Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas Clinical Studies British Journal of Cancer (2006) 95, 862 – 868 & 2006 Cancer Research UK All rights reserved 0007 – 0920/06 $30.00 www.bjcancer.com Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas ,1 2 3 1 2 1 4 1 1 K Ogawa , Y Yoshii , O Inoue , T Toita , A Saito , Y Kakinohana , G Adachi , S Iraha , W Tamaki , 2 2 1 K Sugimoto , A Hyodo and S Murayama 1 2 Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan; Department of Neurosurgery, University of the Ryukyus, Okinawa, Japan; Department of Hyperbaric Medicine, University of the Ryukyus, Okinawa, Japan and Department of Radiology, Naha City Hospital, Okinawa, Japan We conducted a phase II trial to evaluate the efficacy and toxicity of radiotherapy immediately after hyperbaric oxygenation (HBO) with chemotherapy in adults with high-grade gliomas. 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 period of time from completion of decompression to irradiation being less than 15 min. Chemotherapy consisted of procarbazine, nimustine (ACNU) and vincristine and was administered during and after radiotherapy. A total of 41 patients (31 patients with glioblastoma and 10 patients with grade 3 gliomas) were enrolled. All 41 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. Of 30 assessable patients, 17 (57%) had an objective response including four CR and 13 PR. The median time to progression and the median survival time in glioblastoma patients were 12.3 months and 17.3 months, respectively. On univariate analysis, histologic grade (P¼ 0.0001) and Karnofsky performance status (P¼ 0.036) had a significant impact on survival, and on multivariate analysis, histologic grade alone was a significant prognostic factor for survival (P¼ 0.001). Although grade 4 leukopenia and grade 4 thrombocytopenia occurred in 10 and 7% of all patients, respectively, these were transient with no patients developing neutropenic fever or intracranial haemorrhage. No serious nonhaematological or late toxicities were seen. These results indicated that radiotherapy delivered immediately after HBO with chemotherapy was safe with virtually no late toxicity in patients with high-grade gliomas. Further studies are required to strictly evaluate the effectiveness of radiotherapy after HBO for these tumours. British Journal of Cancer (2006) 95, 862–868. doi:10.1038/sj.bjc.6603342 www.bjcancer.com Published online 5 September 2006 & 2006 Cancer Research UK Keywords: radiation therapy; glioma; glioblastoma; hyperbaric oxygen; chemotherapy High-grade gliomas are relatively uncommon tumours, but cause a threefold when irradiation is performed under well-oxygenated disproportionate number of cancer-related deaths because of their conditions compared to anoxic conditions (Gray et al, 1953). high lethality (Fine, 1994; Laperriere et al, 2002). Radiotherapy is a Hyperbaric oxygenation (HBO) improves the oxygen supply to well established treatment for high-grade gliomas and plays an hypoxic tumour cells, and offers one approach to overcome important role in the overall treatment of such patients, although it tumour cell hypoxia such that this treatment has been used in results in only a modest improvement in patient survival (Walker combination with radiotherapy to treat malignant tumours (Jain, et al, 1978; Kristiansen et al, 1981). High-grade gliomas are 1990; Hartmann et al, 2001). In this context, HBO is using oxygen generally considered to be radioresistant since a high fraction of as a drug by dissolving it in the plasma and delivering it to the tumour cells are hypoxic and resistant to radiotherapy as a result tissues independent of haemoglobin. In some clinical trials and (Kayama et al, 1991; Rampling et al, 1994; Collingridge et al, 1999). recent meta-analyses, significant improvements in both local Several reports have indicated that the median pO for high-grade tumour control and patient survival have been seen in patients gliomas studied under anaesthesia was approximately 5–7 mmHg with cancers of the head and neck and uterine cervix (Henk et al, with a significant proportion of observed pO values being 1977; Lindegaard et al, 1996; Overgaard and Horsman, 1996). o2.5 mmHg (Kayama et al, 1991; Collingridge et al, 1999). Nevertheless, the delivery of simultaneous irradiation in combina- Molecular oxygen has long been recognised to be a powerful tion with HBO is complex and time-consuming with some trials modifier of cellular radiation sensitivity. The biological effect of noting increased side effects (Jain, 1990; Dische, 1991; Dowling ionising radiation has been reported to be increased approximately et al, 1992). As a result, the regimen of HBO in combination with simultaneous radiotherapy has not been used as a standard treatment for malignant tumours. *Correspondence: Dr K Ogawa; However, recent studies suggest that the oxygen tension within E-mail: kogawa@med.u-ryukyu.ac.jp tumours improves during HBO with the increase being maintained Received 12 June 2006; revised 17 July 2006; accepted 7 August 2006; for minutes following cessation of HBO (Kinoshita et al, 2000, published online 5 September 2006 Kunugita et al, 2001; Beppu et al, 2002). Many investigators have Radiotherapy after HBO for high-grade gliomas K Ogawa et al reported that malignant glioma cellular metabolism is anaerobic Following HBO, each patient was promptly moved to the treatment with the tumour exhibiting a lower oxygen consumption rate to room and underwent radiotherapy. The period of time from normal white matter (Ito et al, 1982; Tyler et al, 1987; Mineura completion of decompression to irradiation was consistently et al, 1994). The pO of normal brain tissue has been noted to o15 min for each treatment fraction. All patients were gowned decrease quickly after HBO treatment in animal experiments while in regulation nonflammable pyjamas and no patients received the pO in high-grade gliomas falls more slowly after decompres- sedation for each session. sion as a result of the lower rate of oxygen consumption and the reduced blood flow to the tumour (Jamieson and van den Brenk, Radiotherapy 1963). Therefore, in contrast to normal brain tissue, the pO within the tumour may remain elevated for a substantial period of time Radiotherapy began within 4 weeks of surgical resection. Each after decompression. The resultant increase in the oxygen tension irradiation treatment was administered daily after HBO and was within tumour cells would be predicted to sensitise high-grade delivered with megavoltage machines of photon energies X4 MeV. gliomas to the cytotoxic effects of irradiation (Gray et al, 1953; A head-holding device that was transparent to X-rays was used in Hall, 1994). This hypothesis suggests that radiotherapy immedi- order to ensure adequate immobilisation during radiotherapy and ately after HBO may increase the sensitivity of hypoxic tumour reproducibility. The treatment volume for both the initial volume cells to radiotherapy without increasing the injury to normal brain and the boost volume was based on the preoperative computed tissue. Recently, several studies have shown the feasibility of this tomography (CT) or magnetic resonance imaging (MRI) scans, treatment regimen with HBO applied prior to radiotherapy for and CT-guided treatment planning was required. The radiotherapy high-grade gliomas (Kohshi et al, 1999; Beppu et al, 2003; Ogawa schedule consisted of a total dose of 60 Gy prescribed at the et al, 2003). However, there has been little information regarding International Commission on Units and Measurements (ICRU) the clinical efficacy and safety of this treatment strategy. reference point and administered in 30 daily fractions over a In addition to radiotherapy, chemotherapy is often administered period of 6 weeks (5 fractions per week). For the first 40 Gy, the as a peri- or post-radiation treatment for patients with high-grade treatment volume consisted of the contrast-enhancing lesions and gliomas. Although the role of chemotherapy remains controversial, surrounding oedema demonstrated on the CT or MRI scans with a recent meta-analyses have demonstrated an increase in patient 3 cm margin. After 40 Gy, the treatment volume was reduced and survival for patients treated with both chemotherapy and radio- included the contrast-enhancing lesion (without oedema) apparent therapy as opposed to those treated with radiotherapy alone (Fine on the preoperative CT or MRI scans with a 2.5 cm margin. et al, 1993; Stewart, 2002). Moreover, a recent randomised trial also Anticonvulsive drugs, such as phenytoin or zonisamide, were demonstrated that the addition of concurrent chemotherapy administered orally to all patients during and after radiotherapy. (temozolomide) to radiotherapy resulted in a clinically meaningful Corticosteroids were used perioperatively, during the early phase and statistically significant survival benefit for patients with newly of radiotherapy and as necessary thereafter. The corticosteroid diagnosed glioblastoma (Stupp et al, 2005). Therefore, the dose had to remain stable for at least 1 week prior to entry into the standard of care has now shifted from radiotherapy alone to study. concurrent chemo/radiotherapy for these tumours. Based on this background, we conducted a phase II study to Chemotherapy evaluate the efficacy and toxicity of radiotherapy after HBO together with chemotherapy in adults with high-grade gliomas. Initial chemotherapy was administered concurrently with radio- therapy. One course of chemotherapy consisted of procarbazine 2 2 90 mg m orally on days 1–14, nimustine (ACNU) 80 mg m intravenously on day 1 and vincristine 0.5 mg m intravenously MATERIALS AND METHODS on days 1 and 8. Cycles of chemotherapy were repeated at approximately 3 monthly intervals after radiotherapy up to a Patient selection maximal total of four courses or until the tumour progressed or until the patient refused to receive further chemotherapy. All