T2N2-6, T3N1-1), stage IV = 20 (T2N3-8, T3N3-1, T4N0-2, T4N1-2, T4N2-2, T4N3-5). Results: all patients were clinically CR after CRT. Grade 3 and 4 oropharyngeal mucositis were seen in 19(70.3%) and 2(7.4%) respectively. 19(70.3%) patients were required nasogastric feeding tube. Hematologic toxicity were anemia (gr1=48%, gr2=37%, gr3=3.7%) and neutropenia (gr1=29.6%, gr2=22%, gr3=7%, gr4=3.7%), none had thrombocytopenia. 4 patients (14.8%) developed gr1 nephrotoxicity. 8(29.6%) patients developed fever from local infection in the oropharynx requiring parenteral antibiotics therapy. All patients received paclitaxel as planned, 7 patients refused the third cycle of cisplatin. The median duration of RT was 57 days (45-72). To date, the median follow-up time is 25.2 months (12.7-33.9), one patient died of local recurrence at 17 months. 3 patients showed distant metastasis at 12,15 and 24 months. The 2 year DFS was 81.5%. Conclusion: CRT as primary therapy leads to high locoregional control of disease especially in patients with very large cervical nodes. The progression free survival and overall survival need longer time to follow up. Role of adjuvant chemotherapy in those patients with initially intensive CRT is ongoing study.