Jean-Claude Rwigema

Two Strategies for the Development of Mitochondrion-Targeted Small Molecule Radiation Damage Mitigators

PURPOSE To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules. METHODS AND MATERIALS We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/mdm4 protein complex inhibitor BEB55 to mitigate radiation effects by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3 and the human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell lines. The p53-dependent mechanism of action was tested with p53(+/+) and p53(-/-) murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected i.p. with JP4-039, MCF201-89, or BEB55 individually or in combination, after receiving 9.5 Gy total body irradiation (TBI). RESULTS Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all three compounds increased the survival of 32D cl 3 (p = 0.0021, p = 0.0011, p = 0.0038, and p = 0.0073, respectively) and IB3 cells (p = 0.0193, p = 0.0452, p = 0.0017, and p = 0.0019, respectively) significantly relative to that of control irradiated cells. KM101 cells were protected by individual drugs (p = 0.0007, p = 0.0235, p = 0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53(+/+) (p = 0.0396 and p = 0.0071, respectively) and p53(-/-) cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53(-/-) cells. Drugs administered individually or as a mixtures of all three after TBI significantly increased mouse survival (p = 0.0234, 0.0009, 0.0052, and 0.0167, respectively). CONCLUSION Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.

Prospective evaluation of patient-reported quality-of-life outcomes following SBRT ± cetuximab for locally-recurrent, previously-irradiated head and neck cancer

PURPOSE Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for unresectable, previously-irradiated recurrent squamous cell carcinomas of the head and neck (rSCCHN). Here-in, we report the first prospective evaluation of patient-reported quality-of-life (PR-QoL) following re-irradiation with SBRT±cetuximab for rSCCHN. MATERIALS AND METHODS From November 2004 to May 2011, 150 patients with unresectable, rSCCHN in a previously-irradiated field receiving >40 Gy were treated with SBRT to 40-50 Gy in 5 fractions ± concurrent cetuximab. PR-QoL was prospectively acquired using the University of Washington Quality-of-Life Revised (UW-QoL-R). RESULTS Overall PR-QoL, health-related PR-QoL, and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing (p=0.025), speech (p=0.017), saliva (p=0.041), activity (p=0.032) and recreation (p=0.039). CONCLUSIONS Especially for patients surviving >1-year, improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL resulting from rSCCHN. These improvements in PR-QoL transcend all measured domains in a validated PR-QoL assessment tool independent of age, use of cetuximab, tumor volume, and interval since prior irradiation.

Stereotactic body radiation therapy for locally recurrent, previously irradiated nonsquamous cell cancers of the head and neck

Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for patients with recurrent, previously irradiated head and neck cancer; however, data are limited predominantly to squamous cell carcinomas. Herein, we report the efficacy of SBRT in recurrent, nonsquamous cell cancers of the head and neck (NSCHNs).

Stereotactic Radiosurgery to the Resection Cavity of Brain Metastases: A Retrospective Analysis and Literature Review

Purpose: The aim of this study was to analyze results of stereotactic radiosurgery (SRS) as adjuvant therapy for resected brain metastases. Methods: Medical records of patients treated at a single institution with SRS to the postoperative cavity of brain metastases were retrospectively reviewed. Patients who completed the prescribed SRS regimen following gross-total resection and had no previous whole brain radiotherapy were included in the study. Kaplan-Meier analyses were used to estimate local (LC) and intracranial control (IC), and overall survival (OS) rates. Results: Between April 2005 and July 2010, 77 patients (median age 63 years) with 89 metastases met the inclusion criteria. The median prescription dose was 18 Gy (12–27 Gy) delivered in 1–3 fractions for a median target volume of 7.6 cm3 (0.5–59 cm3). The 6-month, 1-year, and 2-year LC rates were 76.1, 76.1, and 74.3%, respectively. The 6-month, 1-year, and 2-year IC rates were 75.2, 54, and 43.6%, respectively. With a median follow-up of 13.8 months, the median OS was 14.5 months (1.9–51.4 months) after SRS. The overall 6-month, 1-year, and 2-year OS rates were 91, 62.5, and 43.6%, respectively. Complications included 2 patients with radiation necrosis. Conclusion: Adjuvant radiosurgery to the tumor cavity of resected brain metastases is well-tolerated and achieves LC in the majority of patients.

Fractionated stereotactic radiosurgery for large brain metastases.

