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Publication Year: 2001
ASCO 927

Concurrent Chemoradiotherapy for Advanced Inoperable Head and Neck Cancer: A Three Year Follow-Up.

Prakash B Chougule et al.

PURPOSE: Addition of chemotherapy to radiotherapy in advanced head and neck cancer has shown a tremendous promise with improvement in loco-regional control and quality of life, but its impact on survival remains controversial. Paclitaxel and Carboplatin have both shown excellent radiosensitization and were utilized concurrently with radiotherapy on an outpatient basis in a phase II trial. METHODS: Conventional radiotherapy to doses between 66-72 Gy was delivered with weekly Taxol (60 mg/m2) and Carboplatin (AUC of 1). Chemoradiotherapy was followed by neck dissection for those who presented with clinically palpable lymph nodes. Forty-three patients were enrolled. Thirteen patients (33%) had stage III disease and 30 (70%) had Stage IV disease. The sites were oropharynx 14, larynx 11, hypopharynx 7, oral cavity 7 and nasopharynx 4. Median followup was 42 months. RESULTS: Of the 41 evaluable patients 28 (68%) had complete response (CR), 11 (27%) had partial response (PR) for an overall response rate of 95%. Twenty-four patients had biopsy from the primary tumor site of whom 20 (83%) were negative. Eight of 11 patients (72%) who underwent neck dissection were pathologically negative. Grade 3-4 mucositis was the predominant toxicity and occurred in 95% of patients. Twenty-four patients (56%) remained disease free at a median followup of 42 months (2 died of intercurrent disease at 15 and 42 months respectively). Two patients developed osteoradionecrosis, (which was corrected surgically), and one developed cartilage necrosis (larynx ca) which healed following hyperbaric oxygen. These three patients remain disease free. CONCLUSION: Concurrent Paclitaxel, Carboplatin and conventional radiotherapy in advanced head and neck cancer offers an excellent response rate with high frequency of pathologic complete responses. High grade mucositis was the most common morbidity. Organ and function preservation could be a major goal with such combined modality approach.

Publication Year: 2001
ASCO 937

Preoperative Chemotherapy with Paclitaxel and Carboplatin and Radiation Achieves High Rates of Local Regional Control but Continued Erosion of Survival by Distant Disease.

Harold Joseph Wanebo et al.

The Brown University Oncology Group has conduced two concurrent preoperative chemo-radiation protocols for advanced (Stage III, IV) head and neck squamous cancer. Preoperative treatment with paclitaxel (P) 60 mg/M2/week, carboplatin (C) 1 AUC and radiation 45Gy (H&N-53) was associated with a 67% complete pathologic response rate at the primary site but with high toxicity. Lower dose P (40 mg/M2/wk) with C (1 Auc/wk) with 45 Gy (H&N 67) achieved a high pathologic response at primary site (90%) and approximately 69% control in the neck. Approximately 31% still had residual disease in the neck (at neck dissection) Long term results with mean follow-up time of 5 yrs (H&N 53) and 3 yr (H&N-67) is shown. Of 20 recurrences, 10% were local, 20% were regional and 70% were distant Conclude: Preoperative chemoradiation with P, C and 45Gy achieves a high local regional response rate and excellent initial control. There is continued erosion of disease-free survival manifested by a high rate of distant failure but low recurrence rate at local and regional sites.


Publication Year: 2001
ASCO 2556

Induction Chemotherapy with Weekly Paclitaxel and Carboplatin Followed by Concurrent Paclitaxel, Carboplatin and Radiotherapy in Advanced Head and Neck Squamous Cell Cancers (HN-SCC): a Phase II Study.

Neal Ready et al.

Concomitant chemoradiation (CRT) for stage III-IV HN-SCC improves locoregional control, organ preservation and survival compared to radiation (RT). A recent study showed more systemic failures than locoregional recurrences in this group . Induction chemotherapy (IT) prior to CRT may potentially eradicate micrometastatic foci and improve survival. This trial evaluates the feasibility and toxicity of IT with weekly paclitaxel- carboplatin. Secondary end points include IT response rates and long term locoregional and distant control. Patients (pts) with Stage III-IVA HN-SCC were stratified into operable and inoperable arms and treated on an outpatient basis. IT with weekly paclitaxel 135 mg/m2 and carboplatin AUC= 2 was given for 6 of 8 weeks. CRT was weekly paclitaxel 40mg/m2, carboplatin AUC= 1 and 1.8 Gy RT daily. After 5 weeks operable pts underwent primary site biopsy; biopsy-positive pts underwent surgery and post-op RT. Biopsy- negative pts received three more weeks of CRT. Inoperable pts received 8 weeks CRT. Twenty pts completing IT are evaluable for toxicity and efficacy. The median age was 63 yrs (50- 78 yrs) and performance status was 0 1. The delivered dose for IT was 85% of planned(paclitaxel 688mg/m2, carboplatin AUC 10). Toxicities included neutropenia (grade 2- 5 pts, grade 3- 6 pts, grade 4- 1 pt) and neuropathy (grade 1- 4 pts, grade 3- 1 pt). No pt had febrile neutropenia or required hospitalisation during IT. Thirteen pts required dose reduction for neutropenia. One pt with diabetes mellitus developed grade 3 neuropathy after 2 weeks of IT and received hyperfractionated RT alone. CRT delays due to IT toxicity were not seen. Response data for 18 pts completing IT is available; 3 had CR, 11 had PR, 3 had SD and 1 had progression. Conclusion: In locally advanced HN-SCC, dose intense weekly induction chemotherapy with paclitaxel- carboplatin prior to CRT is well tolerated, active and does not delay the start of CRT. Toxicity, treatment delays and efficacy data during CRT will be presented.






