Radiochemotherapy with temozolomide for patients with glioblastoma

Background

The objective of this retrospective analysis was to assess long-term outcome and prognostic factors of unselected patients treated for glioblastoma (GB) at a single center with surgery, standard radiotherapy (RT), and concomitant temozolomide (TMZ). From 1999?C2005, the institutional protocol included surgery and RT with TMZ. From 2005 on, adjuvant TMZ was routinely added.

Patients and Methods

Between April 1999 and September 2009, 181 patients with GB were treated with RT (60 Gy in 30 fractions) and concomitant TMZ (75 mg/m²/day throughout RT). Biopsy only had been performed in 53 patients (29.3%), 128 patients (70.7%) had undergone resection, which was complete based on postoperative MRI in 51 patients (28.2%). Adjuvant TMZ was applied in 67 of 181 patients (37%).

Results

Median overall survival (OS) and progression-free survival (PFS) were 15.0 (95% CI, 13.1?C16.8) and 7.2 months (95% CI, 5.9?C8.5), respectively. After complete resection, partial/subtotal resection and biopsy, median OS was 23.20, 14.75, and 7.89 months (p < 0.001), respectively. In multivariate Cox proportional hazards regression models, extent of resection (p < 0.0001), Karnofsky??s performance score (p < 0.0001) and adjuvant TMZ (p = 0.001) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 146 patients (80.7%), while 11 patients (6.1%) discontinued RT. Another 35 patients (19.3%) interrupted concomitant chemotherapy.

Conclusion

RT with concomitant TMZ is a feasible regimen with acceptable toxicity in routine practice. Our data are compatible with a beneficial effect of adjuvant TMZ on OS and PFS.     

Radiotherapy in elderly patients with inoperable esophageal cancer

Background

Radiation oncologists increasingly face elderly cancer patients impaired by comorbidities and reduced performance status. As less data are available for this particular group of patients, the aim of the study was to assess the prognosis of inoperable esophageal cancer patients ≥?70?years undergoing definitive radiotherapy or radiochemotherapy.

Patients and treatment protocol

Patients aged ≥?70 with inoperable carcinoma of the esophagus undergoing definitive radio(chemo)therapy between 1995 and 2006 at the University of Cologne were included retrospectively. Maximal total dose of radiotherapy administered was 63?Gy (5?×?1.8?Gy/week). Chemotherapy consisted of cisplatin (20?mg/m² on days 1–5 and days 29–33) and 5-fluorouracil (650–1,000?mg/m² on days 1–5 and days 29–33). Efficacy was compared with a cohort of 152?patients <?70?years treated with the same protocol during the same time period.

Results

A total of 51?patients aged ?≥?70 with inoperable cancer of the esophagus undergoing definitive therapy were identified (stage I/II 23.5%, stage III 56.9%, stage IV 9.8%; squamous cell carcinoma 74.5%, adenocarcinoma 25.5%). While 15?patients (29.4%) received combined radiochemotherapy (RCT), 40?patients (70.6%) were treated with radiotherapy alone (RT). Median progression-free survival (PFS) was 9.5?months; median overall survival (OS) was 13.9?months. Patients treated with RCT had a 2-year OS rate of 53.3% compared with 16.7% for RT patients (p?=?0.039). The 2-year OS for clinically lymph node negative patients was 38.5% compared with 21.2% for lymph node positive patients (p?=?0.072). Median OS was not significantly different between patients ≥?70?years versus the patient cohort (n?=?152) aged <?70?years (13.9 vs. 7.2?months, p?=?0.072) but PFS showed a significant difference (4.9 vs. 9.5?months, p?=?0.026) in favor of the >?70?years group.

Conclusion

Prognosis in elderly patients with inoperable esophageal cancer undergoing definitive radiotherapy/radiochemotherapy is limited, although it is not inferior to patients <?70?years.     

