New curative approach using embolization followed by moderate-dose radiotherapy after surgical failure for large right heart metastasis.

PURPOSE: Cardiac metastasis is a rare fatal event. An intracavitary right tumor mainly in the ventricle is difficult to manage. Literature reports suggest that cardiac surgery in oligometastatic patients could offer median survival of 1 year. We investigated salvage treatment comprising transcoronary tumor embolization followed 15 days later by cardiac radiotherapy (40.5 Gy/15 fractions). CASES: We report two cases of severe right cardiac metastasis with a history of abdominal cancer managed by this salvage treatment following residual cardiac mass after previous cardiac surgery. CONCLUSION: Both symptomatic patients improved progressively and were locally controlled for at least 1 year without toxicity.

Multimodal strategy for the management of sphenoid osteoradionecrosis: Preliminary results.

OBJECTIVE: Osteoradionecrosis (ORN) of the sphenoid is a rare but potentially lethal complication that can occur after irradiation of nasopharyngeal and clival malignancies. The objective of this study was to describe a multimodal treatment strategy tailored to the clinical signs and to the radiological extent of the disease, and to report on its preliminary results. METHODS: Retrospective monocentric study at a tertiary skull base center. Patients treated for a sphenoid ORN from January 2014 to August 2018 were identified and charts were retrospectively reviewed for demographics, histologic tumor type, previous treatments of the tumor, clinical signs at presentation, radiological data, treatment, and outcomes. Sphenoid ORN was treated by a combination of medical therapy, endovascular treatment, and/or surgery. The use of each of these therapeutic modalities was based on the extent of ORN and on the presenting signs. RESULTS: Seven patients were included: four patients underwent endovascular treatment with occlusion of the internal carotid artery, five patients underwent surgical debridement, and covering of the exposed bone by a local flap, seven patients received antibiotics (in combination with pentoxyphilline, tocopherol, and clodronate in one case). Three patients died after progression of the ORN. The global survival rate was 57% (4/7) with a mean follow-up of 24 months. In one case, ORN was treated successfully by medical treatment only, with a combination of antibiotics, pentoxyphilline, tocopherol, and clodronate. CONCLUSION: This retrospective study describes the results of a management strategy adapted to the extent of the disease in sphenoid ORN and based on medical therapy only, or on a combination of medical therapy, interventional radiology, and/or surgery. LEVEL OF EVIDENCE: 4.

Randomized, Placebo-Controlled Clinical Trial Combining Pentoxifylline-Tocopherol and Clodronate in the Treatment of Radiation-Induced Plexopathy.

PURPOSE: Radiation-induced (RI) plexopathy is a rare peripheral nerve injury after radiation therapy for cancer. No treatment has been shown to slow its progression. A pentoxifylline-vitamin E combination significantly reduced RI fibrosis, and its association with clodronate (PENTOCLO) allowed healing of osteoradionecrosis and reduction of neurologic symptoms in phase 2 trials. METHODS AND MATERIALS: A placebo-controlled, double-blind trial conducted in adults with RI limb plexopathy without cancer recurrence, randomized in 2 arms to PENTOCLO (pentoxifylline 800 mg, tocopherol 1000 mg, clodronate 1600 mg 5 days per week) or triple placebo. The primary outcome measure after 18 months of treatment was the neurologic Subjective Objective Management Analytic (SOMA) score evaluating pain, paresthesia, and motor disability. RESULTS: Between 2011 and 2015, 59 patients were included: 1 false inclusion (neoplastic plexopathy), 29 treated with placebo (group P), and 29 treated with the active drugs (group A); 46 patients presented an upper-limb and 12 a lower-limb plexopathy. The mean delay after irradiation was 26 ± 8 years, for patients with neurologic symptoms for 5 ± 5 years. The median global SOMA scores in the P and A groups, respectively, were 9 (range, 6-11) versus 9 (range, 8-11) at M0 and 9 (range, 5-12) versus 10 (range, 6-11) at M18 without any significant difference. Analysis of the secondary outcomes showed that SOMA score subdomains for pain and paresthesia were more affected in group A (not significant). The frequency of adverse events was similar in the 2 groups (81% of patients): slight expected vascular-gastrointestinal symptoms in A, but a large excess of RI complications (arterial stenosis). CONCLUSIONS: This first randomized drug trial in RI plexopathy failed to show a beneficial effect. More studies are needed in patients with less advanced disease and fewer confounding comorbidities and with a more sensitive measure to detect a therapeutic effect.

Delayed septic radiation-induced calcinosis cutis long after cured anorectal cancer.