Publication Year: 2000
ASCO 1667

Phase II Study of Weekly Carboplatin and Paclitaxel Concurrent with Radiation Therapy (RT) in Patients (Pts) with Locally Advanced, Inoperable Squamous Cell Carcinoma of the Head and Neck (HNSCC). Sanjeev Bahri, Sanjiv S. Agarwala, Elmer Cano, Jonas Johnson, Eugene Myers, Jong-Hyeon Jeong, Rita Johnson, Virginia Dinger, Roger Day, Chandra P Belani, Univ of Pittsburgh Cancer Institute, Pittsburgh, PA.

Combined chemoradiotherapy for locoregionally advanced HNSCC results in improved disease control and survival. Carboplatin (C) and paclitaxel (P) are both active in HNSCC and have radiation sensitizing effects based upon inhibition of DNA repair mechanisms (C) and arrest in G2-M phase of the cell cycle (P). We are conducting a prospective phase II evaluation of weekly C (100 mg/m2) and P (40 mg/m2) concurrent with RT to a maximum dose of 7000 cGy in 180 cGy/day fractions in pts with regionally advanced HNSCC. The dose of P (40 mg/m2) was chosen to avoid the high degree of mucositis seen in previous trials with higher doses (45-60 mg/m2/wk). Eligible pts had previously untreated histologically proven HNSCC that was stage T3N1 or higher without evidence of distant metastases, and considered inoperable or incurable by surgery or radiation. All therapy was administered in the outpatient setting. Percutaneous gastrostomy feeding tubes (PEG/G-tube) were placed prophylactically in all but 2 pts. Of the 30 pts entered (24 male, 8 female), 22 are evaluable for response and 28 for toxicity. Grade 2/3 mucositis was noted in 18%/39% of pts. Other grade 3 toxicities included anemia (11%), skin rash (1 pt), confusion (1 pt), allergic reaction (1 pt) and hyperglycemia (1pt). Grade 4 mucositis or grade 3/4 neutropenia was not encountered. Major response was seen in 17/22 (77%) pts (complete in 10/22 and partial in 7/22). At a median follow-up of 10.5 months (range 2-30), 17/22 evaluable pts are alive (10/22 without evidence of disease progression ,range 9-30 mo). The median survival and the median time to progression have not been reached. The estimated one- and two-year survival is 79% and 69%, respectively. The combination of weekly C and P with radiation therapy is well tolerated and effective in a pts with advanced, inoperable HNSCC. The lower than expected incidence of mucositis and hematologic toxity is attributed in part to the prophylactic placement of PEG/G-tubes and the lower dose of P (40 mg/m2).


Publication Year: 2000
ASCO 1624

A Phase III Comparison of Standard Radiation Therapy (Rt) Versus Rt Plus Concurrent Clsplatin (Ddp) Versus Split-Course Rt Plus Concurrent Ddp and 5-Fluorouracll (5fu) in Patients with Unresectable Squamous Cell Head and Neck Cancer (Schnc): an Intergroup
D J Adelstein et al.

