Phase II Trial of Radiotherapy after Hyperbaric Oxygenation with Multiagent Chemotherapy (Procarbazine, Nimustine, and Vincristine) for High-Grade Gliomas: Long-Term Results

Int J Radiat Oncol Biol Phys. 2011 Mar 17

Department of Radiology, University of the Ryukyus, Okinawa.  2011.
Ogawa K, Ishiuchi S, Inoue O, Yoshii Y, Saito A, Watanabe T, Iraha S, Toita T, Kakinohana Y, Ariga T, Kasuya G, Murayama S.

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.



Hyperbaric Oxygen Treatment Improved Neurophysiologic Performance in Brain Tumor Patients After Neurosurgery and Radiotherapy: A Preliminary Report

Cancer. 2011 Aug 1; 117 (15): 3434-44

2011.  Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Schellart NA, Reits D, van der Kleij AJ, Stalpers LJ.

BACKGROUND: Cognitive performance often is impaired permanently in long-term brain tumor survivors after neurosurgery and radiotherapy. Hyperbaric oxygen treatment (HBOT) stimulates neovascularization of hypoperfused tissue and may result in improved functionality of damaged tissue. In this pilot study, clinical neurophysiologic tests were used to assess the effect of HBOT on brain performance.

METHODS: Ten long-term brain tumor survivors received HBOT for severe cognitive deficits after neurosurgery and radiosurgery. Patients were tested before HBOT and at 6 weeks and 4 months after HBOT. The tests comprised a quantitative electroencephalographic (EEG) examination, the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for memory performance, and 2 cognitive tests, the number connection test (NCT) and the continuous reaction time test (CRTT). Late event-related components (LERCs) of averaged evoked EEG responses to a visual odd-ball stimulus were analyzed from whole-head activity maps. For comparison, a control group of healthy individuals (no HBOT) also were investigated.

RESULTS: After HBOT, the amplitude of the LERC with the longest latency, P3b (involved in object interpretation) was improved significantly (P = .02). The amplitudes of the N200 (occipital, negative) and the intermediate P3a (centroparietal, positive), LERCs with shorter latencies, and of a small, positive, occipital visual component did not change. Neither latencies nor reaction times changed after HBOT. However, P3a and P3b (parietal, positive) latencies were longer in survivors than in healthy individuals. The NCT produced inconclusive results, but the IQCODE revealed an improvement. When outcomes of the NCT, CRTT, IQCODE, and P3b amplitudes were evaluated in common tests, HBOT appeared to provide substantial improvement (P<.006).

CONCLUSIONS: On the basis of the current results, the authors concluded tentatively that HBOT improves neurophysiologic performance in long-term brain tumor survivors.



Oxygenation Inhibits Ovarian Tumor Growth by Downregulating STAT3 and Cyclin-D1 Expressions

2010.  Cancer Biol Ther. 2010 Aug; 10(4):386-90. Epub 2010 Aug 21.
Selvendiran K, Kuppusamy ML, Ahmed S, Bratasz A, Meenakshisundaram G, Rivera BK, Khan M, Kuppusamy P.

Hypoxia, which is commonly observed in many solid tumors, is a major impediment to chemo- or radiation therapy. Hypoxia is also known to overexpress/activate signal transducer and activator of transcription 3 (STAT3) leading to tumor progression as well as drug resistance. We hypothesized that increased oxygenation of the hypoxic tumor may have an inhibitory effect on STAT3 activation and hence tumor-growth inhibition. Mice containing human ovarian cancer xenograft tumor were exposed to hyperbaric oxygen (HBO; 100% oxygen; 2 atm; 90-min duration) daily, for up to 21 days. Mice exposed to HBO showed a significant reduction in tumor volume, with no effect on body weight. STAT3 (Tyr 705) activation and cyclin-D1 protein/mRNA levels were significantly decreased up on HBO exposure. Interestingly, HBO exposure, in combination with weekly administration of cisplatin, also significantly reduced the tumor volume; however, this group of mice had drastically reduced body weight when compared to other groups. While conventional wisdom might suggest that increased oxygenation of tumors would promote tumor growth, the results of the present study indicated otherwise. Hyperoxia appears to inhibit STAT3 activation, which is a key step in the ovarian tumor progression. The study may have important implications for the treatment of ovarian cancer in the clinic.