This study was performed according to the guidelines approved by patients received antiemetics with granisetron and metoclopra- the institutional review board of our institution, with written mide before ACNU administration. informed consent being obtained from all patients. Patients aged 18 years of age or older with a histologically confirmed supratentorial glioblastoma, anaplastic astrocytoma, anaplastic Patient evaluations oligoastrocytoma or anaplastic oligodendroglioma according to The extent of surgical resection was determined from the surgical the World Health Organization (WHO) criteria (2000) who had not records and postoperative CT or MRI scans by the neurosurgeons received prior treatment were eligible to take part in the study. All (YY and SA). Gross total resection represented a complete removal slides were reviewed by the same neuropathologist at our of the visible tumour, partial resection involved a 5–99% volume institution (SA). Other eligibility criteria included the following: reduction and a biopsy sample indicated a o5% resection. All Karnofsky performance status (KPS) score X50%, normal bone patients underwent a complete clinical history and physical marrow function (haemoglobin X10 g dl , white blood cell 1 3 examination, preoperative and postoperative CT and/or MRI (WBC) count X3000ml , platelet count X100 000 mm ), normal scans, complete blood count (CBC), differential white cell count, renal function (serum creatinine o1.2 mg dl ), normal liver platelet count, chemistry survey, neuropsychological testing and a function (AST o1.5 times normal, bilirubin o1.5 mg dl ) and no chest radiograph before entry into the study. CBC, differential evidence of cardiopulmonary disease or sinusitis. white cell count and platelet counts were obtained every week during treatment while a chemistry survey was performed every 2 weeks during treatment. Neurological examination and contrast- Hyperbaric oxygenation enhanced CT or MRI scans were obtained every 6–8 weeks during Hyperbaric oxygenation treatment was performed in a multiplace the first year. During the second year, patients in remission were hyperbaric chamber according to the following schedule: approxi- evaluated with neurological examinations and contrast-enhanced mately 18 min of compression with air, 30–60 min of 100% oxygen CT or MRI scans at 3-month intervals. Neuropsychological inhalation using an oxygen mask at 2.8. Atmospheres absolute and assessment was conducted before radiation therapy and every 6 approximately 18 min of decompression with oxygen inhalation. months thereafter or until the patient could no longer be tested. & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al Assessment of response and toxicity Table 1 Patient characteristics Assessment of response was based on postoperative CT or MRI Characteristic No. of patients scans that were obtained before and after radiotherapy and by Total number of patients 41 neurological examination as described by Macdonald et al (1990). In brief, complete response (CR) was defined as the complete Gender disappearance of all visible tumour, no steroid therapy and a Male 24 neurologically stable or improved condition. Partial response (PR) Female 17 was defined as a X50% reduction in the product of the perpendicular diameters of the contrast-enhancing tumour in Age (years) patients on a stable or decreasing dose of steroids who were Median 57 neurologically stable or improved. Progressive disease (PD) was Range 22 – 73 defined as a 425% increase in the product of the perpendicular KPS (%) diameters of the contrast-enhancing tumour or any new tumour Median 80 seen on CT or MRI scans or neurologically worse, and the steroid Range 50 – 100 dose being stable or increased. All other situations were defined as stable disease (SD). On the other hand, patients with no Histologic grade measurable contrast enhancing disease postoperatively were deemed to be non-assessable for response determination. All toxicities were recorded and graded according to the common toxicity criteria of the National Cancer Institute, version Tumour location 2.0. The dose of chemotherapy was decreased 33% for a nadir WBC Frontal 15 1 1 count 1000–1500ml or platelet count 20 000–50 000ml . For a Other 26 1 1 nadir WBC count o1000ml or platelet count o20 000ml , the Tumour size dose of all agents was decreased by 50%. Chemotherapy was p4cm 10 delayed if the WBC count was o3000ml or the platelet count 1 44cm 31 o100 000ml at the beginning of each cycle until marrow recovery had occurred. Radiotherapy was delayed if the WBC Mental status 1 1 count was o1000ml or the platelet count o20 000ml until Normal 35 marrow recovery had occurred. Chemotherapy was delayed if the Abnormal 6 AST level was elevated or if the direct bilirubin level was less than Radiation from symptom three times normal, until values fell to below twice the upper limit p3 months 22 of normal. Chemotherapy was then restarted at 50% of the initial 43 months 19 dose. Neurologic function Statistical analysis Work 21 Other 20 Overall survival and progression-free survival rates were calculated actuarially according to the Kaplan–Meier method (Kaplan and Histology Meier, 1958) and were measured from the day of surgical resection. GM 31 AA 4 Differences between groups were estimated using the log rank test AO 6 (Mantel, 1966). Multivariate analysis was performed using the Cox regression model (Cox, 1972). A probability level of 0.05 was Extent of resection chosen for statistical significance. Statistical analysis was per- Gross total 11 formed using the SPSS software package (version 11.0; SPSS Inc., Partial 24 Chicago, IL, USA). Biopsy 6 AA¼ anaplastic astrocytoma; AO¼ anaplastic oligodendroglioma; GM¼ glioblasto- ma; KPS¼ arnofsky performance status. RESULTS Patient characteristics Forty-one adults with newly diagnosed supratentorial high-grade Response, survival and prognostic factors gliomas were enrolled onto this trial between January 2000 and December 2003. The patient characteristics are detailed in Table 1. Eleven patients had undergone a gross total resection and had no All patients were followed through December 2005 or until they evaluable tumour at the initiation of protocol therapy. Therefore, died, and were evaluated for efficacy and toxicity of this treatment. 30 of 41 patients could be evaluated for response within 1 month The median follow-up time in the surviving patients was 57.1 after the completion of radiotherapy (glioblastoma: 22 patients, months (range 28.1–70.6 months). grade-3 gliomas: eight patients). Of these 30 patients, 17 (57%) had an objective response including four CR (13%) and 13 PR (43%). Twelve patients (40%) had SD and one patient experienced PD. Treatment delivered At the time of this analysis, 33 patients died (30 patients with All 41 patients completed a total dose of 60 Gy radiotherapy glioblastoma and three patients with grade 3 tumours) and two immediately after HBO with one course of concurrent chemo- patients with grade 3 tumours were alive with evidence of disease therapy. Thirty-three of 41 patients (80%) received further courses progression (follow-up, 36.9 and 28.1 months, respectively). The of chemotherapy after radiotherapy. The total courses of chemo- remaining six patients (one patient with glioblastoma and five therapy administered were four courses in 10 patients, three patients with grade 3 tumours) had no evidence of tumour courses in six patients, two courses in 17 patients, and one course recurrence or disease progression (median follow-up, 68.2 months; in eight patients. range, 34.6–70.6 months). The median time to progression and the British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK Radiotherapy after HBO for high-grade gliomas K Ogawa et al median survival time in glioblastoma patients were 12.3 months DISCUSSION and 17.3 months, respectively. The 2-year actuarial progression- In recent years, radiotherapy immediately after HBO has been free survival and the 2-year actuarial overall survival rates in emerging as an attractive approach for overcoming hypoxia in glioblastoma patients were 10 and 23%, respectively. cancer treatment (Al-Waili et al, 2005; Bennett et al, 2005; Mayer Table 2 indicates the results of univariate and multivariate et al, 2005). Several experimental studies have indicated that the analyses of potential prognostic factors on survival. On univariate elevation in oxygen tension in the tumour is preserved for some analysis, histologic grade (P¼ 0.0001) and Karnofsky performance time following HBO treatment, thereby allowing the administra- status (P¼ 0.036) had a significant impact on survival, and on tion of radiotherapy with an improved tumour/normal tissue multivariate analysis, histologic grade alone was a significant oxygenation ratio (Kinoshita et al, 2000; Kunugita et al, 2001; prognostic factor for survival (P¼ 0.001). Beppu et al, 2002). Using noninvasive MRI, Kinoshita et al (2000) demonstrated that the signal change related to the oxygen tension in SCCVII tumours decreased gradually but fell rapidly in muscle Toxicity after HBO. Beppu et al (2002) conducted a direct stereotactic During HBO treatment, seven of 41 (17%) patients suffered middle measurement of pO in glioblastoma tissue of patients under ear barotrauma requiring tympanostomy with tube placement. various conditions. The pO levels were significantly increased in Five of 41 (12%) patients had complaints of nausea requiring both peritumoral and intratumoral tissues after HBO with a high metoclopramide before each HBO treatment. No patients suffered pO level being maintained until 15 min after HBO in both regions. convulsions during or after HBO. Moreover, performing radiotherapy immediately after HBO had a The major acute toxic effects of chemotherapy (Xgrade 3) significant effect in experimental studies. Kunugita et al (2001) represent the most severe toxicity associated with the study examined the effect of