Int Poster J Dent Oral Med 4 (2002), No. 1 15. Mar. 2002
Int Poster J Dent Oral Med 2002, Vol 4 No 1, Poster 112
A Phase II Trial of Concurrent Paclitaxel, Carboplatin and Radiotherapy in Stage III/IV Resectable Cancer of the Oral Cavity and Oropharynx
Authors: Christian Küttner MD DDS1, André Eckardt MD DDS1, D. Rades MD2, Ingeborg Wildfang MD2, Christof Hofele MD DDS3, Ralf Dammer MD DDS4
1Hannover University Hospital, Department of Oral & Maxillofacial Surgery
2Hannover University Hospital, Department of Radiotherapy
3University Hospital Heidelberg, Department of Oral & Maxillofacial Surgery
4University Hospital Regensburg, Department of Oral & Maxillofacial Surgery
3. - 23.03.2000
24. Deutscher Krebskongress
In the treatment of head and neck cancer chemotherapy used to be limited to metastatic or recurrent settings. During the last twenty years the addition of chemotherapy to aggressive local treatment has been investigated to overcome high local relapse rates. Recent meta-analysis have confirmed data of randomized trials of combined modality treatment concepts and identified the advantage in treatment outcome for patients with concomitant chemoradiotherapy (Munro 1995, El-Sayid et al. 1996, Bourhis et al. 1998). Many chemotherapeutic agents have been used as radiation sensitizers, including platinum compounds, bleomycin, mitomycin, and antimetabolites such as methotrexate and 5-fluoro-uracil. Taxane have been the focus of several multi-modality studies combining chemotherapy and radiotherapy (Aisner et al. 1995, Hoffmann et al. 1996, Chougule et al 1997, Vogt et al. 1998). The efficacy and feasibility of a Paclitaxel/Carboplatin combination with simultaneous radiotherapy could be demonstrated in phase I-II trials (Tab.1).
Both Paclitaxel and Carboplatin have demonstrated high single agent activity in head and cancer as well as radiosenzitizing effects (Hoffmann et al.1996, Leonard et al.1997). Paclitaxel causes a enhancement of the rate and yield of microtubular assembly and prevents microtubular depolimerisation, therefore acting as a mitotic inhibitor in the radiation-sensitive G2/M-phase. Based on documented excellent radiosensitization effects, a prospective phase II trial was initiated using Paclitaxel (P) and Carboplatin (C) with concurrent conventional fractionated radiotherapy followed by surgery of the primary tumor and regional neck nodes.
Patients were eligible for this study if they met the following criteria: histologically confirmed squamous cell carcinoma of the oral cavtiy or oropharynx; resectable stage III and IV disease; ECOG performance status <2; no tumor-specific pretreatment; no major impairment of liver, kidney, bone marrow, lung, or cardiovascular functions. Staging procedures consisted of careful clinical investigation with tattoowing of the resection margins under general anesthesia, neck sonography, computed tomography of the primary lesion and the neck, chest x-ray. The extent of the disease was defined according to the TNM system.
Radiotherapy was applied using a conventional fractionated protocol of 5 x 2,0 Gy/week to a total dose of 40Gy with 6-MeV photons. Using standard premedication Paclitaxel 40mg/m2 was administered as a weekly continous 1-hour infusion in weeks 1-5, followed by Carboplatin AUC 1,5 continous infusion over 30 minutes. Colony-stimulating factors were given only in instances of severe neutropenia with documented infection. Toxicity was grade according to the NCI Common Toxicity Criteria (CTC); and response was assessed according to WHO standards.
Surgery of the primary tumor followed within four weeks after completion of chemoradiation. Resection of the tumor, a suprahyoidal or complete functional neck dissection was performed according to DÖSAK criteria. The mucosal defects were reconstructed in most cases using a fasciocutaneous radial forearm flap.
This study was approved by the ethics committee of our institution. Written informed consent was required from all patients. All patients underwent repeated clinical examination during treatment for identification of response and acute reactions.
