Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways.

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.

Local hyperthermia combined with CTLA-4 blockade induces both local and abscopal effects in a murine breast cancer model.

PURPOSE: To evaluate the antitumor efficacy in local and distant tumors induced by local hyperthermia with CTLA-4 blockade. METHODS: A mouse breast cancer cell line was inoculated into both sides of the legs of mice. The mice were treated with three administrations of CTLA-4 blockade, a single application of local hyperthermia (42.5 °C for 20 min) to the tumor on one side of the leg, or the combination of the two. Tumor growth in locally heated tumors (HT tumors) and unheated distant tumors (UnHT tumors) and overall survival were evaluated. RESULTS: In the combination group, tumor volume significantly decreased for both HT and UnHT tumors compared with the tumors in the untreated and local hyperthermia monotherapy groups. Remarkable efficacy was only observed in the combination therapy group, in which 7 of 18 mice responded to HT and UnHT tumors, with significant prolonged overall survival. CONCLUSIONS: Combination therapy enhanced the antitumor response not only in HT tumors but also in UnHT tumors and prolonged overall survival.

Phase II study of docetaxel, cisplatin, and concurrent radiation followed by platinum-based adjuvant chemotherapy for technically unresectable, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Phase I study of weekly administration of low-dose docetaxel/cisplatin concurrent with conventionally fractionated radiotherapy for locally advanced head and neck squamous cell carcinoma suggested the recommended dose of docetaxel at 10 mg/m2 and cisplatin at 20 mg/m2. Phase II study of the concurrent chemoradiotherapy for technically resectable disease showed satisfactory results. METHODS: This phase II study was designed to address efficacy and safety when patients with technically unresectable disease were treated with concurrent chemoradiotherapy, followed by two cycles of moderate-dose platinum-based adjuvant chemotherapy: docetaxel, cisplatin, and fluorouracil (modified TPF). Modified TPF was replaced with docetaxel/carboplatin when renal impairment became evident. Surgical salvage was considered when residual or recurrent locoregional disease was technically resectable and free of distant metastasis. RESULTS: Of 33 enrolled patients, 31 were analyzable: 24 (78 %) and 18 (58 %) patients completed chemoradiotherapy and adjuvant chemotherapy, respectively; 15 (48 %) patients completed study treatment per protocol, and overall complete response rate was 45 %. Seven patients underwent surgical salvage, which was successful in 4 patients. At a median follow-up of 60.8 months for surviving patients, median progression-free survival and median overall survival were 16.2 and 39.9 months, respectively. Grade 3 or 4 toxicity included mucositis (77 %) and dysphagia (45 %) during the chemoradiotherapy period and neutropenia (100 %) and febrile neutropenia (35 %) during the adjuvant period. No patient died of toxicity. CONCLUSION: The tested regimen seems effective, although there is room for improvement in adjuvant chemotherapy because of the high toxicity and low compliance of modified TPF.

Comparison of acute and subacute genitourinary and gastrointestinal adverse events of radiotherapy for prostate cancer using intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, permanent implant brachytherapy and high-dose-rate brachytherapy.

AIMS AND BACKGROUND: To examine acute and subacute urinary and rectal toxicity in patients with localized prostate cancer monotherapeutically treated with the following four radiotherapeutic techniques: intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, low-dose-rate permanent implant brachytherapy using I-125 seeds, and high-dose-rate brachytherapy. METHODS: One hundred and fifty-six patients with localized prostate cancer were distributed as follows: 57 underwent intensity-modulated radiation therapy, 35 underwent three-dimensional conformal radiation therapy, 37 underwent I-125 implant, and 27 underwent high-dose-rate brachytherapy. The prescribed doses were 70-74 Gy/35-37 fractions, 70 Gy/35 fractions, 145 Gy, and 45.5 Gy/7 fraction/4 days for intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, I-125 implant, and high-dose-rate brachytherapy, respectively. Toxicities (≤6 months) were retrospectively evaluated using the Common Terminology Criteria for Adverse Events version 4.03. RESULTS: The frequency of grade 1 or 2 urinary toxicities using three-dimensional conformal radiation therapy (33/35, 94%) was significantly higher than that with high-dose-rate brachytherapy (18/27, 67%) or intensity-modulated radiation therapy (37/57, 65%) (P <0.05). The frequency of grade 1 or 2 urinary toxicities using I-125 implant was 31/37, 84%. The frequency of grade 1 or 2 gastrointestinal toxicities using three-dimensional conformal radiation therapy (17/35, 49%) was significantly higher than that using I-125 implant (4/37, 11%) or high-dose-rate brachytherapy (0/27, 0%) (P <0.05). Using intensity-modulated radiation therapy, the frequency of grade 1 or 2 gastrointestinal toxicities was 18/57 (32%), which was significantly higher than that using high-dose-rate brachytherapy (0/27, 0%) (P <0.05). Grade 3 or greater adverse events were not observed. CONCLUSIONS: Acute and subacute genitourinary toxicities were observed more frequently after three-dimensional conformal radiation therapy than after high-dose-rate brachytherapy or intensity-modulated radiation therapy. Acute and subacute gastrointestinal toxicities were seen more often after three-dimensional conformal radiation therapy than after brachytherapy (I-125 implant or high-dose-rate brachytherapy).

Potential roles of hyperbaric oxygenation in the treatments of brain tumors.

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain. HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas. The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

Old but new methods in radiation oncology: hyperbaric oxygen therapy.