radiotherapy after HBO in SCCVII tumours treatment for each patient (Table 3). The percentage of grade 3–4 (radiobiological hypoxic fraction: approximately 10%) subcuta- leukopenia, anaemia and thrombocytopenia were 44, 5 and 48%, neously transplanted into C3H/He mice using a growth delay respectively, with three patients (7%) requiring platelet transfu- assay. They noted a significant SCCVII tumour growth delay in the sions and one patient (2%) requiring blood cell transfusions. treated animals within 30 min after HBO with the tumour growth Although grade 4 leukopenia and grade 4 thrombocytopenia delay time being 1.61 times longer than that following radiotherapy occurred in 10 and 7% of all patients, respectively, these were alone. Moreover, oxygenation using HBO also enhanced the transient with no patients developing a neutropenic fever or sensitivity to chemotherapy, because the hypoxic conditions intracranial haemorrhage. Grade 3 nausea occurred in three prevalent in the tissue compromised the chemotherapeutic patients (7%). Three patients (7%) developed grade 3 liver potential of almost all agents (Rampling et al, 1994; Al-Waili dysfunction and were treated conservatively. No other grade 3 or et al, 2005). more severe nonhaematological toxicities were observed in the The current study suggested that radiotherapy administered remaining patients. No severe late toxicities, such as intracranial immediately after HBO with chemotherapy may be promising for haemorrhage and mental deterioration, were evident in the high-grade gliomas. Moreover, the administration of radiotherapy surviving patients at the time of analysis. after HBO enabled the application of conventional fractionation of All patients exhibited alopecia within the treatment field. radiotherapy and the combination of modern radiotherapy Regrowth of hair occurred over a time period of 4–8 months from the end of irradiation. Localised scalp erythema was seen in all patients although no patient experienced moist desquamation. Table 3 Major toxicities (n¼ 41) Grade 3 Grade 4 Comparison of survival according to RPA criteria We analysed our patients according to the recursive partitioning No. % No. % analysis (RPA) prognostic factors (Curren et al, 1993), which are Leukocytes 14 34 4 10 based on a large Radiation Therapy Oncology Group (RTOG) Haemoglobin 2 5 0 0 database of patients with high-grade gliomas (Scott et al, 1998). Platelets 17 41 3 7 Each RPA III, IV and V group in the current study had longer Nausea 3 7 0 0 median survival time and higher 2-year survival than those of Hepatic toxicity 3 7 0 0 RTOG 90-06 results reported from Scott et al (Table 4). Table 2 Univariate and multivariate analysis of various potential prognostic factors in patients with high-grade gliomas P-value Variable Univariate Multivariate RR (95% CI) Histologic grade (grade 3 vs grade 4) 0.0001 0.001 0.133 (0.038 – 0.460) KPS (o70 vs X70%) 0.037 0.336 0.698 (0.336 – 1.451) Neurologic function (vork vs other) 0.138 — — Tumour location (frontal vs others) 0.187 — — RT from symptom (p3 vs 43 M) 0.452 — — Age (o50 vs X50 years) 0.503 — — Mental status (normal vs abnormal) 0.528 — — Gender (female vs male) 0.670 — — Extent of resection (GT, PT vs BT) 0.622 — — Tumour size (p4 vs 44 cm) 0.909 — — BT¼ biopsy; CI¼ confidence intervals; GT¼ gross total resection; KPS¼ Karnofsky performance status; M¼ months; PT¼ partial resection; RR¼ relative risk. & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al Table 4 Comparison of survival according to recursive partitioning analysis criteria Current study RTOG 90-06 No. of patients Median survival (months) 2-year survival (%) No. of patients Median survival (months) 2-year survival (%) RPA class III 15 23.2 47 105 17.5 30 95% CI 12.0 – 34.4 21 – 73 15.6 – 20.2 21 – 39 IV 8 20.4 38 240 11.5 17 95% CI 15.1 – 25.7 4 – 72 10.8 – 12.7 11 – 22 V 15 12.6 20 150 7.4 8 95% CI 9.9 – 18.5 0 – 40 6.2 – 9.1 3 – 12 a b CI¼ confidence intervals; RPA¼ recursive partitioning analysis. Data from Scott et al, 1998. One patient of RPA class I, one patient with class II and one patient RPA class VI were not reported. techniques including patient fixation and three-dimensional barotrauma, all 41 patients were able to complete a total dose of conformal therapy. Several reports have also indicated the 60 Gy radiotherapy with conventional fractionation delivered antitumour activity of irradiation immediately after HBO in immediately after HBO. With regard to chemotherapy, all 41 conventionally fractionated irradiation (Kohshi et al, 1999; Beppu patients could receive one course of concurrent chemotherapy, et al, 2003). Kohshi et al (1999) applied radiotherapy after HBO to and 33 of 41 (80%) patients received further chemotherapies. high-grade glioma patients with residual disease. A total dose of Whereas the spectrum of the nonhaematological toxicity was 50–71 Gy in 20–30 fractions was administered, and 11 of 15 unremarkable, we observed frequent haematological toxicity with patients (73%) treated with radiotherapy immediately after HBO grade 3 and 4 leukopenia and thrombocytopenia (48% of all exhibited 450% tumour reduction. The median survivals in patients). One of the reasons may be the concurrent administra- patients with and without HBO were 24 and 12 months, tion of chemotherapy and radiotherapy in this protocol (Kleinberg respectively, and were significantly different (Po0.05). Beppu et al, 1999). However, the incidence of grade 4 haematological et al (2003) applied radiotherapy after HBO with ACNU and toxicity was less common and was transient. No patients exhibited interferon-beta for high-grade gliomas and 50% of glioblastoma neutropenic fever or intracranial haemorrhage and no serious late patients exhibited 450% tumour reduction. The current study toxicity was evident at the time of this analysis. Several authors also indicated antitumour activity of conventionally fractionated have also used a multidrug chemotherapy regimen containing radiotherapy delivered immediately after HBO with a total dose of ACNU, and they also found that grade 3–4 haematological toxicity 60 Gy in 30 fractions. In the 30 patients in whom it was possible to was frequent, but of short duration with very few treatment-related evaluate the therapeutic response (glioblastoma: 22 patients, grade deaths (Choi et al, 2002; Weller et al, 2003). These results indicated 3 gliomas: eight patients), 17 (57%) had an objective response that the administration of radiotherapy immediately after HBO including four CR (17%) and 13 PR (43%). The median survival with chemotherapy was safe and practical with virtually no late time has been reported to be 11–15 months in several phase toxicity for high-grade gliomas. studies for glioblastoma (Lassen et al, 1999; Choi et al, 2002; Wick Regarding prognostic factors, many studies have reported that et al, 2002; Grossman et al, 2003), and was 17.3 months in the age, KPS, tumour size, histologic grade and the extent of surgical current study. When using RPA analysis criteria, we found that the resection significantly affect the overall survival for high-grade median survival times and 2-year survival rates of RPA III, IV and gliomas (Laperriere et al, 2002; Buckner, 2003). However, the V classes in the current study compared favourably with patients current study found no significant differences in overall survival in the RTOG databases who were treated in a randomised trial in with respect to age, KPS and extent of surgical resection on the early 1990s (Table 4). multivariate analysis, and only histologic grade was a significant However, these favourable results demonstrated in the current prognostic factor for survival. The lack of any significant study should be interpreted with caution. First, the patient differences on survival according to age, KPS and extent of characteristics were generally favourable with 25% of patients surgical resection may be the result of the small number of patients undergoing gross total resection, and 25% of patients having grade in the current study. Another possible reason, however, may be the 3 gliomas. The median age of 57 was relatively young and the improved radiosensitivity by HBO to large residual tumours as median KPS of 80 indicated a group with good performance status. well as small residual tumours. A close association may exist Therefore, one might expect the outcome in this group to be better between KPS, tumour size, and the extent of surgical resection than the average described in the literature for glioblastoma. because the residual tumour size determined by the operation type Second, there is an important difference between the current study sometimes affects KPS (Beppu et al, 2003). Improvement in the and other previous reports (mostly using adjuvant chemotherapy) radiosensitivity of large residual tumours may contribute to an as patients have received concurrent chemotherapy. Comparisons increased response rate and overall survival for patients with low of the recent results with patients receiving concurrent temozo- KPS and/or large residual tumours. Beppu et al (2003) also found lomide in the Stupp trial (Stupp et al, 2005) indicate that the 2-year no significant differences in the response rates with regard to age, survival rates for glioblastoma are much the same: 23% in the KPS, and extent of surgical resection for high-grade gliomas current study and 26.5% in the Stupp trial. Therefore, it is treated with radiotherapy immediately after HBO. They concluded necessary to strictly evaluate the true effectiveness of radiotherapy that radiotherapy after HBO could be applied to patients with poor after HBO for these tumours in further studies. prognostic factors and resulted in tumour response identical to The current study also indicated that the administration of patients with good prognostic factors. Further studies are required radiotherapy immediately after HBO was a safe and practical to determine which