Ulrich Martin Carl

Hyperbaric Oxygen and Radiotherapy

Background:Hyperbaric oxygen (HBO) therapy is the inhalation of 100% oxygen at a pressure of at least 1.5 atmospheres absolute (150 kPa). It uses oxygen as a drug by dissolving it in the plasma and delivering it to the tissues independent of hemoglobin. For a variety of organ systems, HBO is known to promote new vessel growth into areas with reduced oxygen tension due to poor vascularity, and therewith promotes wound healing and recovery of radiation-injured tissue. Furthermore, tumors may be sensitized to irradiation by raising intratumoral oxygen tensions.Method:A network of hyperbaric facilities exists in Europe, and a number of clinical studies are ongoing. The intergovernmental framework COST B14 action “Hyperbaric Oxygen Therapy” started in 1999. The main goal of the Working Group Oncology is preparation and actual implementation of prospective study protocols in the field of HBO and radiation oncology in Europe.Results:In this paper a short overview on HBO is given and the following randomized clinical studies are presented:a) reirradiation of recurrent squamous cell carcinoma of the head and neck after HBO sensitization;b) role of HBO in enhancing radiosensitivity on glioblastoma multiforme;c) osseointegration in irradiated patients; adjunctive HBO to prevent implant failures;d) the role of HBO in the treatment of late irradiation sequelae in the pelvic region.The two radiosensitization protocols (a, b) allow a time interval between HBO and subsequent irradiation of 10–20 min.Conclusion:Recruitment of centers and patients is being strongly encouraged, detailed information is given on www.oxynet.org.Hintergrund:Unter „hyperbarer Sauerstofftherapie“, auch „hyperbare Oxygenation“ (HBO) genannt, versteht man die Atmung von 100% Sauerstoff bei einem Druck von mindestens 1,5 ATA (absolute Atmosphären; 150 kPa). Bei der HBO wird das Medikament Sauerstoff durch erhöhten Umgebungsdruck physikalisch im Plasma gelöst und unabhängig vom Hämoglobin in das Gewebe transportiert. Die HBO unterstützt in schlecht durchbluteten bestrahlten Geweben mit verringerter Sauerstoffspannung die Gefäßneubildung und trägt zur Wundheilung und Erholung des bestrahlten Gewebes bei. Andererseits kann Sauerstoff unter hyperbaren Bedingungen—während oder kurz vor der Strahlentherapie verabreicht—durch Erhöhung der intratumoralen Sauerstoffspannung als Radiosensitizer eingesetzt werden.Methodik:In Europa existiert ein Netzwerk von Druckkammern, an denen klinische Studien laufen. Im Jahr 1999 wurde das europäische Projekt COST B14 „Hyperbare Sauerstofftherapie“ gestartet. Das Hauptziel der Arbeitsgruppe „Onkologie“ ist die Vorbereitung und Implementierung klinischer Studienprotokolle, die sich mit dem Thema „HBO und Strahlentherapie“ beschäftigen.Ergebnisse:Die vorliegende Arbeit gibt einen kurzen Überblick über die Grundlagen und Wirkweise der HBO und stellt folgende zur Rekrutierung offenen randomisierten klinischen Studien vor:a) erneute Bestrahlung rezidivierter Plattenepithelkarzinome im Kopf-Hals-Bereich nach HBO-Sensibilisierung;b) HBO zur Erhöhung der Strahlensensibilität des Glioblastoma multiforme;c) Osseointegration nach Bestrahlung im Hopf-Hals-Bereich—adjuvante HBO zur Verhinderung der Implantatabstoßung;d) HBO bei radiogenen Spätfolgen im Beckenbereich.Die zwei Protokolle zur Strahlensensibilisierung (a, b) erlauben einen Zeitabstand zwischen HBO und nachfolgender Bestrahlung von 10–20 min.Schlussfolgerung:Interessierte Zentren werden eingeladen, sich aktiv an den Studien zu beteiligen (Details s. www.oxynet.org).

HYPERBARIC OXYGEN THERAPY FOR LATE SEQUELAE IN WOMEN RECEIVING RADIATION AFTER BREAST-CONSERVING SURGERY

PURPOSE Persisting symptomatology after breast-conserving surgery and radiation is frequently reported. In most cases, symptoms in the breast resolve without further treatment. In some instances, however, pain, erythema, and edema can persist for years and can impact the patients quality of life. Hyperbaric oxygen therapy was shown to be effective as treatment for late radiation sequelae. The objective of this study was to assess the efficacy of hyperbaric oxygen therapy in symptomatic patients after breast cancer treatment. PATIENTS AND METHODS Forty-four patients with persisting symptomatology after breast-conservation therapy were prospectively observed. Thirty-two women received hyperbaric oxygen therapy in a multiplace chamber for a median of 25 sessions (range, 7-60). One hundred percent oxygen was delivered at 240 kPa for 90-min sessions, 5 times per week. Twelve control patients received no further treatment. Changes throughout the irradiated breast tissue were scored prior to and after hyperbaric oxygen therapy using modified LENT-SOMA criteria. RESULTS Hyperbaric oxygen therapy patients showed a significant reduction of pain, edema, and erythema scores as compared to untreated controls (p < 0.001). Fibrosis and telangiectasia, however, were not significantly affected by hyperbaric oxygen therapy. Seven of 32 women were free of symptoms after hyperbaric oxygen therapy, whereas all 12 patients in the control group had persisting complaints. CONCLUSIONS Hyperbaric oxygen therapy should be considered as a treatment option for patients with persisting symptomatology following breast-conserving therapy.