Objectives:Large brain metastases (>3 cm) present a therapeutic dilemma, as the dose delivered by stereotactic radiosurgery (SRS) in a single fraction is limited by toxicity to adjacent tissues, resulting in suboptimal local control. This study assessed the efficacy and safety of fractionated SRS for the treatment of large brain metastases. Materials and Methods:We identified 36 patients with 37 brain metastases treated with fractionated SRS. The median SRS dose was 24 Gy (range, 12 to 27 Gy) in 2 to 5 fractions and the median treatment volume was 15.6 mL (range, 10 to 82.7 mL). Kaplan-Meier analysis was used to estimate local control and overall survival rates. Results:Of the 21 lesions with available radiographic follow-up, 6 lesions (29%) had a documented local failure, yielding an actuarial progression-free survival at 6 and 12 months of 73% and 63%, respectively. The actuarial 6-month and 1-year overall survival rates were 22% and 13%, respectively. No patients in this cohort experienced acute or late complications secondary to SRS. Conclusions:Fractionated SRS is feasible and safe in patients with large brain metastases. Local control rates appear to be improved when compared with that of single fraction SRS with a relative paucity of treatment-related toxicity.

Intraesophageal manganese superoxide dismutase-plasmid liposomes ameliorates novel total-body and thoracic radiation sensitivity of NOS1-/- mice.

Abstract The effect of deletion of the nitric oxide synthase 1 gene (NOS1−/−) on radiosensitivity was determined. In vitro, long-term cultures of bone marrow stromal cells derived from NOS1−/− were more radioresistant than cells from C57BL/6NHsd (wild-type), NOS2−/− or NOS3−/− mice. Mice from each strain received 20 Gy thoracic irradiation or 9.5 Gy total-body irradiation (TBI), and NOS1−/− mice were more sensitive to both. To determine the etiology of radiosensitivity, studies of histopathology, lower esophageal contractility, gastrointestinal transit, blood counts, electrolytes and inflammatory markers were performed; no significant differences between irradiated NOS1−/− and control mice were found. Video camera surveillance revealed the cause of death in NOS1−/− mice to be grand mal seizures; control mice died with fatigue and listlessness associated with low blood counts after TBI. NOS1−/− mice were not sensitive to brain-only irradiation. MnSOD-PL therapy delivered to the esophagus of wild-type and NOS1−/− mice resulted in equivalent biochemical levels in both; however, in NOS1−/− mice, MnSOD-PL significantly increased survival after both thoracic and total-body irradiation. The mechanism of radiosensitivity of NOS1−/− mice and its reversal by MnSOD-PL may be related to the developmental esophageal enteric neuronal innervation abnormalities described in these mice.

Examining tumor control and toxicity after stereotactic body radiotherapy in locally recurrent previously irradiated head and neck cancers: Implications of treatment duration and tumor volume

Stereotactic body radiotherapy (SBRT) has been studied in locally recurrent previously‐irradiated head and neck cancers; however, the optimum fractionation and patient selection continues to be defined.

A retrospective, deformable registration analysis of the impact of PET-CT planning on patterns of failure in stereotactic body radiation therapy for recurrent head and neck cancer

BackgroundStereotactic body radiation therapy (SBRT) has seen increasing use as a salvage strategy for selected patients with recurrent, previously-irradiated squamous cell carcinoma of the head and neck (rSCCHN). PET-CT may be advantageous for tumor delineation and evaluation of treatment failures in SBRT. We analyzed the patterns of failure following SBRT for rSCCHN and assessed the impact of PET-CT treatment planning on these patterns of failure.MethodsWe retrospectively reviewed 96 patients with rSCCHN treated with SBRT. Seven patients (7%) were treated after surgical resection of rSCCHN and 89 patients (93%) were treated definitively. PET-CT treatment planning was used for 45 patients whereas non-PET-CT planning was used for 51 patients. Categories of failure were assigned by comparing recurrences on post-treatment scans to the planning target volume (PTV) from planning scans using the deformable registration function of VelocityAI™. Failures were defined: In-field (>75% inside PTV), Overlap (20-75% inside PTV), Marginal (<20% inside PTV but closest edge within 1cm of PTV), or Regional/Distant (more than 1cm from PTV).ResultsMedian follow-up was 7.4 months (range, 2.6–52 months). Of 96 patients, 47 (49%) developed post-SBRT failure. Failure distribution was: In-field–12.3%, Overlap–24.6%, Marginal–36.8%, Regional/Distant–26.3%. There was a significant improvement in overall failure-free survival (log rank p = 0.037) and combined Overlap/Marginal failure-free survival (log rank p = 0.037) for those receiving PET-CT planning vs. non-PET-CT planning in the overall cohort (n = 96). Analysis of the definitive SBRT subgroup (n = 89) increased the significance of these findings (overall failure: p = 0.008, Overlap/Marginal failure: p = 0.009). There were no significant differences in age, gender, time from prior radiation, dose, use of cetuximab with SBRT, tumor differentiation, and tumor volume between the PET-CT and non-PET-CT groups.ConclusionsMost failures after SBRT treatment for rSCCHN were near misses, i.e. Overlap/Marginal failures (61.4%), suggesting an opportunity to improve outcomes with more sensitive imaging. PET-CT treatment planning showed the lowest rate of overall and near miss failures and is beneficial for SBRT treatment planning.