high-grade glioma patients might effectively procedure. With the routine use of anticonvulsive drugs and benefit from radiotherapy delivered immediately after HBO for tympanostomy with tube placement in case of middle ear high-grade glioma patients. British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK Radiotherapy after HBO for high-grade gliomas K Ogawa et al In conclusion, performing radiotherapy immediately prospective randomised trials are also warranted to accurately after HBO with chemotherapy was safe with virtually no late determine whether the delivery of radiotherapy immediately toxicity for high-grade gliomas. This treatment strategy after HBO could be beneficial for patients with high-grade may be promising and merits further investigation. Further gliomas. REFERENCES Al-Waili NS, Butler GJ, Beale J, Hamilton RW, Lee BY, Lucas P (2005) Jamieson D, van den Brenk HAS (1963) Measurement of oxygen tensions in Hyperbaric oxygen and malignancies: a potential role in radiotherapy, cerebral tissues of rats exposed to high pressures of oxygen. J Appl chemotherapy, tumor surgery and phototherapy. Med Sci Monit 11: Physiol 18: 869–876 RA279–RA289 Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete Bennett M, Feldmeier J, Smee R, Milross C, Bennett M (2005) Hyperbaric observations. J Am Stat Assoc 53: 457–481 oxygenation for tumour sensitization to radiotherapy. Cochrane Kayama T, Yoshimoto T, Fujimoto S, Sakurai Y (1991) Intratumoral oxygen Database Syst Rev 19: CD005007 pressure in malignant brain tumor. J Neurosurg 74: 55–59 Beppu T, Kamada K, Nakamura R, Oikawa H, Takeda M, Fukuda T, Aradi Kinoshita Y, Kohshi K, Kunugita N, Tosaki T, Yokota A (2000) Preservation H, Ogasawara K, Ogawa A (2003) A phase II study of radiotherapy after of tumour oxygen after hyperbaric oxygenation monitored by magnetic hyperbaric oxygenation combined with interferon-beta and nimustine resonance imaging. Br J Cancer 82: 88–92 hydrochloride to treat supratentorial malignant gliomas. J Neurooncol 61: Kleinberg L, Grossman SA, Piantadosi S, Zeltzman M, Wharam M (1999) 161–170 The effects of sequential vs concurrent chemotherapy and radiotherapy Beppu T, Kamada K, Yoshida Y, Arai H, Ogasawara K, Ogawa A (2002) on survival and toxicity in patients with newly diagnosed high-grade Changes of oxygen pressure in glioblastoma tissue under various astrocytoma. Int J Radiat Oncol Biol Phys 44: 535–543 conditions. J Neurooncol 58: 47–52 Kohshi K, Kinoshita Y, Imada H, Kunugita N, Abe H, Terashima H, Tokui Buckner JC (2003) Factors influencing survival in high-grade gliomas. N, Uemura S (1999) Effects of radiotherapy after hyperbaric oxygenation Semin Oncol 30(6 Suppl 19): 10–14 on malignant gliomas. Br J Cancer 80: 236–241 Choi IS, Lee SH, Kim TY, Bang JS, Paek SH, Kim S, Kim IH, Heo DS, Bang Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, YJ, Kim DG, Jung HW, Kim NY (2002) Phase II study of chemotherapy Hatlevoll R, Lindgren M, Brun A, Lindgren S, Notter G, Andersen AP, with ACNU plus cisplatin followed by cranial irradiation in patients with Elgen K (1981) Combined modality therapy of operated astrocytomas newlydiagnosed glioblastoma multiforme. J Neurooncol 60: 171–176 grade III and IV. Confirmation of the value of postoperative irradiation Collingridge DR, Piepmeier JM, Rockwell S, Knisely JP (1999) Polaro- and lack of potentiation of bleomycin on survival time: a prospective graphic measurements of oxygen tension in human glioma and multicenter trial of the Scandinavian glioblastoma study group. Cancer surrounding peritumoral brain tissue. Radiother Oncol 53: 127–131 47: 649–652 Cox DR (1972) Regression models and life tables. J R Stat Soc 34: 187–220 Kunugita N, Kohshi K, Kinoshita Y, Katoh T, Abe H, Tosaki T, Kawamoto Curren Jr WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fishbach AJ, K, Norimura T (2001) Radiotherapy after hyperbaric oxygenation Chang CH, Rotman M, Asbell SO, Krisch RE (1993) Recursive improves radioresponse in experimental tumor models. Cancer Lett partitioning analysis of prognostic factors in three Radiation Therapy 164: 149–154 Oncology Group malignant glioma trials. J Natl Cancer Inst 85: 704–710 Laperriere N, Zuraw L, Cairncross G (2002) Radiotherapy for newly Dische S (1991) What have we learnt from hyperbaric oxygen? Radiother diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 20(Suppl 1): 71– 74 Oncol 64: 259– 273 Dowling S, Fischer JJ, Rockwell S (1992) Fluosol and hyperbaric oxygen as Lassen U, Kristjansen PE, Wagner A, Kosteljanetz M, Poulsen HS (1999) an adjunct to radiation therapy in the treatment of malignant gliomas: a Treatment of newly diagnosed glioblastoma multiforme with carmustine, pilot study. Biomater Artif Cells Immobilizat Biotechnol 20: 903– 905 cisplatin and etoposide followed by radiotherapy. A phase II study. Fine HA (1994) The basis for current treatment recommendations for J Neurooncol 43: 161– 166 malignant gliomas. J Neurooncol 20: 111 –120 Lindegaard JC, Overgaard J, Bentzen SM, Pedersen D (1996) Is there a Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP (1993) Meta-analysis radiobiologic basis for improving the treatment of advanced stage of radiation therapy with and without adjuvant chemotherapy for cervical cancer? J Natl Cancer Inst Monogr 21: 105–112 malignant gliomas in adults. Cancer 71: 2585–2597 Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. (1990) Response Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The criteria for phase II studies of supratentorial malignant glioma. J Clin concentration of oxygen dissolved in tissues at the time of irradiation Oncol 21: 3547 –3549 as a factor in radiotherapy. Br J Radiol 26: 638– 648 Mantel N (1966) Evaluation of survival data and two new rank order Grossman SA, O’Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, statistics arising in its consideration. Cancer Chemother Rep 50: 163–170 Gilbert M, Newton HB, Hellman R (2003) Phase III study comparing Mayer R, Hamilton-Farrell MR, van der Kleij AJ, Schmutz J, Granstrom G, three cycles of infusional carmustine and cisplatin followed by radiation Sicko Z, Melamed Y, Carl UM, Hartmann KA, Jansen EC, Ditri L, Sminia therapy with radiation therapy and concurrent carmustine in patients P (2005) Hyperbaric oxygen and radiotherapy. Strahlenther Onkol 181: with newly diagnosed supratentorial glioblastoma multiforme: Eastern 113–123 Cooperative Oncology Group Trial 2394. J Clin Oncol 21: 1485 –1491 Mineura K, Sasajima T, Kowada M, Ogawa T, Hatazawa J, Shishido F, Hall EJ (1994) Radiobiology for the Radiologist, 4th ed Lippincott: Uemura K (1994) Perfusion and metabolism in predicting the survival of Philadelphia, pp. 408–417 patients with cerebral gliomas. Cancer 73: 2386 –2394 Hartmann KA, van der Kleij AJ, Carl UM, Hulshof MC, Willers R, Sminia P Ogawa K, Yoshii Y, Inoue O, Toita T, Saito A, Kakinohana Y, Adachi G, (2001) Effects of hyperbaric oxygen and normobaric carbogenon the Ishikawa Y, Kin S, Murayama S (2003) Prospective trial of radiotherapy radiation response of the rat rhabdomyosarcoma R1 H. Int J Radiat after hyperbaric oxygenation with chemotherapy for high-grade gliomas. Oncol Biol Phys 51: 1037–1044 Radiother Oncol 67: 63– 67 Henk JM, Kunkler PB, Smith CW (1977) Radiotherapy and hyperbaric Overgaard J, Horsman MR (1996) Modification of hypoxia-induced oxygen in head and neck cancer. Final report of first controlled clinical radioresistance in tumors by the use of oxygen and sentitizers. Semin trial. Lancet 2: 101–103 Radiat Oncol 6: 10–21 Ito M, Lammertsma AA, Wise RJ, Bernardi S, Frackowiak RS, Heather JD, Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA, Workman P McKenzie CG, Thomas DG, Jones T (1982) Measurement of regional (1994) Direct measurement of pO distribution and bioreductive cerebral blood flow and oxygen utilization in patients with cerebral enzymes in human malignant brain tumors. Int J Radiat Oncol Biol tumors using O and positron emission tomography: analytical Phys 29: 427–431 techniques and preliminary results. Neuroradiology 23: 63–74 Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, Jain KK (1990) Textbook of Hyperbaric Medicine. Hogrefe & Huber Fischbach AJ, Curran Jr WJ (1998) Validation and predictive power of Publishers: Toronto, pp. 408–417 Radiation Therapy Oncology Group (RTOG) recursive partitioning & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al analysis classes for malignant glioma patients: a report using RTOG 90- Walker MD, Alexander Jr E, Hunt WE, MacCarty CS, Mahaley Jr MS, 06. Int J Radiat Oncol Biol Phys 40: 51–55 Mealey Jr J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systemic Strike TA (1978) Evaluation of BCNU and/or radiotherapy in the review and meta-analysis of individual patient data from 12 randomized treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg trials. Lancet 359: 1011 –1018 49: 333–343 Stupp R, Mason W, van der Bent MJ, Weller M, Fisher B, Weller M, Muller B, Koch R, Bamberg M, Krauseneck P (2003) Neuro- Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Oncology Working Group 01 trial of nimustine plus tenitoside vs Curshmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, nimustine plus cytarabine chemotherapy in addition to involved-field Cairncross G, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus radiotherapy in the first line treatment of malignant glioma. J Clin Oncol concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 21: 3276–3284 352: 987–996 Wick W, Hermisson M, Kortmann RD, Kuker WM, Duffner F, Dichgans J, Tyler JL, Diksic M, Villemure JG, Evans AC, Meyer E, Yamanoto YL, Bamberg M, Weller M (2002) Neoadjuvant gemcitabine/treosulfan Feindel W (1987) Metabolic and hemodynamic evaluation of gliomas chemotherapy for newly diagnosed glioblastoma: a phase II study. using positron emission tomography. J Nucl Med 33: 1123–1133 J Neurooncol 59: 151– 155 British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas

Loading next page...