Between 1992 and 1999, the Head and Neck Intergroup conducted a phase III randomized trial in patients with stage III and IV unresectable SCHNC. Patients (pts) were randomized between three treatment arms; Arm A: single daily fractionated (SDF) RT (70 Gy at 2 Gy/day); Arm B: identical RT with concurrent DDP, 100 mg/m2 IV on days 1, 22, and 43; and Arm C: a split course of SDF RT and 3 cycles of concurrent chemotherapy (CT), 30 Gy given with the first, and 3040 Gy given with the third cycle. CT cycles were repeated every 4 weeks and consisted of DDP 75 mg/m2 on day 1, and 5FU 1,000 mg/m2/day as a continuous intravenous infusion, on days 14. Surgical resection was encouraged, if possible, after the second CT cycle on Arm C, and if necessary, as salvage therapy on all three treatment arms. Due to declining accrual, the study was prematurely closed after entry of 295 of the targeted 369 pts. Preliminary results are presented. Although treatment was generally well tolerated, grade 3 or worse toxicity occurred in 53% of Arm A pts versus 86% of Arm B pts (p<0.0001) and 77% of Arm C pts (p<0.001). Death during treatment occurred in 2 pts on Arm A, 4 on Arm B, and 3 on Arm C. With a median follow-up for living pts of 25 months, the 2 and 3 year Kaplan-Meier projected survivals for Arm A are 30% and 20%, compared to 43% and 37% for Arm B (p=0.016), and 40% and 29% for Arm C, (p=0.13). There is no significant difference between Arms B and C. Median survivals are 12.6 months for Arm A, 19.1 months for Arm B, and 14.0 months for Arm C. We conclude that in this poor prognosis group of patients with unresectable SCHNC (1) concurrent CT and radiation can be safely administered with acceptable toxicity within the cooperative group context; (2) the addition of concurrent high-dose single-agent DDP to conventional SDF RT significantly improves survival, and (3) the use of multi-agent CT does not offset the loss of efficacy resulting from split-course RT.



Publication Year: 2000
ASCO 1655

Preoperative Therapy with Reduced Dose Paclitaxel, and Carboplatin and Radiation Achieves a Similar Complete Response Rate to a High Dose Regimen, but with Reduced Toxicity.
H J Wanebo et al.

Preoperative therapy with paclitaxel (P) 60mg/u/M2 carboplatin (C) I-AUC and radiation 45Gy has been associated with high rate of clinical (100%) and pathologic (67%) response, but at a price of high toxicity (Protocol H&N 67). We have completed a second trial with dose reduced paclitaxel 40Mg/M2 , carboplatin (I-AUC), and radiation 45Gy in an effort to achieve similar high response rate, but with reduced toxicity (H&N 67). Methods: Protocol: Patients are staged by triple endoscopy, have a percutaneous placed gastrostomy (PEG) and are treated with concurrent weekly P (40mg/M2) and C (I-AUC), plus radiation 45Gy and are restaged with biopsy of primary site at 45G. If pathology is negative, patient has completion radiation (66-72Gy) and neck dissection if initial neck stage was N 1-3. If biopsy is positive, the patient has resection of primary site and neck dissection. [table] Conclusion: Preop CT and RT using a regimen of dose reduced P achieves a high rate of clinical and pathologic response with reduced toxicity.







Publication Year: 2000
ASCO 1658

Multicenter Phase II Study of Preoperative Concurrent Paclitaxel, Carboplatin and Radiotherapy in Stage III/IV Resectable Cancer of the Oropharynx and Oral Cavity: An Interim Analysis.
Andre Eckardt et al.

Taxol and carboplatin have both demonstrated excellent radiosensitization through two mechanisms, namely cell blockage in G2-M phase and inhibition of DNA repair respectively. A prospective phase II evaluation was initiated using paclitaxel, carboplatin (CBDCA) with concurrent conventional fractionated external beam radiotherapy followed by surgery of the primary tumor and the regional neck nodes. from 6/98-11/99 thirty-five patients received 5 cycles of weekly paclitaxel (4omg/m2), CBDCA (AUC of 1.5) with conventional radiotherapy (40Gy). Within three to four weeks after chemoradiotherapy resection of the tumor with neck dissection in those patients with palpable lymph nodes was performed. For oral and oropharyngeal defect reconstruction a radial forearm flap was used. The patient characteristics were as follows: Men 30; women 5; mean age 45 (range 31-71); stage III 10, stage IV 25. Site:oropharynx 6, oral cavity 29. One patient was excluded for protocol violation; one treatment-related death (2.8%) occured due to septic neutropenia. Thirty-two patients were evaluable for toxicity and response. The clinical was as follows: Complete response (CR) 19/32 (59%); partial rewsponse (PR) 13/32 (41%). Twenty-eight patients (80%) were evaluable for pathologic response after surgical resection. The pathological response was as follows: pCR 15/28 (53%), pPR 13/28 (47%).CTC grade 2 or 3 mucositis occured in all thirty-two patients. Predominant hematological toxicity was leukopenia CTC grade 3(33%),grade 4(10%), thrombocytopenia CTC grade 3 (14%) and hemoglobin CTC grade 3 (14%).Other toxicities involved skin CTC grade 2 (28%),grade 3 (4%).Median follow-up was 6 months (range 2-16 months).Concurrent paclitaxel,carboplatin and radiotherapy as preoperative treatment resulted in excellent clinical and pathological responses. Close monitoring of patients and adequate supportive therapy is strongly recommended.Mucositis was the most common and significant morbidity.This phase II trial will preceed a randomized study of the DÖSAK Cooperative Study Group.