PURPOSE: Calcinosis cutis is an anecdotal local injury seen long after irradiation in cancer survivors. Our purpose was to shed light on this little studied and potentially serious ulceration. CASES: We report two cases of severe perineal-sacral infection with hard lesions, one decade after anorectal cancer irradiation. CT-scans showed extensive calcification and soft tissue inflammation, but previous radiation therapy was overlooked and the diagnosis was not made for several months after various tests, including biopsy. The two patients had different comorbidities and were managed by multidisciplinary collaboration between specialists. Surgery of the sacral ulcer was limited by the accessibility of non-irradiated tissues. In the absence of current guidelines, after radiopathological expertise, we used a "draining" procedure followed by antifibrotic pentoxifylline-tocopherol-clodronate treatment. CONCLUSION: Long after pelvic radiotherapy, symptomatic subcutaneous macrocalcification is suggestive of radiation-induced calcinosis. Prolonged antibiotic therapy followed by PENTOCLO treatment led to clinical improvement.

Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.

PURPOSE: This study aimed to evaluate the efficiency and the tolerance of radiation therapy (RT) on salivary glands in a large series of amyotrophic lateral sclerosis (ALS) patients with hypersalivation. METHODS AND MATERIALS: Fifty ALS patients that had medically failure pretreatment were included in this prospective study. RT was delivered through a conventional linear accelerator with 6-MV photons and 2 opposed beams fields including both submandibular glands and two-thirds of both parotid glands. Total RT dose was 10 Gy in 2 fractions (n=30) or 20 Gy in 4 fractions (n=20). RT efficacy was assessed with the 9-grade Sialorrhea Scoring Scale (SSS), recently prospectively validated as the most effective and sensitive tool to measure sialorrhea in ALS patients. RESULTS: At the end of RT, all patients had improved: 46 had a complete response (92% CR, SSS 1-3) and 4 had a partial response (8% PR, SSS 4-5). A significant lasting salivary reduction was observed 6 months after RT completion: there was 71% CR and 26% PR, and there was a significant SSS reduction versus baseline (P<10(-6)). There was no grade 3 to 4 toxicity, and most side effects (34%) occurred during RT. Nine patients (18%) underwent a second salivary gland RT course, with a 3-months mean delay from the first RT, resulting in a SSS decrease (-77%). Both RT dose regimens induced a significant SSS decrease with no significant toxicity. There were, however, more patients with CR/PR in the 20-Gy protocol (P=.02), and 8 of 9 patients (89%) receiving a second RT course had previously been treated within the 10-Gy protocol. CONCLUSION: Radiation therapy of 20 Gy in 4 fractions is an efficient and safe treatment for ALS patients with sialorrhea. A shorter RT course (10 Gy in 2 fractions) may be proposed in patients in poor medical condition.

MiR-210: A potential therapeutic target against radiation-induced enteropathy.

A previously undescribed and robust miR210 overexpression is shown in intestinal samples obtained from patients with radiation enteropathy and fibrotic cultured cells. In addition, miR-210 overexpression is repressed by antifibrotic treatment combining pentoxifylline and α-tocopherol.

Late radiation injury to peripheral nerves.

Although the peripheral nerve has often been considered as radioresistant, clinical practice demonstrates the occurrence of radiation-induced peripheral neuropathies. Because these complications appear late, usually several years after the course of radiotherapy, their occurrence is explained by improvement in the prognosis of several cancers. Their physiopathology is not fully understood. Compression by radio-induced fibrosis probably plays a central role but direct injury to nerves and blood vessels is probably also involved. The most frequent and best known form of postradiation neuropathy is brachial plexopathy, which may follow irradiation for breast cancer. Recent reports demonstrate that postradiation neuropathies show a great heterogeneity, particularly in the anatomical sites, but also in the clinical, electrophysiological, and neuroimaging features. The link with radiotherapy may be difficult for the clinician to establish. Patients with radiation-induced lumbosacral radiculoplexopathy may be misdiagnosed with amyotrophic lateral sclerosis as they often present with pure lower motor neuron syndrome, or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased CSF protein content can be observed. From a pathophysiological perspective, radiation-induced neuropathy offers an interesting model for deciphering the mechanisms of peripheral neuropathies due to environmental factors. Recent developments show promising strategies for the prevention and treatment of these complications, which have a considerable impact on a patient's quality of life.

Validation of robust tools to measure sialorrhea in amyotrophic lateral sclerosis: a study in a large French cohort.

