From chemoprevention and organ preservation programmes to postoperative management: major achievements and strategies of the EORTC Head and Neck Cancer Group.

The purpose of this article is to review the most significant results of the clinical studies conducted in the past two decades by the EORTC Head and Neck Cancer Group (HNCG). As for phase III trials, the HNCG investigated, besides the efficacy of chemopreventive drugs, the impact of cytostatic agents on various therapeutic targets, in combination or not with surgery and chemotherapy. These targets were: (a) chemo-prevention in curatively treated early stage disease; (b) organ preservation programmes in patients with operable tumour, comparing immediate surgery versus first-line chemotherapy; (c) postoperative management of locally advanced tumours, comparing radio-chemotherapy versus radiotherapy alone. Other phase II and phase III studies were also completed to investigate drug activity in advanced and/or recurrent head and neck squamous cell and adenoid cystic carcinomas. The present article will also analyse the strategies developed within the Group in the field of translational research.

Reirradiation of primary brain tumours: survival, clinical response and prognostic factors.

BACKGROUND AND PURPOSE: First, the aim was to determine the survival and quality of life after reirradiation of relapsing primary malignant brain tumours. The second aim was to assess the influence of a set of potentially prognostic factors on survival. MATERIALS AND METHODS: Forty-two patients received reirradiation for recurring primary brain tumours. The interval between the two consecutive treatments was at least 1 year. External beam irradiation for the initial and recurrent tumour was usually delivered with two opposing lateral fields or two wedged fields in orthogonal directions. The median physical doses of the first and second radiation course were 50 and 46 Gy, respectively. The median cumulative biological equivalent doses (BED) were 200.4 (alpha/beta = 2 Gy) and 115.2 Gy (alpha/beta = 10 Gy). During follow-up, corticosteroid medication and the WHO-performance were registered at regular intervals. The radiological response was assessed by reviewing all available CT- and MRI-films. Potentially prognostic factors with respect to survival were evaluated by both univariate and multivariate analyses. RESULTS: A clinical response (i.e. clinical improvement) was seen in 24% of the patients. Of the evaluable patients, nearly one-third showed a complete (8%) or partial (22%) radiological response. The median overall survival (OS) and progression-free survival (PFS) after retreatment were 10.9 and 8.6 months, respectively. By multivariate analysis, four independent prognostic factors for survival were identified: (1), the WHO-score before retreatment (P = 0.002); (2), the length of the interval between treatments (P = 0.008); (3), the tumour histology; and (4), the response to initial treatment (P values, 0.04). The median survival times for patients with WHO-scores of 0-1 and > or = 2 were 14.0 and 7.4 months, respectively. Patients with oligodendrogliomas had a median OS of 27.5 months, whereas patients with astrocytomas had a median OS of 6.9 months after retreatment. Long-term complications of retreatment were seen in three patients, all of whom had a cumulative BED(2) of > 204 Gy (with alpha/beta = 2 Gy). The quality of life after retreatment, however, was well preserved in the majority of patients. They remained ambulant and capable of self-care until the time of progression which occurred after 8.6 months (median PFS). CONCLUSIONS: After an initial treatment with radiation up to tolerance levels of normal brain tissue, reirradiation of recurring primary brain tumours seems feasible. During the time until clinical progression, patients remained independent with a reasonable quality of life.

The efficacy of Xialine in patients with xerostomia resulting from radiotherapy for head and neck cancer: a pilot-study.

Changes in subjective sensations due to xerostomia before and after administration of Xialine, a xanthan gum-based saliva substitute, were evaluated in 30 patients with radiation-induced xerostomia using the QLQ-H&N35. Xerostomia in general decreased with both Xialine and placebo to almost the same degree. A trend was seen for Xialine to improve problems with speech and senses.

External irradiation versus external irradiation plus endobronchial brachytherapy in inoperable non-small cell lung cancer: a prospective randomized study.

