Jean-Louis Habrand

A case report of pseudoprogression followed by complete remission after proton-beam irradiation for a low-grade glioma in a teenager: the value of dynamic contrast-enhanced MRI

A fourteen years-old boy was treated post-operatively with proton therapy for a recurrent low-grade oligodendroglioma located in the tectal region. Six months after the end of irradiation (RT), a new enhancing lesion appeared within the radiation fields. To differentiate disease progression from radiation-induced changes, dynamic susceptibility contrast-enhanced (DSCE) MRI was used with a T2* sequence to study perfusion and permeability characteristics simultaneously. Typically, the lesion showed hypoperfusion and hyperpermeability compared to the controlateral normal brain. Without additional treatment but a short course of steroids, the image disappeared over a six months period allowing us to conclude for a pseudo-progression. The patient is alive in complete remission more than 2 years post-RT.

Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies

Background Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDAs approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect. Materials and Methods Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported. Results Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didnt find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data. Conclusion PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.BACKGROUNDnPoly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDAs approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect.nnnMATERIALS AND METHODSnHere, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported.nnnRESULTSnSixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didnt find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data.nnnCONCLUSIONnPARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.

Vemurafenib and concomitant stereotactic radiation for the treatment of melanoma with spinal metastases: A case report

A 56-year-old man with BRAFV600E melanoma and spinal metastases treated with vemurafenib and stereotactic radiation showed a partial response without neurological, skin or mucosal toxicity, 8 months after completion of this combination. This case suggests that stereotactic radiation spares normal tissues and might be safer than conventional fractionated radiation with vemurafenib.

Proton beam therapy for skull base chordomas in 106 patients: A dose adaptive radiation protocol

BACKGROUND AND PURPOSEnTo evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas.nnnMATERIAL AND METHODSnBetween May 2006 and October 2012, 106 patients with skull base chordoma were treated by combined photon and proton irradiation. Prescribed dose levels were 68.4, 70.2, 72 and 73.8u202fGy(RBE) in once daily fractionation of 1.8u202fGy(RBE). Dose level and dosimetric constraints to organs at risk depended on postoperative residual Gross Tumor Volume (GTV) coverage. Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method.nnnRESULTSnWith a median follow-up of 61u202fmonths, the 2-year, 4-year, and 5-year LC rates were 88.6%, 78.3%, and 75.1%, respectively. GTVu202f>u202f25u202fmL (pu202f=u202f0.034, HRu202f=u202f2.22; 95%CI 1.06-4.62) was an independent unfavorable prognostic factor of LC. The 2-year, 4-year, and 5-year OS rates were 99%, 90.2%, and 88.3%, respectively. Grade 3-5 late toxicity was observed in 7 patients, resulting in 93% 5-year freedom from high-grade toxicity.nnnCONCLUSIONSnThis study suggests that the probability of LC of skull base chordomas depends on postoperative GTV. The dose adaptive protocol achieves acceptable local control. Future studies should investigate whether further dose escalation to doses in excess of 74u202fGy(RBE) would achieve better results.

Proton therapy for locally advanced breast cancer: a systematic review of the literature

BACKGROUNDnRadiation therapy plays a major role in the management of adjuvant breast cancer with nodal involvement, with an iatrogenic increase of cardio-vascular risk. Photon therapy, even with intensity modulation, has the downsides of high mean heart dose and heterogeneous target coverage, particularly in the case of internal mammary irradiation. This systematic review of the literature aims to evaluate proton therapy in locally advanced breast cancer.nnnMATERIAL AND METHODSnPubMed was searched for original full-text articles with the following search terms: «Proton Therapy» and «Breast Cancer». On-going trials were collected using the words Breast Cancer and Protons.nnnRESULTSn13 articles met the criteria: 6 with passive proton therapy (Double Scattering), 5 with Pencil Beam Scanning (PBS) and 2 with a combination of both. Proton therapy offered a better target coverage than photons, even compared with intensity modulation radiation therapy (including static or rotational IMRT or tomotherapy). With proton therapy, volumes receiving 95% of the dose were around 98%, with low volumes receiving 105% of the dose. Proton therapy often decreased mean heart dose by a factor of 2 or 3, i.e. 1u202fGy with proton therapy versus 3u202fGy with conventional 3D, and 6u202fGy for IMRT. Lungs were better spared with proton therapy than with photon therapy. Cutaneous toxicity observed with double scattering is improved with PBS.nnnCONCLUSIONnProton therapy reduces mean heart dose in breast cancer irradiation, probably reducing late cardio-vascular toxicity. Large clinical studies will likely confirm a clinical benefit of proton therapy.

Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer)

BackgroundUntil 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS).MethodsBetween 2012 and 2016, 193 metastases, smaller than 3xa0cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18xa0months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data.ResultsAfter a median follow-up of 7.4xa0months, LPFS rates at 6, 12 and 18xa0months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18xa0months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HRu2009=u20091.39, CI95% [0.65–2.96], pu2009=u20090.38). Time from planning MRI to first irradiation session longer than 14xa0days was associated with a poorer local control rate. Over this time, LPFS at 12xa0months was reduced from 86 to 70% (pu2009=u20090.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (pu2009=u20090.55). The median OS was 9.6xa0months. Six, 12 and 18xa0months CPFS rates were 54, 24 and 17%, respectively.ConclusionFractionation does not decrease LPFS. Even for small radioresistant brain metastases (<u20093xa0cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1xa0year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013

PURPOSEnThe objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma.nnnMETHODS AND MATERIALSnBetween 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy.nnnRESULTSnMedian follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival.nnnCONCLUSIONSnWe confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.

Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group

BACKGROUNDnRenal cell carcinoma (RCC) is usually considered radioresistant, but stereotactic radiation therapy (SRT) may increase local disease control. This study aimed to assess the benefit of SRT in the management of metastatic RCC patients.nnnMETHODSnData of all RCC patients who received SRT between 2008 and 2015 with curative intent were retrospectively collected in six French referral centres. Local control (LC), progression-free survival (PFS), local recurrence-free survival (LRFS), time to systemic therapy (TTS)xa0and overall survival (OS) were assessed.nnnRESULTSnOne hundred and eighty-eight patients treated with SRT for 252 RCC metastases (brain [nxa0=xa0120]; spine [nxa0=xa075]; and others [nxa0=xa057]) were recensed. SRT was performed for oligoprogressive disease (101 patients), oligometastatic disease (80 patients)xa0or residual tumour after a partial response to systemic treatment (7 patients). The median biologically effective dose was 78xa0Gy. For the whole population, local control rates at 6, 12xa0and 24 months were 87.5%, 82.9%xa0and 77.6%, respectively; median PFS, LRFS, TTSxa0and OS were 8.5, 23.2, 13.2xa0and 29.2 months, respectively. Among patients treated for oligoprogressive/oligometastatic disease, the median PFS, TTS, and OS were 8.6/7.6, 10.5/14.2xa0and 23.2/33.9 months, respectively. Among the 7 patients treated with SRT after partial response to systemic treatment, no relapse occurred for 3 of them after a median follow-up of 22 months. Acute and late severe toxicities were noted in 5 (2.6%) patients.nnnCONCLUSIONSnSRT is effective and safe for oligometastatic and oligoprogressive RCC patients and may delay introduction or change of systemic therapy.

Review of the mechanisms involved in the abscopal effect and future directions with a focus on thymic carcinoma.

The abscopal effect is a rare phenomenon in radiotherapy, leading to impressive tumor regression outside the radiotherapy field. In this article we describe the occurrence of a postradiotherapy abscopal effect in an 89-year-old patient suffering from a metastatic neuroendocrine large-cell thymic carcinoma, the first case of the abscopal effect related to a thymic carcinoma reported in the literature. Along with the description of this case, we discuss and review the main potential mechanisms of bystander and abscopal effects in solid tumors so as to enable clinicians to identify and control these effects more resourcefully in the age of immunotherapy and stereotactic radiotherapy.

Chronic pancreatitis following abdominal radiotherapy: An exceptional case of delayed complication in childhood

To the Editor: The pancreas is rarely associated with delayed toxicity of chemotherapy or radiotherapy (RT) in children, although a significant excess of diabetes mellitus has been related with RT to its tail.[1] We report the case of a 10-year-old male, presenting with a delayed chronic pancreatitis (CP), following previous irradiation given incidentally to the pancreatic head. The child was treated for a large localized retroperitoneal embryonal rhabdomyosarcoma, according to the high-risk rhabdomyosarcoma 2005 International Society of Paediatric Oncology protocol, with six cycles of chemotherapy (combining ifosfamide, vincristine, actinomycin D, and adriamycin), followed by gross resection. Treatment was completed with RT, using 10MVphotons, that delivered 39.6Gy in 22 fractions of 1.8Gy each, through a fourfield technique, from T10 to L4. RT was tolerated well. Dosage to the pancreas was retrospectively 40Gy to the head and 10–20Gy to the tail. Thirty-four months following RT, the child presented with chronic mild diarrhea and abdominal pain. Work-up showed steatorrhea (11–13 g/day), and exocrine pancreatic insufficiency was demonstrated by a low level of fecal pancreatic elastase (79mg/g, normal; >200mg/g). Pancreatic serum enzymes (amylase, lipase) and glucose blood levels were unremarkable. Abdominal ultrasound showed a hyperechogenic pancreatic gland without calcifications. Pancreatic magnetic resonance imaging did not show any canalicular abnormalities. The child was treated with porcine pancreatic extracts with improvement of his symptoms. At 90 months of follow-up, the patient remained alive, with no evidence of disease, and free of digestive symptoms under pancreatic extracts. In animal models, delayed exocrine pancreatic insufficiency and diabetes mellitus have been observed following intraoperative irradiation of the pancreas. Pancreatic fibrosis was dose-dependent and caused by blood vessel and duct damage.[2] CP associated with previous RT has not been reported in children, with the exception of a single debatable case associated with an ampullary carcinoma.[3] Our case is remarkable for the relatively short interval (<3 years) following RT, and by the absence of endocrine manifestations. We suggest that the conjunction of his young age and high dose to pancreatic head, but not tail, might explain this clinical presentation. We also cannot formally eliminate the role of confounders, such as surgical devascularization, and/or chemotherapy. In summary, this case suggests that the endocrine and the exocrine pancreatic functions are both sensitive to radiation injury, and so we recommend that the pancreas be considered an organ at risk when RT is administered to children in this anatomical region. In this situation, we suggest a more systematic screening of pancreatic function in the follow-up of young patients.