Enhancement of tumor radiosensitivity and reduced hypoxiadependent binding of a 2-nitroimidazole with normobaric oxygen and carbogen: A therapeutic comparison with skin and kidneys

To evaluate the therapeutic potential of normobaric oxygen and carbogen as hypoxic-cell sensitizers, both radiosensitization in a mouse mammary carcinoma, mouse skin and kidneys, and the reduction in the proportion of hypoxic tumor cells were quantified in mice breathing air, oxygen, or carbogen. Local tumor control, acute skin reactions, reduced renal clearance, and hematocrit were used as assays. X rays as 10 fractions in 5 days were given to skin and tumors and 10F/12 days to kidneys. In the tumor study, the pre-irradiation breathing time was varied from 2 to 20 min. Hypoxic cells, before and during a 10F/5 day schedule, were quantified using a 2-nitroimidazole with a theophylline side chain. Bioreductively reduced metabolites of this probe were localized in hypoxic cells that were then stained using an immunofluorescent technique and analyzed by flow cytometry. The fraction of cells with high fluorescence intensity was 19% in air, 9% in oxygen, and 3% in carbogen-breathing mice. For all three gases, hypoxia-dependent binding was similar in non-irradiated tumors and those treated with four or nine fractions. Both gases significantly enhanced tumor radiosensitivity (ER = 1.3 to 1.6) and carbogen was slightly more effective than oxygen. With carbogen, maximum sensitization was observed with a 5 min pre-irradiation breathing interval. With oxygen, pre-irradiation breathing times of 2-20 min gave similar sensitization. In skin an enhancement ratio of 1.2 was observed, whereas enhancement ratios for both renal endpoints were significantly lower (1.0 to 1.07). Relative to both tissues, there was therefore a substantial therapeutic gain by irradiating CaNT tumors under both gases, especially with carbogen.

Effects of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat rhabdomyosarcoma R1H

PURPOSE Hypoxic tumor cells are an important factor of radioresistance. Hyperbaric oxygen (HBO) and normobaric carbogen (95% oxygen, 5% carbon dioxide) increase the oxygen delivery to tumors. This study was performed to explore changes of tumor oxygenation during a course of fractionated irradiation and to determine the effectiveness of normobaric carbogen and HBO during the final phase of the radiation treatment. METHODS AND MATERIALS Experiments were performed on the rhabdomyosarcoma R1H growing on WAG/Rij rats. After 20 X-ray fractions of 2 Gy within 4 weeks, oxygen partial pressure (pO2) was measured using the Eppendorf oxygen electrode under ambient conditions, with normobaric carbogen or HBO at a pressure of 240 kPa. Following the 4-week radiation course, a top-up dose of 10-50 Gy was applied in 2-10 fractions of 5 Gy with or without hyperoxygenation. RESULTS HBO but not carbogen significantly increased the median pO2 in irradiated tumors. The radiation doses to control 50% of tumors were 38.0 Gy, 29.5 Gy, and 25.0 Gy for air, carbogen, and HBO, respectively. Both high oxygen content gas inspirations led to significantly improved tumor responses with oxygen enhancement ratios (OERs) of 1.3 for normobaric carbogen and 1.5 for HBO (air vs. carbogen: p = 0.044; air vs. HBO: p = 0.02; carbogen vs. HBO: p = 0.048). CONCLUSION Both normobaric carbogen and HBO significantly improved the radiation response of R1H tumors. HBO appeared to be more effective than normobaric carbogen, both with regard to tumor oxygenation and response to irradiation.

Prophylactic hyperbaric oxygen treatment and rat spinal cord re-irradiation.

Normal tissue injury may lead to severe, life threatening, late side effects after therapeutic use of irradiation. Neurological complications caused by radiation of the spinal cord are ascribed to progressive, irreversible damage to the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in irradiated tissue and has been proven to reduce late radiation injury in several normal tissues when applied during the latent period before complications become manifest. In the present study: (1). the prophylactic potential of HBO; (2). optimal timing of HBO therapy after spinal cord irradiation, i.e. during the latent period; and (3). effect of HBO on the re-irradiation tolerance of the spinal cord were investigated. The rat cervical spinal cord was locally X-ray irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10) included: irradiation alone and irradiation followed by 30 HBO treatments (100% oxygen at 240 kPa for 90 min) during latency, with HBO starting either immediately, 5, 10 or 15 weeks after the primary irradiation course. One year after the primary treatment, the same spinal cord volume was re-irradiated with 20 Gy single dose. During life span, the animals were observed on the incidence of myelitis and the duration of the latent period. The actuarial analysis revealed no significant difference in neurological complications free survival between the irradiation alone and the irradiation+HBO treatment groups. A tendency towards radiosensitization was found in the group in which the primary irradiation course was immediately followed by the HBO treatment course. The data show that HBO applied during the latent period of progressively developing irradiation damage to the spinal cord does not increase the re-irradiation tolerance of this tissue.