PURPOSE: No randomized studies are available on the additional value of endobronchial brachytherapy (EBB) to external irradiation (XRT) regarding palliation of respiratory symptoms (RS). A prospective randomized study was initiated to test the hypothesis that the addition of EBB to XRT provides higher levels of palliation of dyspnea and other RS and improvement of quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) with endobronchial tumour. MATERIALS AND METHODS: Patients with previously untreated NSCLC, stages I-IIIb, WHO-performance status of 0-3 and with biopsy proven endobronchial tumour in the proximal airways were eligible. EBB consisted of two fractions of 7.5 Gy at 1 cm on day 1 and 8. XRT started at day 2. The XRT dose was 30 Gy (2 weeks) or 60 Gy (6 weeks). The EORTC QLQ-C30 and QLQ-LC13 were assessed before treatment and 2 weeks, 6 weeks, 3, 6 and 12 months after treatment. Re-expansion of collapsed lung was tested by the inspiratory vital capacity (IVC) and CT scan of the chest. RESULTS: Ninety-five patients were randomized between arm 1 (XRT alone) (n=48) or arm 2 (XRT+EBB) (n=47). The arms were well balanced regarding pre-treatment characteristics and QoL scores. The compliance for QoL-assessment was >90% at all times. No significant difference between the trial arms was observed with respect to response of dyspnea. However, a beneficial effect of EBB was noted concerning the mean scores of dyspnea over time (P=0.02), which lasted for 3 months. This benefit was only observed among patients with an obstructing tumour of the main bronchus. A higher rate of re-expansion of collapsed lung was observed in arm 2 (57%) compared to arm 1 (35%) (P=0.01). The inspiratory vital capacity (IVC) assessed 2 weeks after radiotherapy improved with 493 cm(3) in arm 2 and decreased 50 cm(3) in arm 1 (P=0.03). No difference was noted regarding the incidence of massive haemoptysis (13 vs. 15%). CONCLUSION: The addition of EBB to XRT in NSCLC is safe and provides higher rates of re-expansion of collapsed lung resulting in a transient lower levels of dyspnea. This beneficial effect was only observed among patients with obstructing tumours in the main bronchus.

The relevance of the revised version of the international lung cancer staging system for non-small-cell lung cancer treated with radiotherapy.

In 1997, the International Union Against Cancer (UICC) introduced a new version of staging for lung cancer. The purpose of this study was to determine the prognostic value of the new UICC staging (1997) among patients with inoperable non-small-cell lung cancer (NSCLC) treated with radiotherapy. The status of a total of 1354 inoperable patients postintrathoracic irradiation for NSCLC was retrospectively analyzed. Restaging was performed according to the staging system of the UICC 1997. The median survival (MS) among patients with stage I disease was 12.4 months. In the case of stage IA disease, the MS was 17.6 months, which was significantly better compared to the 11.2 months observed among patients with stage IB disease (P = 0.002). The MS among patients with clinical T2 N1 M0 disease (stage IIB) was 8.0 months. The MS among those with clinical T3 N0 M0 disease (stage IIB) was 8.6 months, which was not statistically different from the group of patients with stage IIIA disease, who had an MS of 7.6 months. The MS among patients with stage IIIB disease was 6.5 months, and among patients with stage IV disease, MS was 4.0 months. It was concluded that in patients with inoperable NSCLC treated with radiotherapy, the distinction between stages IA and IB disease in the new staging system is clinically relevant. There was no significant difference in survival between patients with stage IIB and IIIA disease. The results clearly show that the prognostic significance of a staging system mainly based on surgically treated patients should be analyzed separately before it can be used among patients treated with nonsurgical modalities.

Cell proliferation and apoptosis in stage III inoperable non-small cell lung carcinoma treated by radiotherapy.

PURPOSE: The purpose of this study was to assess the prognostic value of the expression of p53 and bcl-2, the apoptotic index and the expression of topoisomerase II alpha in patients with inoperable non-small cell lung cancer (NSCLC) treated with high dose radiotherapy. PATIENTS AND METHODS: A number of 161 patients with inoperable NSCLC treated with high dose radiotherapy (60 Gy) were included. Immunohistochemical analysis was used to assess the expression of nuclear p53-protein, topoisomerase II alpha and cytoplasmatic expression of bcl-2, while spontaneous apoptosis was assessed using in situ labeling. The minimal follow up period was 2 years. RESULTS: Local control did not only depend on the presence of p53 expression, but also on the proportion of p53 positive cells. The most important prognostic factor was the apoptotic index. A high apoptotic index was associated with worse local control, more distant metastases and a significantly worse overall survival. No association was noted between the expression of bcl-2 and topoisomerase II alpha with any of the endpoints. CONCLUSION: This study indicates that p53 expression and the apoptotic index are prognostic factors with regard to local control in patients with inoperable NSCLC treated with radiotherapy and by combining these 2 factors, a clinically relevant estimation of the local control probability can be made. The apoptotic index turned out to be the only factor significantly related to survival.

The prognostic impact of quality of life assessed with the EORTC QLQ-C30 in inoperable non-small cell lung carcinoma treated with radiotherapy.