 
/lp/springer-journals/phase-ii-trial-of-radiotherapy-after-hyperbaric-oxygenation-with-5XxKCyNN2Q

References (103)

Publisher
Springer Journals
Copyright
Copyright © 2006 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/sj.bjc.6603342
Publisher site
See Article on Publisher Site

Abstract

Clinical Studies British Journal of Cancer (2006) 95, 862 – 868 & 2006 Cancer Research UK All rights reserved 0007 – 0920/06 $30.00 www.bjcancer.com Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas ,1 2 3 1 2 1 4 1 1 K Ogawa , Y Yoshii , O Inoue , T Toita , A Saito , Y Kakinohana , G Adachi , S Iraha , W Tamaki , 2 2 1 K Sugimoto , A Hyodo and S Murayama 1 2 Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan; Department of Neurosurgery, University of the Ryukyus, Okinawa, Japan; Department of Hyperbaric Medicine, University of the Ryukyus, Okinawa, Japan and Department of Radiology, Naha City Hospital, Okinawa, Japan We conducted a phase II trial to evaluate the efficacy and toxicity of radiotherapy immediately after hyperbaric oxygenation (HBO) with chemotherapy in adults with high-grade gliomas. 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 period of time from completion of decompression to irradiation being less than 15 min. Chemotherapy consisted of procarbazine, nimustine (ACNU) and vincristine and was administered during and after radiotherapy. A total of 41 patients (31 patients with glioblastoma and 10 patients with grade 3 gliomas) were enrolled. All 41 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. Of 30 assessable patients, 17 (57%) had an objective response including four CR and 13 PR. The median time to progression and the median survival time in glioblastoma patients were 12.3 months and 17.3 months, respectively. On univariate analysis, histologic grade (P¼ 0.0001) and Karnofsky performance status (P¼ 0.036) had a significant impact on survival, and on multivariate analysis, histologic grade alone was a significant prognostic factor for survival (P¼ 0.001). Although grade 4 leukopenia and grade 4 thrombocytopenia occurred in 10 and 7% of all patients, respectively, these were transient with no patients developing neutropenic fever or intracranial haemorrhage. No serious nonhaematological or late toxicities were seen. These results indicated that radiotherapy delivered immediately after HBO with chemotherapy was safe with virtually no late toxicity in patients with high-grade gliomas. Further studies are required to strictly evaluate the effectiveness of radiotherapy after HBO for these tumours. British Journal of Cancer (2006) 95, 862–868. doi:10.1038/sj.bjc.6603342 www.bjcancer.com Published online 5 September 2006 & 2006 Cancer Research UK Keywords: radiation therapy; glioma; glioblastoma; hyperbaric oxygen; chemotherapy High-grade gliomas are relatively uncommon tumours, but cause a threefold when irradiation is performed under well-oxygenated disproportionate number of cancer-related deaths because of their conditions compared to anoxic conditions (Gray et al, 1953). high lethality (Fine, 1994; Laperriere et al, 2002). Radiotherapy is a Hyperbaric oxygenation (HBO) improves the oxygen supply to well established treatment for high-grade gliomas and plays an hypoxic tumour cells, and offers one approach to overcome important role in the overall treatment of such patients, although it tumour cell hypoxia such that this treatment has been used in results in only a modest improvement in patient survival (Walker combination with radiotherapy to treat malignant tumours (Jain, et al, 1978; Kristiansen et al, 1981). High-grade gliomas are 1990; Hartmann et al, 2001). In this context, HBO is using oxygen generally considered to be radioresistant since a high fraction of as a drug by dissolving it in the plasma and delivering it to the tumour cells are hypoxic and resistant to radiotherapy as a result tissues independent of haemoglobin. In some clinical trials and (Kayama et al, 1991; Rampling et al, 1994; Collingridge et al, 1999). recent meta-analyses, significant improvements in both local Several reports have indicated that the median pO for high-grade tumour control and patient survival have been seen in patients gliomas studied under anaesthesia was approximately 5–7 mmHg with cancers of the head and neck and uterine cervix (Henk et al, with a significant proportion of observed pO values being 1977; Lindegaard et al, 1996; Overgaard and Horsman, 1996). o2.5 mmHg (Kayama et al, 1991; Collingridge et al, 1999). Nevertheless, the delivery of simultaneous irradiation in combina- Molecular oxygen has long been recognised to be a powerful tion with HBO is complex and time-consuming with some trials modifier of cellular radiation sensitivity. The biological effect of noting increased side effects (Jain, 1990; Dische, 1991; Dowling ionising radiation has been reported to be increased approximately et al, 1992). As a result, the regimen of HBO in combination with simultaneous radiotherapy has not been used as a standard treatment for malignant tumours. *Correspondence: Dr K Ogawa; However, recent studies suggest that the oxygen tension within E-mail: kogawa@med.u-ryukyu.ac.jp tumours improves during HBO with the increase being maintained Received 12 June 2006; revised 17 July 2006; accepted 7 August 2006; for minutes following cessation of HBO (Kinoshita et al, 2000, published online 5 September 2006 Kunugita et al, 2001; Beppu et al, 2002). Many investigators have Radiotherapy after HBO for high-grade gliomas K Ogawa et al reported that malignant glioma cellular metabolism is anaerobic Following HBO, each patient was promptly moved to the treatment with the tumour exhibiting a lower oxygen consumption rate to room and underwent radiotherapy. The period of time from normal white matter (Ito et al, 1982; Tyler et al, 1987; Mineura completion of decompression to irradiation was consistently et al, 1994). The pO of normal brain tissue has been noted to o15 min for each treatment fraction. All patients were gowned decrease quickly after HBO treatment in animal experiments while in regulation nonflammable pyjamas and no patients received the pO in high-grade gliomas falls more slowly after decompres- sedation for each session. sion as a result of the lower rate of oxygen consumption and the reduced blood flow to the tumour (Jamieson and van den Brenk, Radiotherapy 1963). Therefore, in contrast to normal brain tissue, the pO within the tumour may remain elevated for a substantial period of time Radiotherapy began within 4 weeks of surgical resection. Each after decompression. The resultant increase in the oxygen tension irradiation treatment was administered daily after HBO and was within tumour cells would be predicted to sensitise high-grade delivered with megavoltage machines of photon energies X4 MeV. gliomas to the cytotoxic effects of irradiation (Gray et al, 1953; A head-holding device that was transparent to X-rays was used in Hall, 1994). This hypothesis suggests that radiotherapy immedi- order to ensure adequate immobilisation during radiotherapy and ately after HBO may increase the sensitivity of hypoxic tumour reproducibility. The treatment volume for both the initial volume cells to radiotherapy without increasing the injury to normal brain and the boost volume was based on the preoperative computed tissue. Recently, several studies have shown the feasibility of this tomography (CT) or magnetic resonance imaging (MRI) scans, treatment regimen with HBO applied prior to radiotherapy for and CT-guided treatment planning was required. The radiotherapy high-grade gliomas (Kohshi et al, 1999; Beppu et al, 2003; Ogawa schedule consisted of a total dose of 60 Gy prescribed at the et al, 2003). However, there has been little information regarding International Commission on Units and Measurements (ICRU) the clinical efficacy and safety of this treatment strategy. reference point and administered in 30 daily fractions over a In addition to radiotherapy, chemotherapy is often administered period of 6 weeks (5 fractions per week). For the first 40 Gy, the as a peri- or post-radiation treatment for patients with high-grade treatment volume consisted of the contrast-enhancing lesions and gliomas. Although the role of chemotherapy remains controversial, surrounding oedema demonstrated on the CT or MRI scans with a recent meta-analyses have demonstrated an increase in patient 3 cm margin. After 40 Gy, the treatment volume was reduced and survival for patients treated with both chemotherapy and radio- included the contrast-enhancing lesion (without oedema) apparent therapy as opposed to those treated with radiotherapy alone (Fine on the preoperative CT or MRI scans with a 2.5 cm margin. et al, 1993; Stewart, 2002). Moreover, a recent randomised trial also Anticonvulsive drugs, such as phenytoin or zonisamide, were demonstrated that the addition of concurrent chemotherapy administered orally to all patients during and after radiotherapy. (temozolomide) to radiotherapy resulted in a clinically meaningful Corticosteroids were used perioperatively, during the early phase and statistically significant survival benefit for patients with newly of radiotherapy and as necessary thereafter. The corticosteroid diagnosed glioblastoma (Stupp et al, 2005). Therefore, the dose had to remain stable for at least 1 week prior to entry into the standard of care has now shifted from radiotherapy alone to study. concurrent chemo/radiotherapy for these tumours. Based on this background, we conducted a phase II study to Chemotherapy evaluate the efficacy and toxicity of radiotherapy after HBO together with chemotherapy in adults with high-grade gliomas. Initial chemotherapy was administered concurrently with radio- therapy. One course of chemotherapy consisted of procarbazine 2 2 90 mg m orally on days 1–14, nimustine (ACNU) 80 mg m intravenously on day 1 and vincristine 0.5 mg m intravenously MATERIALS AND METHODS on days 1 and 8. Cycles of chemotherapy were repeated at approximately 3 monthly intervals after radiotherapy up to a Patient selection