Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis.

PURPOSE: In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. MATERIAL AND METHODS: We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. RESULTS: In non-small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non-lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. CONCLUSION: Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Mature results of a randomized trial of accelerated hyperfractionated versus conventional radiotherapy in head-and-neck cancer.

PURPOSE: To evaluate long-term late adverse events and treatment outcome of a randomized, multicenter Phase III trial of continuous, hyperfractionated, accelerated radiotherapy (CHART) compared with conventional radiotherapy (CRT) in 918 patients with advanced squamous cell carcinomas of the head and neck. METHODS AND MATERIALS: Survival estimates were obtained for locoregional relapse-free survival, local relapse-free survival, overall survival, disease-specific survival, disease-free survival and for late adverse events. RESULTS: The 10-year estimates (+/-1 standard error) for locoregional relapse-free survival, overall survival, disease-free survival, and disease-specific survival were 43% +/- 2% for CHART and 50% +/- 3% with CRT (log-rank p = 0.2); 26% +/- 2% and 29% +/- 3% (p = 0.4), respectively; 41% +/- 2% and 46% +/- 3% (p = 0.3), respectively; and 56% +/- 3% and 58% +/- 3% (p = 0.5), respectively. There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART (p = 0.002 to 0.05). Severe xerostomia, laryngeal edema, and mucosal necrosis were also significantly lower with CHART (p = 0.02 to 0.05). CONCLUSIONS: Despite the reduction in total dose from 66 Gy to 54 Gy, control of locoregional disease and survival with CHART were similar to those with CRT. These findings, together with the low incidence of long-term severe adverse events, suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withstand the toxicity of concurrent chemoradiotherapy.

Pre-treatment proliferation and the outcome of conventional and accelerated radiotherapy.

This study investigated the influence of pre-treatment proliferation characteristics, assessed by Ki-67 staining, in patients treated in the CHART trial of accelerated radiotherapy in head and neck cancer. Histological material from 402 patients was collected and stained for the presence and pattern of Ki-67 staining. Locoregional control and overall survival were the main clinical endpoints. Increasing Ki-67 positivity was associated with decreasing differentiation (P < 0.001) and increasing N-stage (P < 0.004). Increasing N-stage was also associated with the progression of proliferation pattern from marginal to random (P < 0.001). Using a multivariate model, a trend was seen towards a greater benefit from CHART in the lower Ki-67 tumours (P = 0.08); this became significant by pooling the low and intermediate Ki-67 groups in comparison with the high Ki-67 group (P = 0.032). Tumours with marginal proliferation pattern showed a lower hazard ratio with CHART versus conventional for locoregional control (P = 0.005). The data presented in this study do not support that a high pre-treatment Ki-67 is associated with a therapeutic benefit from accelerated radiotherapy.

Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial.

PURPOSE: Randomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial. There are two distinct hypoxia inducible factors (HIFs) that control different gene response pathways and we assessed them both with endogenous markers of hypoxia, hypoxia inducible factor HIF-2 alpha (HIF-2) and carbonic anhydrase CA9, an indicator of HIF-1 alpha (HIF-1) function. METHODS: Tissue from pre-RT biopsies performed in 198 of 918 patients recruited was analyzed for the immunohistochemical expression of HIF-2 and CA9. RESULTS: A significant association of high HIF2 and of high CA9 reactivity with poor locoregional control (P < .0001 and P = .0002, respectively) and poor survival (P = .0004 and 0.002, respectively) was noted. In multivariate analysis, HIF-2 and CA9 maintained their independent prognostic significance. Coexpression of both pathways had an additive effect, supporting their independent role. The uni-directional hypothesis, that a benefit from randomization to CHART should be seen in the nonhypoxic tumors, was supported by the data (one-tailed P = .04). CONCLUSION: Expression of endogenous markers of hypoxia for the HIF-1 and HIF-2 pathway is strongly associated with radiotherapy failure. Using immunohistochemical methods it is possible to identify subgroups of HNSCC patients who are highly curable with radiotherapy, or who are excellent candidates for clinical trials on hypoxia-targeting drugs in two distinct pathways.

Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial.

PURPOSE: Accelerated repopulation is a main reason for locoregional failure after fractionated radiotherapy for head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) is a key controller of cellular proliferation in HNSCC, which stimulated the current study to look for a direct link between EGFR status and a possible clinical advantage of accelerated radiotherapy. PATIENTS AND METHODS: Immunohistochemical staining for EGFR was performed in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to receive continuous hyperfractionated accelerated radiotherapy versus conventionally fractionated radiotherapy. The EGFR index was estimated as the proportion of tumor cells with EGFR membrane staining. RESULTS: Significant benefit in locoregional tumor control from continuous hyperfractionated accelerated radiotherapy was seen in patients with HNSCC with high EGFR expression (2P = .010) but not in those with low EGFR expression (2P = .85). EGFR status had no significant effect on survival or rate of distant metastases. The EGFR index was significantly associated with histologic grade and microvessel density. There was moderate support for an association between EGFR status and subsite within the head and neck region but no significant association with Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index. CONCLUSION: This study indicates a key role for the EGFR receptor in determining the proliferative cellular response to fractionated radiotherapy in HNSCC. It also shows that we can select the dose-fractionation regime that has the greatest chance of benefiting the patient. These results also encourage further development of EGFR targeting combined with fractionated radiotherapy in HNSCC.