贝伐珠单抗联合替莫唑胺胶囊治疗复发胶质母细胞瘤

目的 研究抗血管生成靶向药贝伐珠单抗联合细胞毒性化疗药替莫唑胺胶囊治疗复发胶质母细胞瘤的临床疗效及安全性。方法 回顾分析海军总医院2014年6月—2015年12月收治的28例复发胶质母细胞瘤患者病例资料,术后均接受贝伐珠单抗联合替莫唑胺方案治疗,第1天至第5天口服替莫唑胺胶囊150-200 mg/m2,28 d为1个周期;静脉滴注贝伐珠单抗5 mg/kg,滴注时间60～90 min,每14天1次,按照实体瘤治疗疗效评价标准评价近期客观疗效,治疗前、治疗后出现病情进展之前进行卡氏评分（Karnofsky performance scale,KPS）和生活质量（quality of life,QOL）评分,药物毒性评价标准采用世界卫生组织抗癌药物急性与亚急性毒性反应分度标准。结果 全部患者均完成至少2周期的化疗治疗,总共完成治疗周期134个,平均4.8个。28例患者中获完全缓解2例（7.14%）,部分缓解9例（32.14%）,病情稳定12例（42.86%）,病情进展5例（17.86%）,缓解率为39.28%。中位无进展生存期5.7个月（95％CI=3.8～6.7）,中位总生存期7.2个月（95％CI=4.6～7.7）。治疗后KPS评分及QOL评分均较治疗前明显提高,差异具有统计学意义（P<0.05）。主要不良反应包括骨髓抑制19例（67.86%）和胃肠道反应12例（42.86%）,多为Ⅰ级（23.40%）和Ⅱ级（14.72%）,Ⅲ级较少（2.30%）,无Ⅳ级。结论 贝伐珠单抗联合替莫唑胺胶囊治疗复发胶质母细胞瘤临床疗效确切,不良反应可耐受,可作为优选的治疗方法。     

Radiotherapy of glioblastoma multiforme

Purpose

With regard to the poor prognosis of patients with glioblastoma multiforme, the aspect of life quality with a minimal treatment time becomes essential. The purpose of the present study is to evaluate whether the results of a radiotherapy schedule using increased single fractions applied over a shortened treatment time is feasible without compromising treatment efficiency or providing more side effects than a conventionally fractionationed treatment.

Patients and Methods

A total of 38 patients (f=21, m=17, mean age 58 years) with histologically proven glioblastoma multiforme were irradiated after (partial) resection (n=29) or stereotactic surgery (n=9) with single doses of 3.5 Gy (ICRU) 5 fractions a week up to a total dose of 42 Gy following individual treatment planning.

Results

Median survival was 45.7 weeks, survival rate after 6 months was 80.9% and decreased to 34.2% after 12 months. Radiotherapy was tolerated without any important acute toxicity or any late side effects during the follow-up period.

Conclusions

The increase of the dose per fraction using a fraction size of 3.5 Gy enhanced neither acute nor late toxicity. The survival rate compared well to those described in the literature. Thus the shortened treatment schedule seems as efficient as conventional radiotherapy. Moreover, it seems preferable with regard to quality of life.     

Short-course radiotherapy in elderly patients with glioblastoma: feasibility and efficacy of results from a single centre

Background

The incidence of glioblastoma (GBM) in the elderly population is currently increasing, with a peak seen between 65 and 84 years. The optimal treatment in terms of both efficacy and quality of life still remains a relevant and debated issue today. The purpose of our study was to evaluate the feasibility of short-course hypofractionated accelerated radiotherapy (HART) in GBM patients aged over 70 years and with a good Karnofsky performance score (KPS).

Methods

A review of medical records at the “Istituto Neurologico C. Besta” was undertaken; patients aged ≥?70 years who had undergone adjuvant HART for GBM between January 2000 and January 2004 were included in the study. HART was administered to a total dose of 45 Gy, 2.5 Gy/fraction, in three daily fractions for three consecutive days/cycle fractions each, delivered in two cycles (split 15 days).

Results

A total of 33 patients were evaluable for the current analysis. Median follow-up was 10 months. According to CTCAE (version 3.0) criteria, none of the patients developed radiation-induced neurological status deterioration or necrosis. KPS evaluation after HART was found to be stable in 73?% of patients, improved in 24?%, and worse in 3?%. The median overall survival time of the entire study population was 8 months (range 2–24).

Conclusions

Our findings suggest that a hypofractionated accelerated schedule can be a safe and effective option in the treatment of GBM in the elderly.     

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

Background

The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM).

Methods

This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002?C2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005?C2007.

Results

Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ.

Conclusion

TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity.     

FET-PET-based reirradiation and chloroquine in patients with recurrent glioblastoma

Background

Treatment of recurrent glioblastoma (rGBM) remains an unsolved clinical problem. Reirradiation (re-RT) can be used to treat some patients with rGBM, but as a monotherapy it has only limited efficacy. Chloroquine (CQ) is an anti-malaria and immunomodulatory drug that may inhibit autophagy and increase the radiosensitivity of GBM.

