A. Kramar

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

Salvage Stereotactic Reirradiation With or Without Cetuximab for Locally Recurrent Head-and-Neck Cancer: A Feasibility Study

PURPOSE Normal tissues tolerance limits the use of reirradiation for recurrent head-and-neck cancers (HNC). Stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. Results of a feasibility study using SBRT with or without cetuximab are reported for reirradiation of recurrent primary HNC. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor, in a previously irradiated area were included. Reirradiation dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the planning target volume. Patients with squamous cell carcinoma received concomitant cetuximab. RESULTS Between June 2007 and January 2010, 40 patients were prospectively treated for 43 lesions. Median age was 60 and median tumor size was 29 mm. Fifteen patients received concomitant cetuximab and 1 received concomitant cisplatin. Median follow-up was 25.6 months with 34 patients evaluable for tumor response. Median overall survival was 13.6 months and response rate was 79.4% (15 complete and 12 partial responses). Grade 3 toxicity occurred in 4 patients. CONCLUSION These results suggest that short SBRT with or without cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. A prospective multicenter Phase II trial of SRT and concomitant cetuximab in recurrent HNC squamous cell carcinoma is ongoing.

Prognostic factors affecting local control of hepatic tumors treated by stereotactic body radiation therapy

PurposeRobotic Stereotactic Body Radiation Therapy with real-time tumor tracking has shown encouraging results for hepatic tumors with good efficacy and low toxicity. We studied the factors associated with local control of primary or secondary hepatic lesions post-SBRT.Methods and materialsSince 2007, 153 stereotactic liver treatments were administered to 120 patients using the CyberKnife® System. Ninety-nine liver metastases (72 patients), 48 hepatocellular carcinomas (42 patients), and six cholangiocarcinomas were treated. On average, three to four sessions were delivered over 12 days. Twenty-seven to 45 Gy was prescribed to the 80% isodose line. Margins consisted of 5 to 10 mm for clinical target volume (CTV) and 3 mm for planning target volume (PTV).ResultsMedian size was 33 mm (range, 5–112 mm). Median gross tumor volume (GTV) was 32.38 cm3 (range, 0.2–499.5 cm3). Median total dose was 45 Gy in three fractions. Median minimum dose was 27 Gy in three fractions. With a median follow-up of 15.0 months, local control rates at one and two years were 84% and 74.6%, respectively. The factors associated with better local control were lesion size < 50 mm (p = 0.019), GTV volume (p < 0.05), PTV volume (p < 0.01) and two treatment factors: a total dose of 45 Gy and a dose–per-fraction of 15 Gy (p = 0.019).ConclusionsDose, tumor diameter and volume are prognostic factors for local control when a stereotactic radiation therapy for hepatic lesions is considered. These results should be considered in order to obtain a maximum therapeutic efficacy.

A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases

PurposeThe purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy.Methods and materialsBetween July 2007 and June 2010, 90 patients were treated with the CyberKnife® SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity.ResultsA total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23–84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7–110 mm) for liver and 12.5 mm (range, 5–63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55–81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1–9.5 months). Observed toxicities included grade 1–3 acute toxicities. One grade 3 and no grade 4 toxicity were reported.ConclusionHigh-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy.SummaryStereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients’ life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens.

Life-expectancy of patients enrolled in phase 1 clinical trials: A systematic review of published prognostic models

Life-expectancy superior to 3 months is a key-eligibility criterion for contemporary oncology phase 1 trials. Nevertheless, there is no reliable and consensual guidance for estimating this criterion. We have conducted a systematic review of published studies investigating the risk factor for 90-day mortality and the inherent generated scores. Nine studies have been published on this topic. Only two of these prognostic models have been validated on an independent dataset. Most of the models are based on a very subjective and investigator-dependent parameter: the performance status. The predictive performance of these prognostic models is poorly evaluated.

Prediction of early death among patients enrolled in phase i trials: Development and validation of a new model based on platelet count and albumin

Background:Selecting patients with ‘sufficient life expectancy’ for Phase I oncology trials remains challenging. The Royal Marsden Hospital Score (RMS) previously identified high-risk patients as those with ⩾2 of the following: albumin <35 g l−1; LDH > upper limit of normal; >2 metastatic sites. This study developed an alternative prognostic model, and compared its performance with that of the RMS.Methods:The primary end point was the 90-day mortality rate. The new model was developed from the same database as RMS, but it used Chi-squared Automatic Interaction Detection (CHAID). The ROC characteristics of both methods were then validated in an independent database of 324 patients enrolled in European Organization on Research and Treatment of Cancer Phase I trials of cytotoxic agents between 2000 and 2009.Results:The CHAID method identified high-risk patients as those with albumin <33 g l−1 or ⩾33 g l−1, but platelet counts ⩾400.000 mm−3. In the validation data set, the rates of correctly classified patients were 0.79 vs 0.67 for the CHAID model and RMS, respectively. The negative predictive values (NPV) were similar for the CHAID model and RMS.Conclusion:The CHAID model and RMS provided a similarly high level of NPV, but the CHAID model gave a better accuracy in the validation set. Both CHAID model and RMS may improve the screening process in phase I trials.

Activity endpoints reported in soft tissue sarcoma phase II trials: Quality of reported endpoints and correlation with overall survival

BACKGROUND Despite extensive research over the past 3 decades, few investigational drugs are considered as promising and these drugs failed to improve overall survival. Therefore we performed a systematic review of the literature to improve our understanding of the reasons that explain these failures. METHODS We reviewed 53 phase II trial reports that investigated new treatments in patients with advanced soft tissue sarcoma from 1999 to 2011. We critically reviewed the selected primary endpoint used in these trials. RESULTS Forty percent of trials were not interpretable because of major inherent methodological flaws. Only 3 primary endpoints were correlated with median overall survival (mOS): 3- and 6-month progression free rates and median progression-free survival. Nevertheless, the mOS was not significantly higher in the cases of active drugs. DISCUSSION We need to improve the definition of primary active endpoints and develop better designs for future trials. The current definition of promising drugs must be refined.

What is the normal tissues morbidity following Helical Intensity Modulated Radiation Treatment for cervical cancer

BACKGROUND AND PURPOSE To report on normal tissues morbidity following IMRT for cervix cancer. MATERIAL AND METHODS The first 61 patients of a prospective series were included. 50 Gy to the PTV 1(pelvis) and 60 Gy to the PTV 2 (centro-pelvic disease and GTV nodes) were delivered concomitantly in 28 fractions, followed by a brachytherapy boost. For the small bowel, 50 Gy was the maximal dose, while V45 and V40 had to be <50 cc and 200 cc, respectively. For the bladder, rectum and sigmoid structures, 60 Gy was the maximal dose, and V45 and V40 had to be <20% and <50%. Acute and late toxicity data were prospectively collected. RESULTS The median follow-up period was 40 months (range: 23-60). 30% and 90% of acute and moderate late side effects were reported respectively. Considering the AUC data of the organs at risk (OAR) DVH, late morbidity and doses were significantly linked (p⩽0.03), predominantly between 10 Gy and 40 Gy, considering the small bowel and sigmoid colon. The high dose regions exhibited no significant impact. CONCLUSION The moderate dose volumes represent the predominant cause of morbidity after IMRT. Prospective trials are thus required to investigate new ways of dose distribution within the OAR.