maximal total of four courses or until the tumour progressed or until the patient refused to receive further chemotherapy. All This study was performed according to the guidelines approved by patients received antiemetics with granisetron and metoclopra- the institutional review board of our institution, with written mide before ACNU administration. informed consent being obtained from all patients. Patients aged 18 years of age or older with a histologically confirmed supratentorial glioblastoma, anaplastic astrocytoma, anaplastic Patient evaluations oligoastrocytoma or anaplastic oligodendroglioma according to The extent of surgical resection was determined from the surgical the World Health Organization (WHO) criteria (2000) who had not records and postoperative CT or MRI scans by the neurosurgeons received prior treatment were eligible to take part in the study. All (YY and SA). Gross total resection represented a complete removal slides were reviewed by the same neuropathologist at our of the visible tumour, partial resection involved a 5–99% volume institution (SA). Other eligibility criteria included the following: reduction and a biopsy sample indicated a o5% resection. All Karnofsky performance status (KPS) score X50%, normal bone patients underwent a complete clinical history and physical marrow function (haemoglobin X10 g dl , white blood cell 1 3 examination, preoperative and postoperative CT and/or MRI (WBC) count X3000ml , platelet count X100 000 mm ), normal scans, complete blood count (CBC), differential white cell count, renal function (serum creatinine o1.2 mg dl ), normal liver platelet count, chemistry survey, neuropsychological testing and a function (AST o1.5 times normal, bilirubin o1.5 mg dl ) and no chest radiograph before entry into the study. CBC, differential evidence of cardiopulmonary disease or sinusitis. white cell count and platelet counts were obtained every week during treatment while a chemistry survey was performed every 2 weeks during treatment. Neurological examination and contrast- Hyperbaric oxygenation enhanced CT or MRI scans were obtained every 6–8 weeks during Hyperbaric oxygenation treatment was performed in a multiplace the first year. During the second year, patients in remission were hyperbaric chamber according to the following schedule: approxi- evaluated with neurological examinations and contrast-enhanced mately 18 min of compression with air, 30–60 min of 100% oxygen CT or MRI scans at 3-month intervals. Neuropsychological inhalation using an oxygen mask at 2.8. Atmospheres absolute and assessment was conducted before radiation therapy and every 6 approximately 18 min of decompression with oxygen inhalation. months thereafter or until the patient could no longer be tested. & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al Assessment of response and toxicity Table 1 Patient characteristics Assessment of response was based on postoperative CT or MRI Characteristic No. of patients scans that were obtained before and after radiotherapy and by Total number of patients 41 neurological examination as described by Macdonald et al (1990). In brief, complete response (CR) was defined as the complete Gender disappearance of all visible tumour, no steroid therapy and a Male 24 neurologically stable or improved condition. Partial response (PR) Female 17 was defined as a X50% reduction in the product of the perpendicular diameters of the contrast-enhancing tumour in Age (years) patients on a stable or decreasing dose of steroids who were Median 57 neurologically stable or improved. Progressive disease (PD) was Range 22 – 73 defined as a 425% increase in the product of the perpendicular KPS (%) diameters of the contrast-enhancing tumour or any new tumour Median 80 seen on CT or MRI scans or neurologically worse, and the steroid Range 50 – 100 dose being stable or increased. All other situations were defined as stable disease (SD). On the other hand, patients with no Histologic grade measurable contrast enhancing disease postoperatively were deemed to be non-assessable for response determination. All toxicities were recorded and graded according to the common toxicity criteria of the National Cancer Institute, version Tumour location 2.0. The dose of chemotherapy was decreased 33% for a nadir WBC Frontal 15 1 1 count 1000–1500ml or platelet count 20 000–50 000ml . For a Other 26 1 1 nadir WBC count o1000ml or platelet count o20 000ml , the Tumour size dose of all agents was decreased by 50%. Chemotherapy was p4cm 10 delayed if the WBC count was o3000ml or the platelet count 1 44cm 31 o100 000ml at the beginning of each cycle until marrow recovery had occurred. Radiotherapy was delayed if the WBC Mental status 1 1 count was o1000ml or the platelet count o20 000ml until Normal 35 marrow recovery had occurred. Chemotherapy was delayed if the Abnormal 6 AST level was elevated or if the direct bilirubin level was less than Radiation from symptom three times normal, until values fell to below twice the upper limit p3 months 22 of normal. Chemotherapy was then restarted at 50% of the initial 43 months 19 dose. Neurologic function Statistical analysis Work 21 Other 20 Overall survival and progression-free survival rates were calculated actuarially according to the Kaplan–Meier method (Kaplan and Histology Meier, 1958) and were measured from the day of surgical resection. GM 31 AA 4 Differences between groups were estimated using the log rank test AO 6 (Mantel, 1966). Multivariate analysis was performed using the Cox regression model (Cox, 1972). A probability level of 0.05 was Extent of resection chosen for statistical significance. Statistical analysis was per- Gross total 11 formed using the SPSS software package (version 11.0; SPSS Inc., Partial 24 Chicago, IL, USA). Biopsy 6 AA¼ anaplastic astrocytoma; AO¼ anaplastic oligodendroglioma; GM¼ glioblasto- ma; KPS¼ arnofsky performance status. RESULTS Patient characteristics Forty-one adults with newly diagnosed supratentorial high-grade Response, survival and prognostic factors gliomas were enrolled onto this trial between January 2000 and December 2003. The patient characteristics are detailed in Table 1. Eleven patients had undergone a gross total resection and had no All patients were followed through December 2005 or until they evaluable tumour at the initiation of protocol therapy. Therefore, died, and were evaluated for efficacy and toxicity of this treatment. 30 of 41 patients could be evaluated for response within 1 month The median follow-up time in the surviving patients was 57.1 after the completion of radiotherapy (glioblastoma: 22 patients, months (range 28.1–70.6 months). grade-3 gliomas: eight patients). Of these 30 patients, 17 (57%) had an objective response including four CR (13%) and 13 PR (43%). Twelve patients (40%) had SD and one patient experienced PD. Treatment delivered At the time of this analysis, 33 patients died (30 patients with All 41 patients completed a total dose of 60 Gy radiotherapy glioblastoma and three patients with grade 3 tumours) and two immediately after HBO with one course of concurrent chemo- patients with grade 3 tumours were alive with evidence of disease therapy. Thirty-three of 41 patients (80%) received further courses progression (follow-up, 36.9 and 28.1 months, respectively). The of chemotherapy after radiotherapy. The total courses of chemo- remaining six patients (one patient with glioblastoma and five therapy administered were four courses in 10 patients, three patients with grade 3 tumours) had no evidence of tumour courses in six patients, two courses in 17 patients, and one course recurrence or disease progression (median follow-up, 68.2 months; in eight patients. range, 34.6–70.6 months). The median time to progression and the British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK Radiotherapy after HBO for high-grade gliomas K Ogawa et al median survival time in glioblastoma patients were 12.3 months DISCUSSION and 17.3 months, respectively. The 2-year actuarial progression- In recent years, radiotherapy immediately after HBO has been free survival and the 2-year actuarial overall survival rates in emerging as an attractive approach for overcoming hypoxia in glioblastoma patients were 10 and 23%, respectively. cancer treatment (Al-Waili et al, 2005; Bennett et al, 2005; Mayer Table 2 indicates the results of univariate and multivariate et al, 2005). Several experimental studies have indicated that the analyses of potential prognostic factors on survival. On univariate elevation in oxygen tension in the tumour is preserved for some analysis, histologic grade (P¼ 0.0001) and Karnofsky performance time following HBO treatment, thereby allowing the administra- status (P¼ 0.036) had a significant impact on survival, and on tion of radiotherapy with an improved tumour/normal tissue multivariate analysis, histologic grade alone was a significant oxygenation ratio (Kinoshita et al, 2000; Kunugita et al, 2001; prognostic factor for survival (P¼ 0.001). Beppu et al, 2002). Using noninvasive MRI, Kinoshita et al (2000) demonstrated that the signal change related to the oxygen tension in SCCVII tumours decreased gradually but fell rapidly in muscle Toxicity after HBO. Beppu et al (2002) conducted a direct stereotactic During HBO treatment, seven of 41 (17%) patients suffered middle measurement of pO in glioblastoma tissue of patients under ear barotrauma requiring tympanostomy with tube placement. various conditions. The pO levels were significantly increased in Five of 41 (12%) patients had complaints of nausea requiring both peritumoral and intratumoral tissues after HBO with a high metoclopramide before each HBO treatment. No patients suffered pO level being maintained until 15 min after HBO in both regions. convulsions during or after HBO. Moreover, performing radiotherapy immediately after HBO had a The major acute toxic effects of chemotherapy (Xgrade 3) significant effect in experimental studies. Kunugita et al (2001) represent the most severe toxicity associated with the study examined the