Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: A randomized phase II study.

BACKGROUND: Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM. MATERIAL AND METHODS: After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity. RESULTS: The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable. CONCLUSIONS: Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.

Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer. A five year follow up.

BACKGROUND AND PURPOSE: Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer. MATERIAL AND METHODS: 750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1-2, N0 glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2 Gy/day, 5 days/week in 49 days, total dose 68 Gy) or accelerated fractionation (1.1+2.0 Gy/day, 5 days/week in 35 days, total dose 68 Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6 months and 1, 2 and 5 years after start of treatment. RESULTS: The AF group reported HRQoL was significantly lower at eRT and at 3 months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6 months and 5 years. Scores related to functional oral intake never reached baseline. CONCLUSION: In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.

Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial.

BACKGROUND AND PURPOSE: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers. MATERIAL AND METHODS: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, N0 glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1Gy+2Gy per day, 5days/week for 4.5weeks, total dose 68Gy) and conventional fractionation (CF) (2Gy per day, 5days/week for 7weeks, total dose 68Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma. RESULTS: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p=0.75). LRC at 5years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p=0.99). The estimated cancer specific survival (CSS) at 5years was 62.2% (AF) and 63.3% (CF) (p=0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16- tumours. CONCLUSION: This update confirms the results of the 2-year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect.

Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma--the ARTSCAN study.

BACKGROUND AND PURPOSE: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF. MATERIALS AND METHODS: Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment. RESULTS: The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects. CONCLUSION: Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated.

The potential of proton beam radiation therapy in gastrointestinal cancer.

A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In gastrointestinal cancers, it is assessed that at least 345 patients, mainly non-resectable rectal cancers, oesophageal and liver cancers, are eligible. Great uncertainties do however exist both in the number of patients with gastrointestinal cancers suitable for radiation therapy, and in the proportion of those where proton beams may give sufficiently better results.

The potential of proton beam radiation for palliation and reirradiation.

A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. If an estimated 1% of the palliative treatments can be administered by protons with substantial benefits to the patient, almost 100 patients per year in Sweden would be eligible. It is further estimated that around 150 patients per year in need of reirradiation would benefit from radiation with protons compared to photons.

The potential of proton beam radiation therapy in head and neck cancer.

A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In head and neck cancer, including thyroid cancer, it is assessed that at least 300 patients annually will gain sufficiently from proton beam therapy, both to improve tumour control and to decrease toxicity to compensate for the increased treatment costs using protons.

Intraoperative radiotherapy for patients with carcinoma of the pancreas.

BACKGROUND/AIMS: Local recurrence is one of the most common sites of failure after resection of exocrine pancreatic adenocarcinoma. Intraoperative radiotherapy (IORT) involves delivery of high doses of irradiation to the pancreas in patients with locally advanced disease, and to the surgical bed following pancreatic resection while uninvolved and dose-limiting tissues are displaced. Here we report our current experience with IORT in patients with pancreatic cancer. METHODS: IORT was given as adjuvant treatment in 18 and palliatively in 37 patients. External beam radiotherapy (EBRT) was in addition delivered to 10 patients in the resection group and 29 in the palliation group. The cancer diagnosis was verified histologically and/or cytologically in all patients. RESULTS: There was no hospital mortality. Among the resected patients the postoperative complication rate was 44% (8/18). The corresponding figure after palliative operation was 14% (5/37). None of the postoperative complications were regarded as a consequence of IORT. Symptoms and complaints were observed after EBRT in 70 and 90%, respectively, in the two groups. However, no symptom was serious in nature. After resection the median survival time was 9 months (range 3-58) and local recurrence was diagnosed in 33% (6/18). In the palliatively treated patients the median survival was 7 months (range 2-30) and pain requiring opioids was present in 89% (24/27) of the patients within 6 months. CONCLUSION: In this nonrandomized study no apparent beneficial effects were seen after IORT in patients with pancreatic cancer, neither adjuvantly nor palliatively. However, radiotherapy did not lead to any major complications.

Number of patients potentially eligible for proton therapy.

A group of Swedish radiation oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy in a facility where one of the principal aims is to facilitate randomized and other studies in which the advantage of protons can be shown and the magnitude of the differences compared with optimally administered conventional radiation treatment, also including intensity-modulated radiation therapy (IMRT) and brachytherapy, can be shown. The estimations have been based on current statistics of tumour incidence in Sweden, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours together with information on normal tissue complication rates. In Sweden, it is assessed that between 2200 and 2500 patients annually are eligible for proton beam therapy, and that for these patients the potential therapeutic benefit is so great as to justify the additional expense of proton therapy. This constitutes between 14-15% of all irradiated patients annually.

A systematic overview of radiation therapy effects in oesophageal cancer.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for oesophageal cancer is based on data from 42 randomized trials and 2 meta-analyses. A total of 44 scientific articles are included, involving 5 772 patients. The conclusions reached can be summarized as follows: There is fairly strong evidence that preoperative radiotherapy does not improve the survival in patients with potentially resectable oesophageal cancer. There is moderate evidence that preoperative chemo-radiotherapy has no beneficial impact on the survival of patients with potentially resectable oesophageal cancer. There is no scientific evidence that postoperative radiotherapy improves survival in patients with resectable oesophageal cancer. The documentation is, however, poor, consisting of only three randomized trials. There is fairly strong evidence that concomitant (but not sequential) chemo-radiotherapy gives significantly better survival rate than radiotherapy alone in inoperable oesophageal cancer. The results of the reported clinical trials are, however, conflicting, and no solid conclusion can be drawn. Hyperfractionated radiotherapy has been compared with conventionally fractionated radiotherapy in two randomized studies with conflicting results and no firm conclusion can be drawn.