PURPOSE: The purpose of this study was to assess the prognostic significance of pretreatment quality of life (QoL) scores and symptom scores in a group of patients treated with high dose radiotherapy. MATERIAL AND METHODS: A total of 198 patients treated with external irradiation (>/=60 Gy) were included. In all these patients, baseline QoL was assessed using the EORTC QLQ-C30. The prognostic significance of a number of non-QoL and QoL parameters with regard to survival was estimated in both univariate and multivariate analyses. RESULTS: In a multivariate model including the non-QoL parameters, performance status, weight loss and N-classification were independent prognostic factors for survival. After entering the QoL parameters in the model, global QoL was the strongest prognostic factor, while performance status lost its significance. Subsequently, a significant interaction term was found between N-classification and global QoL, indicating that global QoL was an independent prognostic factor but that the effect varied as a function of N-status. In N+ patients, the median survival in the group with low scores for global QoL was 4.5 months, which was significantly worse (P<0.0001) compared with the high score group in which the median survival was 12.9 months. CONCLUSION: Global QoL is a strong prognostic factor for survival in patients with NSCLC who have pathological lymph nodes at presentation and who are treated with radical or curative radiotherapy.

Effect of CT-based treatment planning on portal field size and outcome in radiation treatment of localized prostate cancer.

The portal field sizes of 361 consecutive patients treated with curative radiotherapy for localized prostate cancer were measured. The introduction of CT-based information resulted in a significant increase of field sizes, leading to an almost doubling of the treated volume, some increase in late rectal toxicity, but also in local control.

Is the chest radiograph a reliable tool in the assessment of tumor response after radiotherapy in nonsmall cell lung carcinoma?

BACKGROUND: The purpose of this study was to evaluate whether the chest radiograph is a reliable tool to assess response to radiotherapy. MATERIALS AND METHODS: Pre- and post-treatment chest radiographs and computed tomographs (CT) of 63 patients with nonsmall cell lung cancer (NSCLC) treated by radiotherapy were reviewed by four observers with regard to suitability for tumor measurement, and response. Suitability for tumor measurement was expressed as the number of measurable diameters. In addition, the consequences to clinical outcome were studied by survival analysis. RESULTS: The CT turned out to be more suited for tumor measurement before as well as after radiotherapy, resulting in an increase of the number of measurable cases. The number of measurable cases with CT was 52 (83%) as compared to 28 (44%) with chest radiography. Especially in case of centrally localized tumors, the presence of an atelectasis, or squamous cell carcinoma, CT contributed to a higher rate of measurable cases. The interobserver agreement with regard to response using chest radiograph was good (mean kappa = 0.74). In 25 of 28 cases (89%) measurable with CT as well as with chest radiograph, response was equally classified. When CT was used, the median survival of the responders was 14.2 months as compared to 6.8 months of the nonresponders. When chest radiograph was used, the median survival of these groups was 12.0 and 6.6 months respectively, which was not significantly different when response was assessed by CT. CONCLUSION: We conclude that CT is more suited for tumor measurement because more measurable lesions can be found and more evaluable lesions on chest radiograph become measurable on CT. The chest radiograph does have a valuable role to play in those lesions that are measurable because of the good interobserver agreement with regard to the response classification, the high overall agreement between CT and chest radiograph in case of measurable cases, and the lack of important differences with regard to survival.

A single session of intraluminal brachytherapy in palliation of oesophageal cancer.

Between September 1987 and September 1993, 88 patients with oesophageal cancer were treated by a single session of intraluminal brachytherapy of 15 Gy prescribed at 1 cm distance from the central axis, using MDR137Cs (n = 51) during the first part of the study and HDR192Ir (n = 37) during the second part of the study. All patients were regarded as inoperable. Improvement of dysphagia, assessed 4-6 weeks after treatment, was noted in 50 of 75 (67%) evaluable patients, whereas swallowing ability was completely restored in 47% of them. Relapse of dysphagia occurred in 28 (37%) patients during follow-up. Additional palliative treatment consisted of endoprosthesis in 14 (19%), a second course of brachytherapy in 13 (17%), one or more dilatations only in 11 (15%) and laser treatment in four (5%) patients. One non-fatal haemorrhage and five fistulae occurred, all in the presence of tumour. Two severe ulcerations without evidence of tumour were noted, both managed by combined curative treatment. The median survival of the group investigated was 5.5 months. An exophytic, non-circular growth pattern was associated with a better response. In a multivariate analysis the presence of distant metastases (p = 0.0028), weight loss (p = 0.0051) and an exophytic growth pattern (p = 0.0199) were associated with a worse survival. The present data indicate that a single session of ILB is appropriate in the palliation of dysphagia in patients with inoperable oesophagal cancer showing bad prognostic signs. Up to now there has been no clear evidence for benefit of addition of ERT.