Hyperbaric Oxygen as a Chemotherapy Adjuvant in the Treatment of Osteosarcoma

Oncol Rep. 2009 Nov;22(5):1045-50

Kawasoe Y, Yokouchi M, Ueno Y, Iwaya H, Yoshida H, Komiya S

Although hyperbaric oxygen has been shown to enhance the efficacy of radiotherapy and
chemotherapy for the treatment of several malignant tumors, the impact of hyperbaric oxygen on osteosarcoma has not yet been demonstrated. In this study, we investigated the efficacy of hyperbaric oxygen alone and in combination with an anti-cancer drug as an adjuvant to chemotherapy. In vitro, highly metastatic murine osteosarcoma cell lines were exposed to hyperbaric oxygen and cell viability was examined. Hyperbaric oxygen alone significantly suppressed cell proliferation, and hyperbaric oxygen plus carboplatin exhibited significant synergism in suppression of cell proliferation. In vivo, C3H mice were
subcutaneously inoculated with osteosarcoma cells and divided into four groups: control, hyperbaric oxygen, carboplatin, and carboplatin plus hyperbaric oxygen. After 5 weeks, increase in both tumor volume and number of lung metastases was significantly suppressed in the hyperbaric oxygen group. Concomitant hyperbaric oxygen clearly enhanced the chemotherapeutic effects of carboplatin on both tumor growth and lung metastasis in osteosarcoma-bearing mice. Moreover, mortality in the carboplatin plus hyperbaric oxygen group was significantly lower than in the other three groups. These findings suggest that hyperbaric oxygen plus carboplatin combination therapy could be an appropriate therapeutic regimen for the treatment of patients with osteosarcoma.



Lung Metastatic Load Limitation with Hyperbaric Oxygen

Undersea Hyperb Med. 2007 Mar-Apr;34(2):83-90

Haroon AT, Patel M, Al-Mehdi AB

Despite some theoretical concern about cancer-enhancing effects of hyperbaric oxygen (HBO2) therapy, it is frequently administered to cancer patients. We evaluated the growth of murine breast cancer cells in the lung after hyperbaric oxygen treatment in an experimental metastasis assay. Young nu/nu mice were injected intravenously with 3 x 10(3) 4T1-GFP tumor cells per g body weight followed by lung isolation, perfusion, and intact organ epifluorescence microscopy 1 to 37 days after injection. A group of animals (n=32) was exposed once daily for 5 days a week to 45 min of 2.8 ATA hyperbaric oxygen (HBO2) in a research animal HBO2 chamber. Control animals (n=31) were not subjected to HBO2 treatment, but received similar intravenous administration of 3 x 10(3) 4T 1-GFP tumor cells. Single tumor cells and colonies were counted in the subpleural vessels in areas of about 0.5 cm2 of lung surface. HBO2 treatment did not lead to an increase in the number of the large or small colonies in the lungs. Rather, a significant reduction in the number of the large colonies was observed at 1 and 16 to 21-day periods of measurements after hyperbaric treatment. However, most importantly, there was a significant decrease in large colony size in the HBO2 group during all periods of observation. The results indicate that HBO2 is not prometastatic for breast cancer cells; rather it restricts the growth of large tumor cell colonies.



Hyperbaric Oxygen Therapy for Malignancy: a Review

World J Surg. 2006 Dec;30(12):2112-31.

Daruwalla J, Christophi C.

One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center.  Hypoxia has a major impact on various aspects of tumor cell function and proliferation. Hypoxic tumor cells are relatively insensitive to conventional therapy owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome. One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress. This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.


Hyperbaric Oxygen: Does it Promote Growth or Recurrence of Malignancy?

Undersea Hyperb Med. 2003 Spring;30(1):1-18.

Feldmeier J, Carl U, Hartmann K, Sminia P.

It has been a concern that a therapeutic modality recommended as an adjunct to healing and administered to promote proliferation of fibroblasts, epithelial cells and blood vessels in a wound could also lead to proliferation of malignant cells and angiogenesis in a malignant tumor. The first reported concern that hyperbaric oxygen (HBO2) might have cancer growth enhancing effects appeared in a paper by Johnson and Lauchlan in 1966. In a series of patients treated with HBO2 radiosensitization, they reported a more frequent than expected incidence of metastases and an unusual pattern of metastases. The published literature from clinical reports, animal studies and cell culture studies are reviewed. Putative mechanisms whereby HBO2 could have carcinogenic effects are discussed. The processes of angiogenesis in wound healing and in cancer growth are compared and contrasted. In vitro, in vivo and clinical studies strongly suggest no more than a neutral effect of HBO2 on tumor growth. In fact some studies suggest a negative impact of HBO2 on malignant progression or formation. For angiogenesis, similarities in wound healing and cancer are striking but significant differences are found including the relative importance of angiogenic factors and the process of cessation of angiogenesis. Tumors that grow in hypoxic environments are more prone to

metastases and more lethal to the patient. They are also more likely to mutate toward resistant genotypes.  Discussion of postulated mechanisms of carcinogenesis including free radical and immunosuppressive effects points out why they are not likely to enhance or cause cancer growth or initiation.

In conclusion, the published literature on tumor angiogenesis mechanisms and other possible mechanisms of cancer causation or accelerated growth provides little basis for HBO2 to enhance malignant growth or metastases. A history of malignancy should not be considered a contraindication for HBO2 therapy.