effect of radiotherapy after HBO in SCCVII tumours treatment for each patient (Table 3). The percentage of grade 3–4 (radiobiological hypoxic fraction: approximately 10%) subcuta- leukopenia, anaemia and thrombocytopenia were 44, 5 and 48%, neously transplanted into C3H/He mice using a growth delay respectively, with three patients (7%) requiring platelet transfu- assay. They noted a significant SCCVII tumour growth delay in the sions and one patient (2%) requiring blood cell transfusions. treated animals within 30 min after HBO with the tumour growth Although grade 4 leukopenia and grade 4 thrombocytopenia delay time being 1.61 times longer than that following radiotherapy occurred in 10 and 7% of all patients, respectively, these were alone. Moreover, oxygenation using HBO also enhanced the transient with no patients developing a neutropenic fever or sensitivity to chemotherapy, because the hypoxic conditions intracranial haemorrhage. Grade 3 nausea occurred in three prevalent in the tissue compromised the chemotherapeutic patients (7%). Three patients (7%) developed grade 3 liver potential of almost all agents (Rampling et al, 1994; Al-Waili dysfunction and were treated conservatively. No other grade 3 or et al, 2005). more severe nonhaematological toxicities were observed in the The current study suggested that radiotherapy administered remaining patients. No severe late toxicities, such as intracranial immediately after HBO with chemotherapy may be promising for haemorrhage and mental deterioration, were evident in the high-grade gliomas. Moreover, the administration of radiotherapy surviving patients at the time of analysis. after HBO enabled the application of conventional fractionation of All patients exhibited alopecia within the treatment field. radiotherapy and the combination of modern radiotherapy Regrowth of hair occurred over a time period of 4–8 months from the end of irradiation. Localised scalp erythema was seen in all patients although no patient experienced moist desquamation. Table 3 Major toxicities (n¼ 41) Grade 3 Grade 4 Comparison of survival according to RPA criteria We analysed our patients according to the recursive partitioning No. % No. % analysis (RPA) prognostic factors (Curren et al, 1993), which are Leukocytes 14 34 4 10 based on a large Radiation Therapy Oncology Group (RTOG) Haemoglobin 2 5 0 0 database of patients with high-grade gliomas (Scott et al, 1998). Platelets 17 41 3 7 Each RPA III, IV and V group in the current study had longer Nausea 3 7 0 0 median survival time and higher 2-year survival than those of Hepatic toxicity 3 7 0 0 RTOG 90-06 results reported from Scott et al (Table 4). Table 2 Univariate and multivariate analysis of various potential prognostic factors in patients with high-grade gliomas P-value Variable Univariate Multivariate RR (95% CI) Histologic grade (grade 3 vs grade 4) 0.0001 0.001 0.133 (0.038 – 0.460) KPS (o70 vs X70%) 0.037 0.336 0.698 (0.336 – 1.451) Neurologic function (vork vs other) 0.138 — — Tumour location (frontal vs others) 0.187 — — RT from symptom (p3 vs 43 M) 0.452 — — Age (o50 vs X50 years) 0.503 — — Mental status (normal vs abnormal) 0.528 — — Gender (female vs male) 0.670 — — Extent of resection (GT, PT vs BT) 0.622 — — Tumour size (p4 vs 44 cm) 0.909 — — BT¼ biopsy; CI¼ confidence intervals; GT¼ gross total resection; KPS¼ Karnofsky performance status; M¼ months; PT¼ partial resection; RR¼ relative risk. & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al Table 4 Comparison of survival according to recursive partitioning analysis criteria Current study RTOG 90-06 No. of patients Median survival (months) 2-year survival (%) No. of patients Median survival (months) 2-year survival (%) RPA class III 15 23.2 47 105 17.5 30 95% CI 12.0 – 34.4 21 – 73 15.6 – 20.2 21 – 39 IV 8 20.4 38 240 11.5 17 95% CI 15.1 – 25.7 4 – 72 10.8 – 12.7 11 – 22 V 15 12.6 20 150 7.4 8 95% CI 9.9 – 18.5 0 – 40 6.2 – 9.1 3 – 12 a b CI¼ confidence intervals; RPA¼ recursive partitioning analysis. Data from Scott et al, 1998. One patient of RPA class I, one patient with class II and one patient RPA class VI were not reported. techniques including patient fixation and three-dimensional barotrauma, all 41 patients were able to complete a total dose of conformal therapy. Several reports have also indicated the 60 Gy radiotherapy with conventional fractionation delivered antitumour activity of irradiation immediately after HBO in immediately after HBO. With regard to chemotherapy, all 41 conventionally fractionated irradiation (Kohshi et al, 1999; Beppu patients could receive one course of concurrent chemotherapy, et al, 2003). Kohshi et al (1999) applied radiotherapy after HBO to and 33 of 41 (80%) patients received further chemotherapies. high-grade glioma patients with residual disease. A total dose of Whereas the spectrum of the nonhaematological toxicity was 50–71 Gy in 20–30 fractions was administered, and 11 of 15 unremarkable, we observed frequent haematological toxicity with patients (73%) treated with radiotherapy immediately after HBO grade 3 and 4 leukopenia and thrombocytopenia (48% of all exhibited 450% tumour reduction. The median survivals in patients). One of the reasons may be the concurrent administra- patients with and without HBO were 24 and 12 months, tion of chemotherapy and radiotherapy in this protocol (Kleinberg respectively, and were significantly different (Po0.05). Beppu et al, 1999). However, the incidence of grade 4 haematological et al (2003) applied radiotherapy after HBO with ACNU and toxicity was less common and was transient. No patients exhibited interferon-beta for high-grade gliomas and 50% of glioblastoma neutropenic fever or intracranial haemorrhage and no serious late patients exhibited 450% tumour reduction. The current study toxicity was evident at the time of this analysis. Several authors also indicated antitumour activity of conventionally fractionated have also used a multidrug chemotherapy regimen containing radiotherapy delivered immediately after HBO with a total dose of ACNU, and they also found that grade 3–4 haematological toxicity 60 Gy in 30 fractions. In the 30 patients in whom it was possible to was frequent, but of short duration with very few treatment-related evaluate the therapeutic response (glioblastoma: 22 patients, grade deaths (Choi et al, 2002; Weller et al, 2003). These results indicated 3 gliomas: eight patients), 17 (57%) had an objective response that the administration of radiotherapy immediately after HBO including four CR (17%) and 13 PR (43%). The median survival with chemotherapy was safe and practical with virtually no late time has been reported to be 11–15 months in several phase toxicity for high-grade gliomas. studies for glioblastoma (Lassen et al, 1999; Choi et al, 2002; Wick Regarding prognostic factors, many studies have reported that et al, 2002; Grossman et al, 2003), and was 17.3 months in the age, KPS, tumour size, histologic grade and the extent of surgical current study. When using RPA analysis criteria, we found that the resection significantly affect the overall survival for high-grade median survival times and 2-year survival rates of RPA III, IV and gliomas (Laperriere et al, 2002; Buckner, 2003). However, the V classes in the current study compared favourably with patients current study found no significant differences in overall survival in the RTOG databases who were treated in a randomised trial in with respect to age, KPS and extent of surgical resection on the early 1990s (Table 4). multivariate analysis, and only histologic grade was a significant However, these favourable results demonstrated in the current prognostic factor for survival. The lack of any significant study should be interpreted with caution. First, the patient differences on survival according to age, KPS and extent of characteristics were generally favourable with 25% of patients surgical resection may be the result of the small number of patients undergoing gross total resection, and 25% of patients having grade in the current study. Another possible reason, however, may be the 3 gliomas. The median age of 57 was relatively young and the improved radiosensitivity by HBO to large residual tumours as median KPS of 80 indicated a group with good performance status. well as small residual tumours. A close association may exist Therefore, one might expect the outcome in this group to be better between KPS, tumour size, and the extent of surgical resection than the average described in the literature for glioblastoma. because the residual tumour size determined by the operation type Second, there is an important difference between the current study sometimes affects KPS (Beppu et al, 2003). Improvement in the and other previous reports (mostly using adjuvant chemotherapy) radiosensitivity of large residual tumours may contribute to an as patients have received concurrent chemotherapy. Comparisons increased response rate and overall survival for patients with low of the recent results with patients receiving concurrent temozo- KPS and/or large residual tumours. Beppu et al (2003) also found lomide in the Stupp trial (Stupp et al, 2005) indicate that the 2-year no significant differences in the response rates with regard to age, survival rates for glioblastoma are much the same: 23% in the KPS, and extent of surgical resection for high-grade gliomas current study and 26.5% in the Stupp trial. Therefore, it is treated with radiotherapy immediately after HBO. They concluded necessary to strictly evaluate the true effectiveness of radiotherapy that radiotherapy after HBO could be applied to patients with poor after HBO for these tumours in further studies. prognostic factors and resulted in tumour response identical to The current study also indicated that the administration of patients with good prognostic factors. Further studies are required radiotherapy immediately after HBO was a safe and practical to determine which high-grade glioma patients might effectively procedure. With the routine use of anticonvulsive drugs and benefit