Molecular biomarkers and site of first recurrence after radiotherapy for head and neck cancer.

The prognostic significance of a panel of molecular biomarkers in head and neck squamous cell carcinoma (HNSCC) for first failure site (primary (T), nodal (N) or distant (M)) was analysed in 309 patients randomised to continuous hyperfractionated accelerated radiotherapy (CHART) vs. conventionally fractionated radiotherapy. Multivariate competing risks analysis was performed using an accelerated failure-time model. First-order interactions between each marker and trial arm were also tested. Bcl2-positivity increased the time to T- and N-failures, increasing cyclin D1 score decreased the time to N-failures. A random proliferative pattern and low Ki-67 decreased the time to M-failures. A high CD31 score was associated with a significantly longer time to T-failure after CHART, but not after conventional fractionation. Risks of T-, N- and M-failures could be estimated for individual patients. Competing risks analysis of failure sites allows the rational selection of patients for more aggressive loco-regional or systemic therapy.

Audit of effectiveness of routine follow-up clinics after radiotherapy for cancer: a report of the REACT working group of ESTRO.

BACKGROUND AND PURPOSE: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on recording providing education, and ameliorating the consequences of treatment (REACT). An European audit was carried out as part of which to assess the usefulness of current follow-up practices. PATIENTS AND METHODS: Over a 4-month period in 15 cancer centres in 10 countries, patients attending for routine follow-up completed a questionnaire covering their expectations of and satisfaction with the visit. This was matched with a questionnaire completed by the physician about the content and usefulness of the consultation. The feasibility of a short toxicity scale developed by Dische and Saunders was also investigated. RESULTS: In total, 2303 matched questionnaires were analysed. Forty percent of the patients had symptoms or medical problems related to their disease. In 18% there was a positive finding on clinical examination. In 28% investigations were undertaken part of departmental routine practice. Ten percent of the investigations showed an abnormal result. Ninety nine percent of physicians and 85% of the patients expressed satisfaction. Using the short toxicity scale rates of recording toxicity could be increased from 28 to 93%. CONCLUSIONS: There is wide variation in follow-up practices among European centres. There was a low incidence of positive findings clinically or with routine investigations. A simple scale for recording morbidity has proved easy to use by departments, which have not routinely used one of the standard measures. Further work will attempt to produce an European guideline for effective routine follow-up after radiotherapy.

Hyperbaric oxygen therapy in the treatment of radio-induced lesions in normal tissues: a literature review.

Late complications are one of the major factors limiting radiotherapy treatment, and their treatment is not codified. Hyperbaric oxygen (HBO) has been used in combination with radiotherapy for over half a century, either to maximise its effectiveness or in an attempt to treat late complications. In this latter case, retrospective trials and case reports are prevailing in literature. This prompted European Society for Therapeutic Radiotherapy and Oncology and European Committee for Hyperbaric Medicine to organise a consensus conference in October 2001, dealing with the HBO indications on radiotherapy for the treatment and prevention of late complications. This updated literature review is part of the documents the jury based its opinion on. A systematic search was done on literature from 1960 to 2004, by only taking into account the articles that appeared in peer review journals. Hyperbaric oxygen treatment involving complications to the head and neck, pelvis and nervous system, and the prevention of complications after surgery in irradiated tissues have been studied. Despite the small number of controlled trials, it may be indicated for the treatment of mandibular osteoradionecrosis in combination with surgery, haemorrhagic cystitis resistant to conventional treatments and the prevention of osteoradionecrosis after dental extraction, whose level of evidence seems to be the most significant though randomised trials are still necessary. The other treatment methods are also outlined for each location.

Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy.

PURPOSE: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy. RESULTS: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule. CONCLUSIONS: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule.

Measuring postirradiation subcutaneous soft-tissue fibrosis: state-of-the-art and future directions.

Clinician-based rating scales and quantitative instruments used to quantify the severity of soft-tissue fibrosis were reviewed to determine if they were reliable and valid measures for clinical and research use. Existing clinician-based measures, the Medical Research Council (MRC) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG), have preliminary testing of reliability and validity such that they provided a basis for the development of a revised measure. The revised measure, designed for use in National Cancer Institute-Common Toxicity Criteria for Adverse Events v3.0, evaluates subcutaneous and deep-tissue fibrosis separately and each is graded on a 5-point scale. The revised measure needs to be tested for reliability and validity, and it is recommended that it be used in concert with the MRC and/or EORTC/RTOG scales until such evidence is available and its utility can be determined. Quantitative measures, although attractive from a research perspective, will have limited clinical and multisite utility because of the apparatus required and the associated costs. Finally, a framework for evaluating fibrosis and the consequences of fibrosis is presented.

Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas.

PURPOSE: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma. METHODS AND MATERIALS: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D(prolif) of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given. RESULTS: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently. CONCLUSIONS: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.