303 Invited Current status of chemoradiation in head and neck cancer

S103

Saturday, 21 September 2002

Symposia HEAD AND THERAPY 303

NECK:

RADIOTHERAPY

AND

CHEMO-

Invited

Current status of chemoradiation in head and neck cancer

V. Budach Univ.-Klinikum Charit& Klinik fEtrStrahlentherapie, Campus Chadt6 Mitre, Berlin, Germany The prognosis of locally advanced and inoperable H&N-cancer is still dismal with conventionally fractionated radiotherapy alone. In an attempt to improve the therapeutic ratio (TR) altered fractionation schemes and combinations of radiotherapy and chemotherapy have been investigated during the last 15 years. The results of hyperfractionation were convincing in terms of LRC and in 50% of the studies also for OS. However, a significantly higher rate of acute toxicity was observed, but so far no increased rate of late morbidity. Accelerated radiotherapy, however, did not result in similar results. Marginally higher LRC- and OS*rates are related with increasing late morbidity rates if the total dose is not reduced, The rationale for improving the TR by RCT is an addition or synergism of cytotoxic effects at the tumour site and a dissociation of toxicities at the surrounding normal tissues. The results of meta-analysee, in particular those of the largest meta-analysis in H&N-cancer based on individual patients data of 10.741 patients showed neither for neo-adjuvant nor for adjuvant chemotherapy any benefit in terms of LRC or OS. Only concurrent RCT has shown a 19% reduction of the mortality rates resulting in a 8% net OS-benefit @ 5 years (40% vs. 32%). The therapeutic benefit was larger with multiagent chemotherapy compared with mono-ohemotherapy. The best drugs for a combination with radiotherapy are cis-Platinum, 5-FU and Mitomycin C. The benefit from adding chemotherapy to irradiation minimizes with increasing age of the patients. It is unclear until now whether altered fractionation schemes are necessary in conjunction with concurrent chemotherapy. Most of the studies addressing RCT are based on a constant level of radiation dose in both treatment arms supplemented by some drugs in the experimental arm. For the RCT-treatment this results in increased acute toxioities and sometimes also late radiation damages to normal tissues, Future concurrent RCT-studies should be based on iso-toxicity and iso-morbidify assumptions for both treatment arms. If at the same level of acute and late sequelae RCT turns out to be better, the hypothesis of an improved TR is fulfilled. Simultaneous RCT based on DDP, 5-FU and Mitomycin C cornbinations has nowadays become the standard of care for locally advanced and inoperable H&N cancer. Whether altered fractionation schemes are of additional benefit in terms of LRC and OS is not yet established and needs further investigation, 304

Invited

ARCON: how to select patients for this new treatment strategy?

J.H.A.M. Kaanders 1, K./.E.M. Wijffe/s1,2, H.A.M. Marres2, M, Rijpkema3, J.A. Raleigh4, A. Heerschap3, A.J. van der Koge/1 1University Medical Centre Nijmegen, Department of Radiation Oncology, Nijmegen, The Netherlands 2University Medical Centre Nijmegen, Department of Otolaryngology, Nijmegen, The Netherlands 3University Medical Centre Nijmegen, Department of Radiology, Nijmegen, The Netherlands 4UNC School of Medicine, Radiation Oncology and Toxicology, Chapel Hill, USA "ARCON" combines accelerated radiotherapy, to counteract tumor cell repopulation, with the hyperoxic gas carbogen and nicotinamide to reduce diffusion-limited and perfusion-limited hypoxia. High local control rates are obtained in advanced head and neck cancers with this new treatment strategy providing an excellent opportunity for organ preservation: Thus far, selection of patients for ARCON has been mainly based on clinical tumor

characteristics. A more sophisticated and logical approach would be to select patients by characterization of the microenvironmental tumor profile. A number of assays that are of potential interest as selection tools for ARCON and other oxygenation modifying treatments will be discussed. Hypoxia markers detectable by immunohistochemistry are currently of great interest because they provide a registration of the distribution of hypoxia at the microregional level. Pimonidazole is a nitroimidazole marker of hypoxia that irreversibly binds at tissue pC2 values below 10 mmHg. Pimonidazole binding was significantly correlated with Iocoregional control and diseasefree survival in a group of 42 patients with advanced head and neck cancer. These associations disappeared in a subgroup of patients treated with ARCON, strongly suggesting that this assay can provide a selection tool for hypoxia modifying treatments on an individual patient basis. In the same group of patients, pimonidazole binding was compared with the expression pattern of carbonic anhydrase-9 (CA9), a putative endogenous marker of hypoxia. The distribution patterns of pimonidazole and CA9 were simitar although the CA9 signal was generally observed already at shorter distances from blood vessels suggesting that upregulation of CA9 occurs already at intermediate oxygenation levels. A correlation between CA9 expression and treatment outcome was not observed. Finally, preliminary results indicate that dynamic contrast enhanced MRI and blood oxygen level dependent MRI as methods to measure tumor vascularity and tumor oxygenation can be used to monitor treatment induced changes and have potential as predictors of treatment outcome after ARCON. 305 Invited T r e a t m e n t o f the unknown primary in the neck

C. Grau Aarhus University hospital, Department of Onco/ogy, Aarhus C, Denmark Cervical lymph node metastases from unknown primary turnouts (CUP) are rare, constituting only about 2% of all new head and neck cancers. However, the management of these patients remains a major challenge in oncology. Pooling together data from large series, it appears that lymph nodes are most frequently observed in level II and III. A proper examination of the head and neck mucosa including endoscopy under general anesthesia is important. Biopsies should be taken from any suspicious site or blindly from sites of possible origin of the primary, e.g. base of tongue, piriform sinus or nasopharynx. A systematic tonsillectomy has been recommended since up to 26% of invasive squamous cell carcinoma are detected in that site. Initial MRI and PET may be beneficial. Recommended treatments vary from surgery alone in selected cases, limited field radiotherapy, where only the ipsilateral neck is treated, or extensive prophylactic irradiation of all potential mucosal sites as well as both sides of the neck. There is no clear evidence supporting the systematic use of chemotherapy. CUP patients have clinical features and prognosis similar to other head and neck malignancies. The median 5-year survival rate ranges from 15 to 65%. Nodal stage is the single most important prognostic parameter in most published series. For patientstreated with neck dissection, other prognostic factors for survival include number of positive nodes, histopathological grading, and extracapsular extension. Frequent sites of emerging occult primaries (after initial treatment) are oropharynx, hypopharynx and oral cavity. Emerging primades outside the head and neck region are primarily located in the lung and oesophagus. Extensive irradiation of both sides of the neck and the mucoea in the entire pharyngeal axis and larynx results in less emerging mucoeal primaries but no difference in survival in retrospective series. The studies are, however, difficult to interpret due to selection bias. A prospective randomised intergroup study (EORTC 24001-22005) has therefore been designed to test if equivalent disease-free survival can be obtained with selective ipsilateral neck irradiation compared to extensive irradiation of mucosa, and neck node areas on both sides of the neck. Besides addressing an important clinical problem, this trial is unique since due to the intercontinental collaboration of co-operative groups (EORTC, ARC, DAHANCA, FHNOWG, NCIC, RTOG, TROG, UKCCCR).