from radiotherapy delivered immediately after HBO for tympanostomy with tube placement in case of middle ear high-grade glioma patients. British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK Radiotherapy after HBO for high-grade gliomas K Ogawa et al In conclusion, performing radiotherapy immediately prospective randomised trials are also warranted to accurately after HBO with chemotherapy was safe with virtually no late determine whether the delivery of radiotherapy immediately toxicity for high-grade gliomas. This treatment strategy after HBO could be beneficial for patients with high-grade may be promising and merits further investigation. Further gliomas. REFERENCES Al-Waili NS, Butler GJ, Beale J, Hamilton RW, Lee BY, Lucas P (2005) Jamieson D, van den Brenk HAS (1963) Measurement of oxygen tensions in Hyperbaric oxygen and malignancies: a potential role in radiotherapy, cerebral tissues of rats exposed to high pressures of oxygen. J Appl chemotherapy, tumor surgery and phototherapy. Med Sci Monit 11: Physiol 18: 869–876 RA279–RA289 Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete Bennett M, Feldmeier J, Smee R, Milross C, Bennett M (2005) Hyperbaric observations. J Am Stat Assoc 53: 457–481 oxygenation for tumour sensitization to radiotherapy. Cochrane Kayama T, Yoshimoto T, Fujimoto S, Sakurai Y (1991) Intratumoral oxygen Database Syst Rev 19: CD005007 pressure in malignant brain tumor. J Neurosurg 74: 55–59 Beppu T, Kamada K, Nakamura R, Oikawa H, Takeda M, Fukuda T, Aradi Kinoshita Y, Kohshi K, Kunugita N, Tosaki T, Yokota A (2000) Preservation H, Ogasawara K, Ogawa A (2003) A phase II study of radiotherapy after of tumour oxygen after hyperbaric oxygenation monitored by magnetic hyperbaric oxygenation combined with interferon-beta and nimustine resonance imaging. Br J Cancer 82: 88–92 hydrochloride to treat supratentorial malignant gliomas. J Neurooncol 61: Kleinberg L, Grossman SA, Piantadosi S, Zeltzman M, Wharam M (1999) 161–170 The effects of sequential vs concurrent chemotherapy and radiotherapy Beppu T, Kamada K, Yoshida Y, Arai H, Ogasawara K, Ogawa A (2002) on survival and toxicity in patients with newly diagnosed high-grade Changes of oxygen pressure in glioblastoma tissue under various astrocytoma. Int J Radiat Oncol Biol Phys 44: 535–543 conditions. J Neurooncol 58: 47–52 Kohshi K, Kinoshita Y, Imada H, Kunugita N, Abe H, Terashima H, Tokui Buckner JC (2003) Factors influencing survival in high-grade gliomas. N, Uemura S (1999) Effects of radiotherapy after hyperbaric oxygenation Semin Oncol 30(6 Suppl 19): 10–14 on malignant gliomas. Br J Cancer 80: 236–241 Choi IS, Lee SH, Kim TY, Bang JS, Paek SH, Kim S, Kim IH, Heo DS, Bang Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, YJ, Kim DG, Jung HW, Kim NY (2002) Phase II study of chemotherapy Hatlevoll R, Lindgren M, Brun A, Lindgren S, Notter G, Andersen AP, with ACNU plus cisplatin followed by cranial irradiation in patients with Elgen K (1981) Combined modality therapy of operated astrocytomas newlydiagnosed glioblastoma multiforme. J Neurooncol 60: 171–176 grade III and IV. Confirmation of the value of postoperative irradiation Collingridge DR, Piepmeier JM, Rockwell S, Knisely JP (1999) Polaro- and lack of potentiation of bleomycin on survival time: a prospective graphic measurements of oxygen tension in human glioma and multicenter trial of the Scandinavian glioblastoma study group. Cancer surrounding peritumoral brain tissue. Radiother Oncol 53: 127–131 47: 649–652 Cox DR (1972) Regression models and life tables. J R Stat Soc 34: 187–220 Kunugita N, Kohshi K, Kinoshita Y, Katoh T, Abe H, Tosaki T, Kawamoto Curren Jr WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fishbach AJ, K, Norimura T (2001) Radiotherapy after hyperbaric oxygenation Chang CH, Rotman M, Asbell SO, Krisch RE (1993) Recursive improves radioresponse in experimental tumor models. Cancer Lett partitioning analysis of prognostic factors in three Radiation Therapy 164: 149–154 Oncology Group malignant glioma trials. J Natl Cancer Inst 85: 704–710 Laperriere N, Zuraw L, Cairncross G (2002) Radiotherapy for newly Dische S (1991) What have we learnt from hyperbaric oxygen? Radiother diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 20(Suppl 1): 71– 74 Oncol 64: 259– 273 Dowling S, Fischer JJ, Rockwell S (1992) Fluosol and hyperbaric oxygen as Lassen U, Kristjansen PE, Wagner A, Kosteljanetz M, Poulsen HS (1999) an adjunct to radiation therapy in the treatment of malignant gliomas: a Treatment of newly diagnosed glioblastoma multiforme with carmustine, pilot study. Biomater Artif Cells Immobilizat Biotechnol 20: 903– 905 cisplatin and etoposide followed by radiotherapy. A phase II study. Fine HA (1994) The basis for current treatment recommendations for J Neurooncol 43: 161– 166 malignant gliomas. J Neurooncol 20: 111 –120 Lindegaard JC, Overgaard J, Bentzen SM, Pedersen D (1996) Is there a Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP (1993) Meta-analysis radiobiologic basis for improving the treatment of advanced stage of radiation therapy with and without adjuvant chemotherapy for cervical cancer? J Natl Cancer Inst Monogr 21: 105–112 malignant gliomas in adults. Cancer 71: 2585–2597 Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. (1990) Response Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The criteria for phase II studies of supratentorial malignant glioma. J Clin concentration of oxygen dissolved in tissues at the time of irradiation Oncol 21: 3547 –3549 as a factor in radiotherapy. Br J Radiol 26: 638– 648 Mantel N (1966) Evaluation of survival data and two new rank order Grossman SA, O’Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, statistics arising in its consideration. Cancer Chemother Rep 50: 163–170 Gilbert M, Newton HB, Hellman R (2003) Phase III study comparing Mayer R, Hamilton-Farrell MR, van der Kleij AJ, Schmutz J, Granstrom G, three cycles of infusional carmustine and cisplatin followed by radiation Sicko Z, Melamed Y, Carl UM, Hartmann KA, Jansen EC, Ditri L, Sminia therapy with radiation therapy and concurrent carmustine in patients P (2005) Hyperbaric oxygen and radiotherapy. Strahlenther Onkol 181: with newly diagnosed supratentorial glioblastoma multiforme: Eastern 113–123 Cooperative Oncology Group Trial 2394. J Clin Oncol 21: 1485 –1491 Mineura K, Sasajima T, Kowada M, Ogawa T, Hatazawa J, Shishido F, Hall EJ (1994) Radiobiology for the Radiologist, 4th ed Lippincott: Uemura K (1994) Perfusion and metabolism in predicting the survival of Philadelphia, pp. 408–417 patients with cerebral gliomas. Cancer 73: 2386 –2394 Hartmann KA, van der Kleij AJ, Carl UM, Hulshof MC, Willers R, Sminia P Ogawa K, Yoshii Y, Inoue O, Toita T, Saito A, Kakinohana Y, Adachi G, (2001) Effects of hyperbaric oxygen and normobaric carbogenon the Ishikawa Y, Kin S, Murayama S (2003) Prospective trial of radiotherapy radiation response of the rat rhabdomyosarcoma R1 H. Int J Radiat after hyperbaric oxygenation with chemotherapy for high-grade gliomas. Oncol Biol Phys 51: 1037–1044 Radiother Oncol 67: 63– 67 Henk JM, Kunkler PB, Smith CW (1977) Radiotherapy and hyperbaric Overgaard J, Horsman MR (1996) Modification of hypoxia-induced oxygen in head and neck cancer. Final report of first controlled clinical radioresistance in tumors by the use of oxygen and sentitizers. Semin trial. Lancet 2: 101–103 Radiat Oncol 6: 10–21 Ito M, Lammertsma AA, Wise RJ, Bernardi S, Frackowiak RS, Heather JD, Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA, Workman P McKenzie CG, Thomas DG, Jones T (1982) Measurement of regional (1994) Direct measurement of pO distribution and bioreductive cerebral blood flow and oxygen utilization in patients with cerebral enzymes in human malignant brain tumors. Int J Radiat Oncol Biol tumors using O and positron emission tomography: analytical Phys 29: 427–431 techniques and preliminary results. Neuroradiology 23: 63–74 Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, Jain KK (1990) Textbook of Hyperbaric Medicine. Hogrefe & Huber Fischbach AJ, Curran Jr WJ (1998) Validation and predictive power of Publishers: Toronto, pp. 408–417 Radiation Therapy Oncology Group (RTOG) recursive partitioning & 2006 Cancer Research UK British Journal of Cancer (2006) 95(7), 862 – 868 Clinical Studies Clinical Studies Radiotherapy after HBO for high-grade gliomas K Ogawa et al analysis classes for malignant glioma patients: a report using RTOG 90- Walker MD, Alexander Jr E, Hunt WE, MacCarty CS, Mahaley Jr MS, 06. Int J Radiat Oncol Biol Phys 40: 51–55 Mealey Jr J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systemic Strike TA (1978) Evaluation of BCNU and/or radiotherapy in the review and meta-analysis of individual patient data from 12 randomized treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg trials. Lancet 359: 1011 –1018 49: 333–343 Stupp R, Mason W, van der Bent MJ, Weller M, Fisher B, Weller M, Muller B, Koch R, Bamberg M, Krauseneck P (2003) Neuro- Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Oncology Working Group 01 trial of nimustine plus tenitoside vs Curshmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, nimustine plus cytarabine chemotherapy in addition to involved-field Cairncross G, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus radiotherapy in the first line treatment of malignant glioma. J Clin Oncol concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 21: 3276–3284 352: 987–996 Wick W, Hermisson M, Kortmann RD, Kuker WM, Duffner F, Dichgans J, Tyler JL, Diksic M, Villemure JG, Evans AC, Meyer E, Yamanoto YL, Bamberg M, Weller M (2002) Neoadjuvant gemcitabine/treosulfan Feindel W (1987) Metabolic and hemodynamic evaluation of gliomas chemotherapy for newly diagnosed glioblastoma: a phase II study. using positron emission tomography. J Nucl Med 33: 1123–1133 J Neurooncol 59: 151– 155 British Journal of Cancer (2006) 95(7), 862 – 868 & 2006 Cancer Research UK

Journal

British Journal of CancerSpringer Journals

Published: Sep 5, 2006

There are no references for this article.