Patients and methods

Between January 2012 and August 2013, we treated five patients with histologically confirmed rGBM with re-RT and 250 mg CQ daily.

Results

Treatment was very well tolerated; no CQ-related toxicity was observed. At the first follow-up 2 months after finishing re-RT, two patients achieved partial response (PR), one patient stable disease (SD), and one patient progressive disease (PD). One patient with reirradiated surgical cavity did not show any sign of PD.

Conclusion

In this case series, we observed encouraging responses to CQ and re-RT. We plan to conduct a CQ dose escalation study combined with re-RT.     

Increased signal intensity within glioblastoma resection cavities on fluid-attenuated inversion recovery imaging to detect early progressive disease in patients receiving radiotherapy with concomitant temozolomide therapy

Purpose

Our study tested the diagnostic accuracy of increased signal intensity (SI) within FLAIR MR images of resection cavities in differentiating early progressive disease (ePD) from pseudoprogression (PsP) in patients with glioblastoma treated with radiotherapy with concomitant temozolomide therapy.

Methods

In this retrospective study approved by our Institutional Review Board, we evaluated the records of 122 consecutive patients with partially or totally resected glioblastoma. Region of interest (ROI) analysis assessed 33 MR examinations from 11 subjects with histologically confirmed ePD and 37 MR examinations from 14 subjects with PsP (5 histologically confirmed, 9 clinically diagnosed). After applying an N4 bias correction algorithm to remove B0 field distortion and to standardize image intensities and then normalizing the intensities based on an ROI of uninvolved white matter from the contralateral hemisphere, the mean intensities of the ROI from within the resection cavities were calculated. Measures of diagnostic performance were calculated from the receiver operating characteristic (ROC) curve using the threshold intensity that maximized differentiation. Subgroup analysis explored differences between the patients with biopsy-confirmed disease.

Results

At an optimal threshold intensity of 2.9, the area under the ROC curve (AUROC) for FLAIR to differentiate ePD from PsP was 0.79 (95% confidence interval 0.686–0.873) with a sensitivity of 0.818 and specificity of 0.694. The AUROC increased to 0.86 when only the patients with biopsy-confirmed PsP were considered.

Conclusions

Increased SI within the resection cavity of FLAIR images is not a highly specific sign of ePD in glioblastoma patients treated with the Stupp protocol.

     

Phase II clinical study of boron neutron capture therapy combined with X-ray radiotherapy/temozolomide in patients with newly diagnosed glioblastoma multiforme—Study design and current status report

Recently, we reported our clinical experiences of boron neutron capture therapy (BNCT) for the newly diagnosed glioblastoma. The major differences of our protocol from the other past studies were simultaneous use of both sodium borocapate and boronophenylalanine, and combination with fractionated X-ray irradiation.These results showed the efficacy of combination therapy with external beam X-ray irradiation and BNCT. For our future study, we planned the multi-centric phase II clinical study for newly diagnosed glioblastoma patients in Japan (OSAKA-TRIBRAIN0902, NCT00974987).     

MRI perfusion in determining pseudoprogression in patients with glioblastoma

We examine the role of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion in differentiating pseudoprogression from progression in 20 consecutive patients with treated glioblastoma. MRI perfusion was performed, and relative cerebral blood volume (rCBV), relative peak height (rPH), and percent signal recovery (PSR) were measured. Pseudoprogression demonstrated lower median rCBV (P=.009) and rPH (P<.001), and higher PSR (P=.039) than progression. DSC MRI perfusion successfully identified pseudoprogression in patients who did not require a change in treatment despite radiographic worsening following chemoradiotherapy.     

Benefits of contrast-enhanced SWI in patients with glioblastoma multiforme

Introduction

SWI can help to identify high-grade gliomas (HGG). The objective of this study was to analyse SWI and CE-SWI characteristics, i.e. the relationship between contrast-induced phase shifts (CIPS) and intratumoral susceptibility signals (ITSS) and their association with tumour volume in patients with glioblastoma multiforme (GBM).

Materials and methods

MRI studies of 29 patients were performed to evaluate distinct susceptibility signals comparing SWI and CE-SWI characteristics. The relationship between these susceptibility signals and CE-T1w tumour volume was analysed by using Spearman’s rank correlation coefficient and Kruskal-Wallis-test. Tumour biopsies of different susceptibility signals were performed in one patient.