From 5/98 to 10/99 twenty-eight patients (23 males, 5 females) with stage III (6 pts.) and stage IV (22 pts.) desease were enrolled. The mean age was 54 years (range 40-71). Six patients had squamous cell carcimona of the oropharynx and twenty-two patients of the oral cavity.
A total of 115 cycles of chemotherapy was administered to the patient population. Patients data of this ongoing trial are summarized in Tab. 2.
Twenty-seven patients were evaluable for toxicity and response (Tab.3). One early death was reported due to septic neutropenia. Clinical response was as follows: CR (14/27 52%); PR (13/27 48%).
CTC grade 2 or 3 mucosistis occured in all patients. Hematologic toxicity was as follows: hemoglobin CTC grade 3 (14%), leukocytes CTC grade 1 (24%), grade 3 (33%), grade 4 (10%), thrombocytes CTC grade 2 (10%), grade 3(14%).
Major non-hematologic toxicity was mucositis and dermatitis (Tab.4).
Median value of leucocytes, hemoglobin, and thrombocytes are shown in Fig.1a-c. Twenty-three patients were evaluable for pathologic response after surgical resection. Pathological response was as follows: pCR (10/23 44%); pPR(13/23 56%).
With a median follow-up of 10 months the 1-year-survival is 88% (Tab.5)
|Fig. 1a: Leucocytes
|Fig. 1b: Hemoglobin
|Fig. 1c: Thrombocytes
The prognosis of advanced squamous cell carcinoma of the head and neck remains poor. Concurrent P/C and radiotherapy resulted in excellent clinical and pathological response rates in advanced stage disease (pCR 44%, pPR 56%). Mucositis was the most common and significant toxicity. The treatment can be performed on outpatient basis. The present phase II trial preceeds a randomized study of the DÖSAK Cooperative Group.
- AisnerJ,Belani CP,Kearns C, Conley B, Hiponia D, Engstrom C, Zuhowski E, Egorin MJ: Feasibility and pharmacokinetics of paclitaxel, carboplatin, and concurrent radiothrapy for regionally advanced squamous cell carcinoma of the head and neck and for regionally advanced non-small cell lung cancer
Sem Oncol, 1995, 22(Suppl12), S.17-21
- Bourhis J, Pignon JP, Designe L, Luboinski M, Guerin S, Domenge D: On behalf of the MACH-NC Collaborative group: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC):Loco-regional treatment vs same treatment + chemotherapy (CT)
Proc Am Soc Clin Oncol, 1998, 17, S.386a
- El-Sayed, S, Nelson N: Adjuvant and adjubctive chemotherapy in the management f squamaous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials
J Clin Oncol, 1996, 14, S.838-847
- Hoffmann W, Heinrich V, Belka C, Budach W, Schmidberger H, Bochtler H, Rodemann, Bamberg M: Präklinische und klinische Ergebnisse in der simultanen Radiochemotherapie von Kopf-Hals-Tumoren mit Paclitaxel
Strahlenther Onkol, 1996, 172, (Suppl I), S.15-20
- Leonard CE, Chan CD, et al.: Paclitaxel enhances in vitro radiosensitivity of squamous cell carcinoma cell lines of the head and neck
Cancer Res, 1997, 56, S.5198-520
- Munro A: An overview of randomized controlled trials of adjuvant chemotherapy in head and neck cancer
Brit J Cancer, 1995, 71, S.83-91
- Vogt HG, Martin T, Capizello A, Kolotas C, Hey S, Schneider L, Dornoff W, Fountzilas G, Templin T, Kettner H, Zamboglou N: Concurrent Paclitaxel and Radiotherapy - Treatment Feasibility Studies
Strahlenther Onkol, 1998, 174(Suppl I), S.24-28
- Eckardt A, Wildfang I, Karstens JH: Simultane Radiochemotherapie mit Taxol/Carboplatin bei fortgeschrittenen, operablen Kopf-Hals-Tumoren - Vorläufige Ergebnisse
Strahlenther Onkol, 1999, 175(Suppl III), S.11-13
This poster was submitted by
Christian Küttner MD DDS.
Christian Küttner MD DDS
Medizinische Hochschule Hannover