Emmanuelle Tresch

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.

Image-based response assessment of liver metastases following stereotactic body radiotherapy with respiratory tracking

ObjectiveTo describe post-CyberKnife® imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST).Subjects and MethodsImaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated.ResultsComplete response (CR) was 3.6% (95% CI: 0.1–18%) and 18% (95% CI: 6–37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41–78%) by RECIST and 64% (95% CI: 44%–81%) by CC.ConclusionUse of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity.

A Dosimetric Comparison of Tomotherapy and Volumetric Modulated Arc Therapy in the Treatment of High-Risk Prostate Cancer With Pelvic Nodal Radiation Therapy

PURPOSE To compare the dosimetric results of volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) in the treatment of high-risk prostate cancer with pelvic nodal radiation therapy. METHODS AND MATERIALS Plans were generated for 10 consecutive patients treated for high-risk prostate cancer with prophylactic whole pelvic radiation therapy (WPRT) using VMAT and HT. After WPRT, a sequential boost was delivered to the prostate. Plan quality was assessed according to the criteria of the International Commission on Radiation Units and Measurements 83 report: the near-minimal (D98%), near-maximal (D2%), and median (D50%) doses; the homogeneity index (HI); and the Dice similarity coefficient (DSC). Beam-on time, integral dose, and several organs at risk (OAR) dosimetric indexes were also compared. RESULTS For WPRT, HT was able to provide a higher D98% than VMAT (44.3 ± 0.3 Gy and 43.9 ± 0.5 Gy, respectively; P=.032) and a lower D2% than VMAT (47.3 ± 0.3 Gy and 49.1 ± 0.7 Gy, respectively; P=.005), leading to a better HI. The DSC was better for WPRT with HT (0.89 ± 0.009) than with VMAT (0.80 ± 0.02; P=.002). The dosimetric indexes for the prostate boost did not differ significantly. VMAT provided better rectum wall sparing at higher doses (V70, V75, D2%). Conversely, HT provided better bladder wall sparing (V50, V60, V70), except at lower doses (V20). The beam-on times for WPRT and prostate boost were shorter with VMAT than with HT (3.1 ± 0.1 vs 7.4 ± 0.6 min, respectively; P=.002, and 1.5 ± 0.05 vs 3.7 ± 0.3 min, respectively; P=.002). The integral dose was slightly lower for VMAT. CONCLUSION VMAT and HT provided very similar and highly conformal plans that complied well with OAR dose-volume constraints. Although some dosimetric differences were statistically significant, they remained small. HT provided a more homogeneous dose distribution, whereas VMAT enabled a shorter delivery time.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BackgroundTo identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC).MethodsIn this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method.ResultsDuring follow up (median: 6 [0.4–9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treament (HR = 1.9 [1.2–3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0–3.2], p = 0.040).ConclusionOne EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

Comparison of Response Evaluation Criteria in Solid Tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: A retrospective analysis

BACKGROUND To assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin. METHODS Eligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist. RESULTS The retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m(2) given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2-33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052). CONCLUSIONS Choi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.

Adapted Prescription Dose for Monte Carlo Algorithm in Lung SBRT: Clinical Outcome on 205 Patients

Purpose SBRT is the standard of care for inoperable patients with early-stage lung cancer without lymph node involvement. Excellent local control rates have been reported in a large number of series. However, prescription doses and calculation algorithms vary to a great extent between studies, even if most teams prescribe to the D95 of the PTV. Type A algorithms are known to produce dosimetric discrepancies in heterogeneous tissues such as lungs. This study was performed to present a Monte Carlo (MC) prescription dose for NSCLC adapted to lesion size and location and compare the clinical outcomes of two cohorts of patients treated with a standard prescription dose calculated by a type A algorithm or the proposed MC protocol. Patients and Methods Patients were treated from January 2011 to April 2013 with a type B algorithm (MC) prescription with 54 Gy in three fractions for peripheral lesions with a diameter under 30 mm, 60 Gy in 3 fractions for lesions with a diameter over 30 mm, and 55 Gy in five fractions for central lesions. Clinical outcome was compared to a series of 121 patients treated with a type A algorithm (TA) with three fractions of 20 Gy for peripheral lesions and 60 Gy in five fractions for central lesions prescribed to the PTV D95 until January 2011. All treatment plans were recalculated with both algorithms for this study. Spearman’s rank correlation coefficient was calculated for GTV and PTV. Local control, overall survival and toxicity were compared between the two groups. Results 205 patients with 214 lesions were included in the study. Among these, 93 lesions were treated with MC and 121 were treated with TA. Overall survival rates were 86% and 94% at one and two years, respectively. Local control rates were 79% and 93% at one and two years respectively. There was no significant difference between the two groups for overall survival (p = 0.785) or local control (p = 0.934). Fifty-six patients (27%) developed grade I lung fibrosis without clinical consequences. GTV size was a prognostic factor for overall survival (HR = 1.026, IC95% [1.01–1.041], p<0.001) and total dose was a prognostic factor for local control (HR = 0.924, IC95% [0.870–0.982], p = 0.011). D50 of the GTV calculated with MC correlated poorly with the D95 of the PTV calculated with TA (r = 0.116) for lesions with a diameter of 20 mm or less. For lesions larger than 20 mm, spearman correlation was higher (r = 0.618), but still insufficient. Conclusion No difference in local control or overall survival was found between patients treated with a type A or a type B algorithm in our cohort. A size and location adapted GTV-based prescription method could be used with a type B algorithm. External validation of these results is warranted.