Results

Comparison of SWI and CE-SWI demonstrated different susceptibility signals. Susceptibility signals visible on SWI images are consistent with ITSS; those only seen on CE-SWI were identified as CIPS. Correlation with CE-T1w tumour volume revealed that CIPS were especially present in small or medium-sized GBM (Spearman’s rho r?=?0.843, P?<?0.001). Histology identified the area with CIPS as the tumour invasion zone, while the area with ITSS represented micro-haemorrhage, highly pathological vessels and necrosis.

Conclusion

CE-SWI adds information to the evaluation of GBM before therapy. It might have the potential to non-invasively identify the tumour invasion zone as demonstrated by biopsies in one case.

Key Points

? MRI is used to help differentiate between low- and high-grade gliomas. ? Contrast-enhanced susceptibility-weighted MRI (CE-SWI) helps to identify patients with glioblastoma multiforme. ? CE-SWI delineates the susceptibility signal (CIPS and ITSS) more than the native SWI. ? CE-SWI might have the potential to non-invasively identify the tumour invasion zone.     

Early Morbidity after Radiotherapy with or without Chemotherapy in Advanced Head and Neck Cancer

BACKGROUND: Data on early treatment-related morbidity after radiotherapy alone (RT; 217 patients) or combined with chemotherapy (RT + CT; 182 patients) of head and neck squamous cell carcinoma are analyzed. PATIENTS AND METHODS: The patients were treated between November 1985 and November 1996 in four Swiss centers that independently introduced combined-modality therapy in selected cases of head and neck cancer. RT schedules varied among the four centers, but within each institution all patients received the same dose-fractionation schedule irrespective of whether they had CT or not. The following early morbidity items were evaluated: skin, mucosa, larynx, salivary glands, dysphagia, weight loss, and toxic death. Toxicity was scored using the EORTC/RTOG scale. RESULTS: Although considerable variation was noted among the treatment schedules/centers, the main findings are as follows: (1) early morbidity was significantly enhanced after all five RT + CT schedules compared with RT alone; (2) typically, a third of the patients lost > 10% of their body weight during concurrent RT + CT as compared with 10% of the patients receiving RT alone; (3) at 12 weeks, the prevalence of grade 2 morbidity was 25-60% after RT + CT as compared with 4-20% after RT alone. CONCLUSION: A number of early morbidity items were found to be more prevalent and/or more severe after RT + CT than after RT alone.     

Radiobiological evaluation and correlation with the local effect model (LEM) of carbon ion radiation therapy and temozolomide in glioblastoma cell lines

Purpose:?To investigate the cytotoxic effect of high linear-energy transfer (LET) carbon irradiation on glioblastoma cells lines in combination with temozolomide (TMZ).

Methods and materials:?The cell lines U87-MG expressing wild-type p53 and LN229 expressing both mutant and wild-type p53 were irradiated with monoenergetic carbon ion beams (LET 172 keV/μm) or an extended Bragg peak (LET 103 keV/μm) after treatment with 10 μM or 20 μM TMZ. Cytotoxicity was measured by a clonogenic survival assay, and cell growth as well as cell cycle progression, were examined.

Results:?The p53 mutant was more sensitive to X-ray irradiation than the p53 wild type cell line, which was also expressed in a shorter G2 block. High LET carbon ions show an increased biological effectiveness in both cell lines, which is consistent with the predictive calculations by the Local Effect Model (LEM) introduced by Scholz et al. The cell line LN229 was more sensitive to TMZ treatment than the U87MG cell line expressing wild-type p53 only. The combination of TMZ and irradiation showed an additive effect in both cell lines.

Conclusion:?High LET carbon ion irradiation is significantly more effective for glioblastoma cell lines compared to photon irradiation. An additional treatment with TMZ may offer a great chance especially for several tumor types.     

Pretreatment Proliferation and Local Control in Bladder Cancer after Radiotherapy with or without Concurrent Chemotherapy