The presence of hypoxic tumor cells is widely regarded as one of the main reasons behind the failure to control malignant tumors with radiotherapy treatments. Since hyperbaric oxygenation (HBO) improves the oxygen supply to the hypoxic tumor cells, HBO therapy has previously been used in combination with simultaneous radiotherapy to treat malignant tumors. In some clinical trials, significant improvements in local control and survival have been seen in cancers of the head and neck and the uterine cervix. However, the delivery of simultaneous HBO therapy and radiotherapy is both complex and time-consuming, with some trials reporting increased side effects. As a result, the regimen of HBO therapy in combination with simultaneous radiotherapy has yet to be used as a standard treatment for malignant tumors. In recent years, however, radiotherapy immediately after HBO therapy has been emerging as an attractive approach for overcoming hypoxia in cancer treatment. Several studies have reported that radiotherapy immediately after HBO therapy was safe and seemed to be effective in patients with high-grade gliomas. Also, this approach may protect normal tissues from radiation injury. To accurately estimate whether the delivery of radiotherapy immediately after HBO therapy can be beneficial in patients with high-grade gliomas and other cancers, further prospective studies are warranted.

Phase II trial of radiotherapy after hyperbaric oxygenation with multiagent chemotherapy (procarbazine, nimustine, and vincristine) for high-grade gliomas: long-term results.

PURPOSE: To analyze the long-term results of a Phase II trial of radiotherapy given immediately after hyperbaric oxygenation (HBO) with multiagent chemotherapy in adults with high-grade gliomas. METHODS AND MATERIALS: Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO, with the time interval from completion of decompression to start of irradiation being less than 15 minutes. Chemotherapy consisting of procarbazine, nimustine, and vincristine and was administered during and after radiotherapy. RESULTS: A total of 57 patients (39 patients with glioblastoma and 18 patients with Grade 3 gliomas) were enrolled from 2000 to 2006, and the median follow-up of 12 surviving patients was 62.0 months (range, 43.2-119.1 months). All 57 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. The median overall survival times in all 57 patients, 39 patients with glioblastoma and 18 patients with Grade 3 gliomas, were 20.2 months, 17.2 months, and 113.4 months, respectively. On multivariate analysis, histologic grade alone was a significant prognostic factor for overall survival (p < 0.001). During treatments, no patients had neutropenic fever or intracranial hemorrhage, and no serious nonhematologic or late toxicities were seen in any of the 57 patients. CONCLUSIONS: Radiotherapy delivered immediately after HBO with multiagent chemotherapy was safe, with virtually no late toxicities, and seemed to be effective in patients with high-grade gliomas.

Radiotherapy for uterine cervical cancer: results of the 1995-1997 patterns of care process survey in Japan.

OBJECTIVE: The aim of this study is to establish Japanese national practice patterns for uterine cervical cancer patients who received radiotherapy without surgery. METHODS: The Japanese Patterns of Care Study (JPCS) conducted a national survey of 73 institutions using two-stage cluster sampling, and collected specific information on 591 patients with uterine cervical cancer treated by radiotherapy without planned surgery between 1995 and 1997. RESULTS: The median age of the patients was 70 years. Karnofsky performance status (KPS) was >/=90 for 37%. Most patients (95%) had histology of squamous cell carcinoma. Ten percent were stage I, 29% stage II, 48% stage III and 13% stage IVA. Photon beams of 10-14 MV were the most used for external beam radiotherapy (EBRT). The beam energy utilized varied significantly by institution strata. Midline block was used in approximately 70% of institutions. Intracavitary brachytherapy (ICBT) was performed in 77%. Institution strata correlated significantly with the ICBT application. The majority of patients (89%) were treated with high-dose-rate (HDR) ICBT. The median single point A dose of HDR-ICBT was 600 cGy. The median summated point A dose from EBRT and HDR-ICBT was 5800 cGy (range: 1196-8600). The median overall treatment time including ICBT was 49 days. Twenty-four percent of the patients received chemotherapy. Concurrent chemoradiation was performed in 5%. CONCLUSIONS: The JPCS established the Japanese national practice patterns of care for uterine cervical cancer patients treated with radiotherapy without planned surgery between 1995 and 1997. This survey demonstrated that the institutional strata significantly affected several practice patterns.

Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II).

Procarbazine [N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide], a hydrazine derivative, which has been shown to have effective antineoplastic activity, induces cancer in some experimental animals and humans. To clarify a new mechanism for its carcinogenic effect, we examined DNA damage induced by procarbazine in the presence of metal ion, using 32P-5'-end-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. Procarbazine plus Cu(II) induced piperidine-labile and formamidopyrimidine-DNA glycosylase-sensitive lesions at the 5'-ACG-3' sequence, complementary to a hotspot of the p53 gene, and the 5'-TG-3' sequence. Catalase partially inhibited DNA damage, suggesting that not only H(2)O(2) but also other reactive species are involved. Procarbazine plus Cu(II) significantly increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, which was completely inhibited by calatase. Electron spin resonance spin-trapping experiments revealed that methyl radicals were generated from procarbazine and Cu(II). On the basis of these findings, it is considered that procarbazine causes DNA damage through non-enzymatic formation of the Cu(I)-hydroperoxo complex and methyl radicals. In conclusion, in addition to alkylation, oxidative DNA damage may play important roles in not only antitumor effects but also mutagenesis and carcinogenesis induced by procarbazine.

Prospective trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas.

Twenty-one patients with high-grade gliomas were enrolled in a prospective trial of radiotherapy after hyperbaric oxygenation (HBO). Radiotherapy was administered in daily 2-Gy fractions up to a total dose of 60 Gy, and each fraction was delivered immediately after HBO. The current study indicated that radiotherapy immediately after HBO with chemotherapy was feasible for high-grade gliomas.