There is an unmet need for validated tools to measure sialorrhea in amyotrophic lateral sclerosis, especially to evaluate treatments. We assessed the inter-/intra-rate reviewer reliability of two scales: the Oral Secretion Scale (OSS), specifically developed for ALS patients, and the Sialorrhea Scoring Scale (SSS), initially developed for Parkinson's disease patients. Sialorrhea was rated in 69 ALS consecutive patients by four evaluators: two neurologists, one nurse and one speech therapist. Inter-rater reliability was evaluated by the light kappa coefficient and intra-rater reliability by the weighted kappa coefficient. We also compared patients' and caregivers' answers. Results demonstrated that the two scales present a high inter-/intra-rater reliability: weighted kappas were 0.85 for both scales and light kappas 0.89 for the OSS and 0.88 for the SSS. Both scales also showed a good intra-profession reliability (OSS kappa = 0.84; SSS kappa = 0.79) and agreement between patients' and caregivers' answers. The SSS showed a higher responsiveness compared to OSS. In conclusion, both Oral Secretion Scale and Sialorrhea Scoring Scale are reliable tools to measure sialorrhea in ALS patients. Because of the wide range of salivation degrees, SSS may be more sensitive as a tool to evaluate treatments in patients with severe hypersialorrhea.

Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa.

Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.

Radiation-induced neuropathy in cancer survivors.

Radiation-induced peripheral neuropathy is a chronic handicap, frightening because progressive and usually irreversible, usually appearing several years after radiotherapy. Its occurrence is rare but increasing with improved long-term cancer survival. The pathophysiological mechanisms are not yet fully understood. Nerve compression by indirect extensive radiation-induced fibrosis plays a central role, in addition to direct injury to nerves through axonal damage and demyelination and injury to blood vessels by ischaemia following capillary network failure. There is great clinical heterogeneity in neurological presentation since various anatomic sites are irradiated. The well-known frequent form is radiation-induced brachial plexopathy (RIBP) following breast cancer irradiation, while tumour recurrence is easier to discount today with the help of magnetic resonance imaging and positron emission tomography. RIBP incidence is in accordance with the irradiation technique, and ranges from 66% RIBP with 60Gy in 5Gy fractions in the 1960s to less than 1% with 50Gy in 2Gy fractions today. Whereas a link with previous radiotherapy is forgotten or difficult to establish, this has recently been facilitated by a posteriori conformal radiotherapy with 3D-dosimetric reconstitution: lumbosacral radiculo-plexopathy following testicular seminoma or Hodgkin's disease misdiagnosed as amyotrophic lateral sclerosis. Promising treatments via the antioxidant pathway for radiation-induced fibrosis suggest a way to improve the everyday quality of life of these long-term cancer survivors.

Radiation-induced enteropathy: molecular basis of pentoxifylline-vitamin E anti-fibrotic effect involved TGF-ß1 cascade inhibition.

BACKGROUND: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. METHODS: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-ß1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. RESULTS: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-ß1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-ß1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway. CONCLUSIONS: The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-ß1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.

Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial.

PURPOSE: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treatment with pentoxifylline and vitamin E reduces radiation-induced fibrosis and ORN with a good prognosis. We previously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is useful in healing sternocostal and some mandibular ORN. Is PENTOCLO effective in ORN of poor prognosis? METHODS: 54 eligible patients previously irradiated for head and neck cancer (among 72 treated) a mean 5 years previously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery and hyperbaric oxygen had been ineffective. The mean length of exposed bone (D) was 17 ± 8 mm as primary endpoint, and the mean Subjective, Objective, Management, and Analytic evaluation of injury (SOMA) score was 16 ± 4. Between August 2000 and August 2008, all patients were given daily oral PENTOCLO: 800 mg pentoxifylline, 1,000 IU vitamin E, and 1,600 mg clodronate 5 days per week alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 days per week. The duration of treatment was related to consolidated healing. RESULTS: Prolonged treatment (16 ± 9 months) was safe and well tolerated. All patients improved, with an exponential progressive--(f[t] = a.exp(-b.t)--and significant (p < 0.0001) reduction of exposed bone (D), respectively (months): D(2) -42%, D(4) -62%, D(6) -77%, D(12) -92%, and D(18) -96%, combined with iterative spontaneous sequestrectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improvement was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA(6) -64%, SOMA(12) -89%, and SOMA(30) -96%. CONCLUSION: Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a randomized trial.

Sciatic nerve moneuropathy: an unusual late effect of radiotherapy.

In this study we report a progressive sciatic mononeuropathy occurring 13 years after radiotherapy (56-Gy prescribed dose) for a synovial sarcoma of the thigh. Conformal dosimetric reconstitution showed that irradiation was heterogeneous and that the sciatic nerve received 66 Gy over a 25-cm length. Magnetic resonance imaging (MRI) showed muscle fibrosis and increased sciatic nerve diameter. Our observation suggests that the risk of late mononeuropathy should be considered when large-volume and high-dose radiotherapy includes a nerve trunk.

Significant clinical improvement in radiation-induced lumbosacral polyradiculopathy by a treatment combining pentoxifylline, tocopherol, and clodronate (Pentoclo).

