Electronic brachytherapy for treatment of non-melanoma skin cancers: clinical results and toxicities.

PURPOSE: Although surgical approaches are standard for most non-melanomatous skin cancers, some patients are not candidates due to medical co-morbidities or functional or cosmetic or lesion location. High-dose-rate electronic brachytherapy (HDR-EBT) may be an alternative treatment modality. MATERIAL AND METHODS: A retrospective chart review was conducted from April 2011 to April 2013. All lesions were pathologically confirmed as malignant basal cell or squamous cell carcinoma. A HDR-EBT system delivered a median biological equivalent dose of 50 Gy total to a depth of 0.1-0.5 cm using various sizes of applicators. Treatment feasibility, acute and late toxicity, cosmetic outcomes, and local recurrence were assessed. RESULTS: Thirty-three patients with a mean age of 76 years with 50 cutaneous lesions were treated. Locations included 17 extremity lesions and 33 head and neck lesions. After treatments, acute grade 3 moist desquamation developed in 9 of the lesions (18%). Acute grade 4 ulceration developed in 3 lesions in the lower extremity (6%) and 1 upper lip lesion (2%). These toxicities were improved after a median of 20 days. Amongst the 4 lesions with grade 4 toxicities, a greater proportion were in lower extremity lesions compared to head and neck lesions (75% vs. 25%). There was no difference in the rate of grade 3 and 4 toxicities between patients aged ≤ 75 years and aged > 75 years (p = 0.082). With a mean long-term follow-up of 45.6 months, there was 1 local recurrence treated with surgery and no reported late toxicities. CONCLUSIONS: Our experience with HDR-EBT for non-melanomatous skin cancers is encouraging in terms of efficacy and convenience for patients. Our long-term follow-up shows a good response in all treated sites. Caution should be used for extremity sites, and more fractionated regimens should be considered to avoid severe acute toxicities.

Radiotherapeutic management of vestibular schwannomas using size- and location-adapted fractionation regimens to maximize the therapeutic ratio.

BACKGROUND: We evaluated and compared the radiographic and clinical outcomes of patients with vestibular schwannomas treated with single fraction stereotactic radiosurgery (SRS), 5 fractions of hypofractionated stereotactic radiation therapy (hSRT), or 25 to 30 fractions of conventionally fractionated stereotactic radiation therapy (cfSRT). METHODS AND MATERIALS: Fifty-six patients treated with LINAC-based SRS (median, 12.5 Gy), hSRT (25 Gy), or cfSRT (median, 54 Gy) were retrospectively reviewed. Fractionation was based on the size of the tumor, proximity to the brainstem, and potential risk of neurological sequelae. Median follow-up time was 55.2 months. RESULTS: The pretreatment median tumor diameter was significantly smaller for SRS (1.14 cm) compared with hSRT (1.7 cm) (P = .03) and cfSRT (2.0 cm) (P < .001). The overall local tumor control was 96.4%: 100% SRS, 100% hSRT, and 90% cfSRT (P = .19). Tumor regression was observed in 53.3% of SRS, 76.2% of hSRT, and 90% of cfSRT (P = .05). There was less transient expansion of tumors treated with cfSRT (5%) than with SRS (53.3%) or hSRT (28.6%) (P = .005). The median time to regression was 13.8 months for SRS, 14.2 months for hSRT, and 5.5 months for cfSRT (P = .34). There was a 3.6% incidence of grade 3 trigeminal neuropathy, but there was no grade 3 facial neuropathy. CONCLUSIONS: All 3 regimens demonstrated similar excellent local control with minimal toxicity; however, the ability of hSRT to treat larger tumors with comparable outcomes to SRS and greater patient convenience when compared with cfSRT suggest that hSRT may offer the optimal treatment approach.

Feasibility of tomotherapy for postoperative irradiation of lower extremity sarcomas.