PURPOSE: To investigate whether the addition of chemotherapy to radiotherapy (RT) is beneficial particularly in bladder tumors that possess the capacity for rapid proliferation. PATIENTS AND METHODS: The Ki-67 index was evaluated by immunohistochemistry on pretreatment biopsies from 136 patients treated by transurethral tumor resection (TURBT) and RT (n=50) or platin-based radiochemotherapy (RCT; n=86). Ki-67 expression was correlated with response to RT/RCT and long-term local control rates. The median follow-up was 43 months. RESULTS: The percentage of Ki-67-positive cells ranged from 1.5% to 89%. Complete response (CR) was observed in 100/131 patients (76%, five without restaging TURBT). A statistically significant association between high Ki-67 index (>or= median) and CR was noted for patients receiving RCT (93% vs. 66% for Ki-67 < median; p=0.001), but not for patients treated with RT alone (p=0.12). Long-term local control was 39% for patients treated with RT, and 44% for patients after RCT (p=0.49). Patients with high Ki-67 index did significantly better when subjected to combined RCT (55% vs. 33% with low Ki-67 index; p=0.006), whereas no difference between high and low Ki-67 status was observed in the RT group (39% each; p=0.57). On multivariate analysis, Ki-67 status was an independent predictor for local failure in the RCT group (risk ratio, 0.43; p=0.007). Disease-specific survival was significantly better after RCT (62%) as compared with RT (42%; p=0.03), however, the Ki-67 index was not related to this endpoint. CONCLUSION: Rapid proliferation is associated with improved local control, if patients are treated with concurrent RCT. The cytostatic effect of concurrent chemotherapy may effectively inhibit repopulation during fractionated RT.     

Chromosome aberrations in patients treated with telecobalt therapy for glioblastoma

The yield of dicentric chromosomes has been recorded in peripheral blood lymphocytes of patients undergoing telecobalt therapy for glioblastoma. Blood samples were taken by venipuncture, prior to the first radiotherapy session and 24 h after 10, 20 and 30 Gy to the tumor volume. On the basis of the maximum likelihood method, the yield of chromosome aberrations was best fitted by a linear quadratic dose-response relationship. According to this relationship, the dose inducing ten dicentrics at the target volume is 58 Gy, a value considerably higher than those found after radiotherapy for mammary carcinoma (15 Gy) or for pelvic tumors (5.62 Gy). Our results indicate that, in the case of fractionated exposures, confined to a small volume of the body, it is not possible to estimate the total dose administered and that the method only provides an estimate of the proportion of the lymphocytes irradiated.     

Radiotherapy of glioblastoma: is shortening of the treatment time justifiable?]

Survival of glioblastoma patients can be double by postoperative radiation but nevertheless rarely exceeds one year. It is therefore desirable to minimize treatment time and hospitalisation. Aim of our study is to investigate the feasibility of a reduction of treatment time by accelerated fractionation. Out of 110 patients treated for glioblastoma from 1975 to 1988 in our institution postoperative radiation was performed in 79 patients using three different fractionation schedules: 60 Gy in six weeks, single fractions 2 Gy (n = 38), 35 Gy in two weeks, single fractions 3.5 Gy (n = 27), 45.5 Gy in 2.5 weeks, single fractions 3.5 Gy (n = 14). No statistically significant differences in both the mean overall and disease free survival were evaluated between the three groups. The larger fraction size was well tolerated and no relevant increase of early or late adverse reactions occurred. As the duration of treatment can be reduced from six to two weeks, this accelerated fractionation schedule seems to be a reasonable alternative to conventional fractionation.     

Surgery and Chemotherapy for Small Cell Lung Cancer in Stages I–II with or without Radiotherapy

PURPOSE: To analyze the effectiveness of surgery and chemotherapy with or without radiotherapy in the management of limited small cell lung cancer (LSCLC) in stages I and II. PATIENTS AND METHODS: 39 patients (median age 62 years) with LSCLC in stages pT1 or pT2 and pN0 or pN1 (stages IA-IIB) who had a tumor resection and systematic lymph node dissection were reviewed retrospectively. The median follow-up period was 29 months. 35 patients (90%) received a median of four cycles of a platinum-containing chemotherapy postoperatively. 16 patients (41%) received an adjuvant thoracic radiotherapy (TRT, median 50 Gy); 21 patients (54%) received a prophylactic cranial irradiation (PCI, median 30 Gy). RESULTS: The median overall survival for all patients was 47 months, resulting in actuarial 1-, 3-, and 5-year survival rates of 97%, 58%, and 49%, respectively. Distant metastases were found in 13 patients (33%) after a median of 16 months. Patients who received an adjuvant TRT showed a trend toward improved thoracic recurrence-free survival (p = 0.06) and improved overall survival (p = 0.07) compared to those treated with surgery and chemotherapy only. Brain metastasis-free survival (p = 0.01) and overall survival (p = 0.01) were improved significantly in patients who received a PCI. CONCLUSION: Surgical tumor resection may be considered for carefully selected patients. Adjuvant chemotherapy and PCI are recommended for all patients. Adjuvant TRT is currently used in patients with positive lymph nodes (pN1), because the probability of a subclinical involvement of the mediastinal lymphatic system appears to be increased in these patients.