Stereotactic body radiotherapy for the treatment of presacral recurrences from rectal cancers

PURPOSE Management of recurrent presacral rectal cancer is often not amenable to curative surgery. The goal of this study is to evaluate the safety and efficacy of cyberknife stereotactic body radiotherapy (SBRT) in the management of presacral recurrences. MATERIALS AND METHODS Between April 2003 and October 2008, 14 patients with presacral tumors from rectal adenocarcinoma were SBRT treated. Eleven patients were treated with 36 Gy in 3 fractions and 3 patients were treated with single fraction of 12, 16 or 18 Gy. Tumor response was assessed using response evaluation and criteria in solid tumor (RECIST) criteria. Toxicities were assessed with common terminology criteria adverse events v 3.0. Pain control was assessed. RESULTS One patient (6.7%) received SBRT as boost therapy. All patients had prior radiotherapy [median 50.4 Gy (20 - 81 Gy)]. Median tumor volume was 52.5 cc (19 - 110 cc). At initial follow-up of a median 4.9 months (1 - 16.3 months), treatment responses were complete response (n=3) and stable disease (n=8). With a median follow-up of 16.5 months (6 - 69 months), the one- and two-year LC rates were 90.9 and 68.2%, respectively, and the one- and two-year OS rates were 90 and 78.8%, respectively. No factors were significantly predictive of LC and OS. There were no grade 3 or 4 toxicities. Fifty percent (n=7) of our patients experienced pain with recurrence before treatment and 4 (57.1%) of them reported no pain after completion of their SBRT. CONCLUSIONS Stereotactic body radiotherapy for presacral recurrence of rectal adenocarcinoma is an efficacious and well-tolerated treatment modality which allows for palliation of pain.

Abstract 492: Esophageal administration of manganese superoxide dismutase plasmid liposomes (MnSOD-PL) reverses thoracic irradiation sensitivity of nitric oxide synthase one homologous recombinant negative (NOS1 -/-) mouse

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC NOS1 -/- mice are more sensitive to 29 Gy thoracic or 9.5 Gy total body irradiation (TBI) than control C57BL/6NHsd, or NOS2 -/- or NOS3 -/- mice (p < 0.0001 and p = 0.0006). Histological examination of the esophagus, lungs, heart and intestine revealed no explanation of the rapid death of NOS1 -/- mice. Blood and bone marrow isolates six days after TBI (1 day before the NOS1 -/- mouse death) showed similar decrease in blood counts for all the mouse strains. NOS1 -/- mouse marrow irradiated to doses ranging from 0 to 8 Gy showed CFU-GM, BFU-E and CFU-GEMM radiosensitivity similar to that from control mice. There were also no differences in serum electrolytes, liver or renal function tests in irradiated NOS1 -/- compared to C57BL/6NHsd mice. RNA extracted from esophagus, stomach or intestine at day 0, 1 or 6 following 9.5 total body irradiation showed by qualitative RT-PCR analysis of TNF-σ, NF-κβ, and INF-γ similar cytokine expression between NOS1 -/- and C57BL/6NHsd mice. NOS1 -/- and C57BL/6NHsd mice were irradiated to 9.5 Gy total body or 20 Gy to the thoracic cavity and observed by video camera. NOS1 -/- mice had seizures before death following both TBI or thoracic irradiation, while no seizures were detected in dying C57BL/6NHsd mice. NOS1 -/- mice irradiated to 9.5 Gy to the brain (with the remainder of the body shielded) did not produce death from seizures. NOS1 -/- were intraesophageally administered MnSOD-PL (100 µg plasmid DNA) and irradiated to 20 Gy to the upper body 24 hr later. NOS1 -/- mice administered MnSOD-PL had normalized survival compared to control irradiated NOS1 -/- mice: 50% survival at 12 days for irradiated control NOS1 -/- mice compared to 128 days for MnSOD-PL treated NOS1 -/- mice (p = 0.0311). The data indicate that esophageal neuronal abnormalities which cause pyloric stenosis in the strain may be responsible for both the rapid thoracic irradiation sensitivity leading to seizure and its reversal by intraesophageal MnSOD-PL gene therapy. Supported by NIAID grant U19AI068021, and NIH grant T32AG21885 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 492.