AIMS AND BACKGROUND: To evaluate the effectiveness of helical tomotherapy-based image-guided radiotherapy (IGRT) following surgery for lower extremity sarcoma. METHODS AND STUDY DESIGN: A retrospective review of three patients undergoing postoperative irradiation with tomotherapy for lower extremity sarcoma was conducted. Planning target volume (PTV) coverage, acute side effects, long-term complications and functional results were assessed. RESULTS: Tomotherapy allows adequate coverage of the PTV without an excessive radiation dose to the normal adjacent structures. Radiotherapy side effects were acceptable with no treatment breaks. All patients were disease free with no complications and no impairment of their daily activity at the last follow-up. CONCLUSION: IGRT delivered by tomotherapy may be ideally suited for sarcoma of the extremities because of its ability to achieve a high radiation dose along with excellent normal tissue sparing. Further prospective studies should be conducted to confirm this hypothesis.

Feasibility of tomotherapy-based image-guided radiotherapy for locally advanced oropharyngeal cancer.

PURPOSE: The study aims to assess the feasibility of tomotherapy-based image-guided (IGRT) radiotherapy for locally advanced oropharyngeal cancer. A retrospective review of 33 patients undergoing concurrent chemoradiation for locally advanced oropharyngeal cancers was conducted. Radiotherapy planning, treatment toxicity and loco-regional control were assessed. RESULTS: At a median follow-up of 32 months (6-47 months), no patient developed loco-regional recurrence. Two patients (6%) developed distant metastases. Grade 3-4 acute toxicity was respectively 72% and 25% for mucositis and gastrointestinal toxicity. Two patients (6%) had long-term dependence on tube feedings. Dose-volume histogram demonstrated excellent target volume coverage and low radiation dose to the organs at risk for complications. CONCLUSIONS AND CLINICAL RELEVANCE: IGRT provides excellent loco-regional control but acute toxicity remains significant and needs to be addressed in future prospective trials. The feasibility of Tomotherapy to decrease radiation dose to the normal tissues merits further investigations.

Feasibility of intensity-modulated and image-guided radiotherapy for functional organ preservation in locally advanced laryngeal cancer.

PURPOSE: The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits. RESULTS: At a median follow-up of 20 months (range 6-57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient). CONCLUSIONS AND CLINICAL RELEVANCE: Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures.

Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer.

BACKGROUND: To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases. METHODS: A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed. RESULTS: Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p < 0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p < 0.0001) CONCLUSION: Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage.

Sensitivity to low-dose/low-LET ionizing radiation in mammalian cells harboring mutations in succinate dehydrogenase subunit C is governed by mitochondria-derived reactive oxygen species.

It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O2 metabolism lead to persistent heritable increases in steady-state levels of intracellular superoxide (O2(•U+2212)) and hydrogen peroxide (H2O2) that contribute to the biological effects of radiation. Hamster fibroblasts (B9 cells) expressing a mutation in the gene coding for the mitochondrial electron transport chain protein succinate dehydrogenase subunit C (SDHC) demonstrate increases in steady-state levels of O2•- and H2O2. When B9 cells were exposed to low-dose/low-LET radiation (5-50 cGy), they displayed significantly increased clonogenic cell killing compared with parental cells. Clones derived from B9 cells overexpressing a wild-type human SDHC (T4, T8) demonstrated significantly increased surviving fractions after exposure to 5-50 cGy relative to B9 vector controls. In addition, pretreatment with polyethylene glycol-conjugated CuZn superoxide dismutase and catalase as well as adenoviral-mediated overexpression of MnSOD and/or mitochondria-targeted catalase resulted in significantly increased survival of B9 cells exposed to 10 cGy ionizing radiation relative to vector controls. Adenoviral-mediated overexpression of either MnSOD or mitochondria-targeted catalase alone was equally as effective as when both were combined. These results show that mammalian cells over expressing mutations in SDHC demonstrate low-dose/low-LET radiation sensitization that is mediated by increased levels of O2•- and H2O2. These results also support the hypothesis that mitochondrial O2•- and H2O2 originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses.

Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability.

Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH(2)) oxidation indicative of increased steady-state levels of O2(.-) and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation-induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O2(.-) production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a "mutator phenotype" by increasing steady-state levels of O2(.-) and H2O2.