Radiation-induced (RI) peripheral neuropathy is a rare and severe delayed complication of radiotherapy that is spontaneously irreversible, with no standard of treatment. We previously developed a successful antioxidant treatment in RI fibrosis and necrosis. Two patients with progressive worsening RI lumbosacral polyradiculopathy experienced over several years a significant clinical improvement in their neurological sensorimotor symptoms with long-term pentoxifylline-tocopherol-clodronate treatment, and good safety.

Postradiation lumbosacral radiculopathy with spinal root cavernomas mimicking carcinomatous meningitis.

Lumbosacral radiculopathy is a rare complication of radiotherapy and may be challenging to differentiate from diagnosis of a tumor recurrence. We reviewed the records of three patients with a past history of cancer and radiotherapy who were referred for suspicion of carcinomatous meningitis on lumbar MRI, but whose final diagnosis was radiation-induced lumbosacral radiculopathy. The three patients developed a progressive lumbosacral radiculopathy at 20, 13, and 47 years after lumbar radiotherapy delivered for renal cancer, Hodgkin's disease, and a seminoma, respectively. MRI showed a diffuse, nodular enhancement of the cauda equina nerve roots on T1 sequences, suggestive of leptomeningeal metastasis. A slowly progressive clinical course over several years and negative cerebrospinal fluid cytologic analysis ruled out the diagnosis of carcinomatous meningitis. Because of the radiologic findings, a biopsy was performed in two patients. In the first, a biopsy limited to the arachnoid excluded a malignant infiltration. In the second, a biopsy of the enhancing lesions demonstrated spinal root cavernomas. These observations, together with three recent case reports in the literature, delineate a syndrome of "radiationinduced lumbosacral radiculopathy with multiple spinal root cavernomas" that mimics carcinomatous meningitis on MRI. Its diagnosis is important in order to avoid inappropriate treatment and useless or dangerous spinal root biopsies.

Current management for late normal tissue injury: radiation-induced fibrosis and necrosis.

Radiation-induced fibrosis (RIF) and radionecrosis (RN) are late complications that are usually considered irreversible. Usual management strategy includes eliminating local and general aggravating factors and controlling acute and chronic inflammation with steroids. Thanks to progress in understanding the pathophysiology of these lesions, several lines of treatment have been developed in clinical practice. However, results of clinical studies are difficult to compare because of variations in severity of RIF, method of RIF assessment, availability of efficient therapeutic drugs, treatment duration, and quality of trial design. For moderate established RIF, current management strategy mainly includes (1) anti-inflammatory treatment with corticosteroids or interferon gamma; (2) vascular therapy with pentoxifylline (PTX) or hyperbaric oxygen (HBO); and (3) antioxidant treatment with superoxide dismutase, tocopherol (vitamin E), and, most successfully, with a PTX-vitamin E combination. On the basis of etiology, RN can be managed by (1) anti-inflammatory treatment with corticosteroids and possibly clodronate, (2) vascular therapy with HBO and PTX, (3) antioxidant treatment with a PTX-vitamin E combination, and (4) a PTX-vitamin E-clodronate combination. Controlled randomized trials are now necessary to identify the best treatment at each step of RIF. In the future, these treatments of fibrosis and necrosis should include targeted drugs (such as growth factors) to take organ specificities into account.

Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis.

PURPOSE: Significant regression of radiation (RT) -induced fibrosis (RIF) has been achieved after treatment combining pentoxifylline (PTX) and alpha-tocopherol (vitE). In this study, we focus on the maximum response, how long it takes to achieve response, and changes after treatment discontinuation. PATIENTS AND METHODS: Measurable superficial RIF was assessed in patients treated by RT for breast cancer in a long-treatment (24 to 48 months) PTX-vitE (LPE) group of 37 patients (47 RIFs) and in a short-treatment (6 to 12 months) PTX-vitE (SPE) group of seven patients (eight RIFs). Between April 1995 and April 2000, women were treated with a daily combination of PTX (800 mg) and VitE (1,000 IU). RESULTS: Combined PTX-vitE was continuously effective and resulted in exponential RIF surface area regression (-46% for LPE and -68% for SPE at 6 months, -58% for LPE and -69% for SPE at 12 months, -63% for LPE and -62% for SPE at 18 months, and -68% for LPE at 24 and 36 months). The mean estimated maximal treatment effect was 68% RIF surface area regression. The mean time to this effect was 24 months and was shorter (16 months) in more recent RIF (< 6 years since RT) than in older RIF (28 months; P = .0003). Symptom severity (Subjective Objective Medical Management and Analytic Evaluation score) was halved in both groups. After treatment discontinuation, mean RIF surface area at 1 year had increased by +40% in the SPE group (rebound) and +8.5% in the LPE group. CONCLUSION: Under combined PTX-vitE treatment, RIF regression was exponential, with a two-thirds maximum response after a mean of 2 years. There was a risk of a rebound effect if treatment was too short. Long treatment (>/= 3 years) is recommended in patients with severe RIF.