Effect of field size and length of plantar spur on treatment outcome in radiation therapy of plantar fasciitis: the bigger the better?

PURPOSE Radiation therapy is well established in the treatment of painful plantar fasciitis or heel spur. A retrospective analysis was conducted to investigate the effect of field definition on treatment outcome and to determine the impact of factors potentially involved. METHODS AND MATERIALS A review of treatment data of 250 patients (285 heels) with a mean follow-up time of 11 months showed that complete symptom remission occurred in 38%, partial remission in 32%, and no change in 19% (11% were lost to follow-up). Variables such as radiologic evidence of plantar spurs, their length, radiation dose, field size, age, sex, and onset of pain before administration of radiation therapy were investigated in univariate and multivariate regression analyses. RESULTS Treatment response depended upon age >53 years, length of heel spur ≤6.5 mm (or no radiologic evidence of a heel spur), and onset of pain <12 months before radiation therapy. Patients with these clinical prerequisites stood a 93% chance of clinical response. Without these prerequisites, only 49% showed any impact. No influence of field size on treatment outcome became evident. CONCLUSION Patients with short plantar heel spurs benefit from radiation therapy equally well as patients without any radiologic evidence. Moreover, smaller field sizes have the same positive effect as commonly used large field definitions covering the entire calcaneal bone. This leads to a recommendation of a considerable reduction of field size in future clinical practice.

Radiotherapy of the rhabdomyosarcoma R1H of the rat: postoperative radiotherapy.

Rhabdomyosarcoma R1H of the rat was excised aiming for a complete macroscopic local excision. Adjuvant radiotherapy was performed from the third postoperative day on. Former tumor sites were locally irradiated with 200 kVp X rays 4 times per week over a period of 6 weeks. Total doses of 0, 15, 30, 45 and 60 Gy were applied. The tumor volume was measured and the time to regrow to initial volume was assessed. The results were compared to the effect of a standard radiotherapy alone with 30 fractions of 2 Gy applied within 6 weeks. All tumors recurred despite of the irradiation treatment. At high total doses (greater than 30 Gy), adjuvant radiotherapy was found to improve short term tumor response considerably, whereas no positive effect was seen at low doses. After a total dose of 60 Gy and long time intervals after start of treatment, radiotherapy alone and a combination of surgery and radiotherapy seem to be isoeffective in our tumor system.

Emerging Role of Hypofractionated Radiotherapy with Simultaneous Integrated Boost in Modern Radiotherapy of Breast Cancer

Hypofractionated radiotherapy for breast cancer is becoming increasingly important. The scientific background of this development as well as the introduction of the simultaneous integrated boost to the primary tumor region in this context are discussed here.

Combined modality treatment of bone metastases: response of the rhabdomyosarcoma R1H of the rat to postoperative irradiation combined with local release of daunorubicin from acrylic cement

Reconstruction techniques for pathological fractures caused by bone metastases often include acrylic cement to stabilise defects. The aim of this study was to test in a rodent model, whether outcome could be improved by local chemotherapy from an anticancer drug added to the acrylic cement. Tumour excision 17 days after transplantation into the femur was followed by fractionated irradiation. Supplementation of acrylic cement with daunorubicin led to a considerable reduction of TCD37% from 72.9 Gy (62.2-82.8) to 29.3 Gy (21.8-37.5) (P = 0.0007). Local chemotherapy diffusing from bone cement combined with postoperative radiotherapy was highly effective in the experimental system studied.

Late radiation sequelae as a consequence of breast-conserving therapy with cobalt irradiation aggravated by various risk factors

This report deals with a 71-year-old female patient who developed cancer in her right breast 20 years ago, underwent breast-conserving surgery and received normofractionated radiotherapy with a 60Co unit. 19 years later, fibroids and calcified tissue appeared in her right mammary fold. Furthermore, a deep ulceration developed in this region during chemotherapy of bronchial carcinoma. Apart from being a Type 2 diabetic with arterial hypertension, she was also a habitual smoker. After extensive wound debridement and vacuum-assisted sealing therapy, the affected ribs were dissected and a latissimus dorsi flap was implanted. Our focus here is on the interaction of contributing risks for the development of late radiation sequelae, such as physical (especially unintended hot spots during 60Co irradiation) and pathophysiological factors (comorbidities and morbid affections). Fortunately, side-effects such as these are rare nowadays. As this case shows, however, they can be effectively handled by employing modern plastic surgery techniques.