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.

Hypofractionated stereotactic boost in intermediate risk prostate carcinoma: Preliminary results of a multicenter phase II trial (CKNO-PRO)

Purpose Dose escalation may improve curability in intermediate-risk prostate carcinoma. A multicenter national program was developed to assess toxicity and tumor response with hypofractionated stereotactic boost after conventional radiotherapy in intermediate-risk prostate cancer. Methods and material Between August 2010 and April 2013, 76 patients with intermediated-risk prostate carcinoma were included in the study. A first course delivered 46 Gy by IMRT (68.4% of patients) or 3D conformal radiotherapy (31.6% of patients). The second course delivered a boost of 18 Gy (3x6Gy) within 10 days. Gastrointestinal (GI) and genitourinary (GU) toxicities were evaluated as defined by NCI-CTCAE (v4.0). Secondary outcome measures were local control, overall and metastasis-free survival, PSA kinetics, and patient functional status (urinary and sexual) according to the IIEF5 and IPSS questionnaires. Results The overall treatment time was 45 days (median, range 40–55). Median follow-up was 26.4 months (range, 13.6–29.9 months). Seventy-seven per cent (n = 58) of patients presented a Gleason score of 7. At 24 months, biological-free survival was 98.7% (95% CI, 92.8–99.9%) and median PSA 0.46 ng/mL (range, 0.06–6.20 ng/mL). Grade ≥2 acute GI and GU toxicities were 13.2% and 23.7%, respectively. Grade ≥2 late GI and GU toxicities were observed in 6.6% and 2.6% of patients, respectively. No grade 4 toxicity was observed. Conclusions Hypofractionated stereotactic boost is effective and safely delivered for intermediate-risk prostate carcinoma after conventional radiation. Mild-term relapse-free survival and tolerance results are promising, and further follow-up is warranted to confirm the results at long term. Trial registration ClinicalTrials.gov NCT01596816.

Novel Technique for Hepatic Fiducial Marker Placement for Stereotactic Body Radiation Therapy

PURPOSE To report experience with fiducial marker insertion and describe an advantageous, novel technique for fiducial placement in the liver for stereotactic body radiation therapy with respiratory tracking. METHODS AND MATERIALS We implanted 1444 fiducials (single: 834; linked: 610) in 328 patients with 424 hepatic lesions. Two methods of implantation were compared: the standard method (631 single fiducials) performed on 153 patients from May 2007 to May 2010, and the cube method (813 fiducials: 610 linked/203 single) applied to 175 patients from April 2010 to March 2013. The standard method involved implanting a single marker at a time. The novel technique entailed implanting 2 pairs of linked markers when possible in a way to occupy the perpendicular edges of a cube containing the tumor inside. RESULTS Mean duration of the cube method was shorter than the standard method (46 vs 61 minutes; P<.0001). Median numbers of skin and subcapsular entries were significantly smaller with the cube method (2 vs 4, P<.0001, and 2 vs 4, P<.0001, respectively). The rate of overall complications (total, major, and minor) was significantly lower in the cube method group compared with the standard method group (5.7% vs 13.7%; P=.013). Major complications occurred while using single markers only. The success rate was 98.9% for the cube method and 99.3% for the standard method. CONCLUSIONS We propose a new technique of hepatic fiducial implantation that makes use of linked fiducials and involves fewer skin entries and shorter time of implantation. The technique is less complication-prone and is migration-resistant.

Chemotherapy Drug Extravasation in Totally Implantable Venous Access Port Systems: How Effective is Early Surgical Lavage?:

Purpose Totally implantable venous access port systems (TIVAPS) are a widely used and an essential tool in the efficient delivery of chemotherapy. Chemotherapy drug extravasation (CDE) can have dire consequences and will delay treatment. The purpose of this study is to both clarify the management of CDE and show the effectiveness of early surgical lavage (ESL). Methods Patients who had presented to the Cancer Center of Lille (France) with TIVAPS inserted between January 2004 and April 2013 and CDE had their medical records reviewed retrospectively. Results Thirty patients and 33 events were analyzed. Implicated agents were vesicants (51.5%), irritants (45.5%) and non-vesicants (3%). Huber needle malpositionning was involved in 27 cases. Surgery was performed in 97% of cases, 87.5% of which were for ESL with 53.1% of the latter requiring TIVAPS extraction. Six patients required a second intervention due to adverse outcomes (severe cases). Vesicants were found to be implicated in four out of six severe cases and oxaliplatin in two others. Extravasated volume was above 50 ml in 80% of cases. Only one patient required a skin graft. Conclusions CDEs should be managed in specialized centers. ESL allows for limited tissue contact of the chemotherapy drug whilst using a simple, widely accessible technique. The two main factors that correlate with adverse outcome seem to be the nature of the implicated agent (vesicants) and the extravasated volume (above 50 ml) leading to worse outcomes. Oxaliplatin should be considered as a vesicant.