Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study

We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCβ] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status ≥60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m² daily) followed by adjuvant temozolomide (200 mg/m²) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if ≤1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.     

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.     

Decreasing radiation therapy utilization in adult patients with glioblastoma multiforme: A population-based analysis

BACKGROUND:

The purpose of this study was to assess what factors influence radiation therapy (RT) utilization in patients with glioblastoma and to ascertain how patterns of care have changed over time.

METHODS:

A total of 9103 patients with supratentorial glioblastoma in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2006 were analyzed. Demographic information was obtained, including age, sex, race, year of diagnosis, and marital status. Treatment characteristics included receipt of RT and surgical resection.

RESULTS:

In total, 76.8% of patients received RT, whereas 78% received resection. Patients of male sex, who were currently married, who were <65 years old, and who underwent resection were more likely to receive RT. The average annual percentage change in RT utilization in the years 1990‐2006 was ?0.41% (95% confidence interval [CI], ?0.23 to ?0.58), whereas for resection it was 0.26% (95% CI, 0.03 to 0.50). This equates to a 6.5% decrease in RT utilization and a 4.2% increase in resection during this time period. Patients treated with RT had a 2‐year overall survival of 11.4%, compared with 5.2% in those not treated with RT (P < .00001). Multivariate analysis showed that younger age (continuous; odds ratio [OR], 0.97; P < .0001), marital status (OR, 1.62; P < .0001), surgical resection (OR, 1.72; P < .0001), and year of diagnosis 1998‐2006 compared with 1990‐1997 (OR, 0.82; P < .0001) were associated with RT utilization, whereas sex, lesion size, and race were not.

CONCLUSIONS:

SEER data show a decreasing utilization of RT in patients with glioblastoma from 1990 to 2006. Patients who were older, who were unmarried, and who underwent biopsy only were less likely to receive RT. Cancer 2012. © 2012 American Cancer Society.     

Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma

BackgroundPulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM).MethodsThis is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation.ResultsTwenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)–mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID.ConclusionsTreatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.     

逐步递量加速超分割放射治疗局部晚期鼻咽癌

目的：研究逐步递量加速超分割放射治疗（ＥＨＡＲＴ）局部晚期鼻咽癌的近期疗效和急性反应。方法：１９９９年４月－２０００年２月６４例Ｔ３－４Ｎ０Ｍ０、ＫＰＳ≥８０的鼻咽癌患者进入本研究,并随机分为常规分割放疗（ＣＦＲＴ）组和ＥＨＡＲＴ组,每组各３２例;ＣＦＲＴ组采用２Ｇｙ／次,５次／周的方法,鼻咽靶区中心总剂量６８－７６Ｇｙ,中位数７０Ｇｙ,３４－３８次,７－８周;上颈部剂量４６－５６Ｇｙ,２３－２８     

Modeling the efficacy of the extent of surgical resection in the setting of radiation therapy for glioblastoma

Standard therapy for glioblastoma (GBM) includes maximal surgical resection and radiation therapy. While it is established that radiation therapy provides the greatest survival benefit of standard treatment modalities, the impact of the extent of surgical resection (EOR) on patient outcome remains highly controversial. While some studies describe no correlation between EOR and patient survival even up to total resection, others propose either qualitative (partial versus subtotal versus complete resection) or quantitative EOR thresholds, below which there is no correlation with survival. This work uses a mathematical model in the form of a reaction–diffusion partial differential equation to simulate tumor growth and treatment with radiation therapy and surgical resection based on tumor‐specific rates of diffusion and proliferation. Simulation of 36 tumors across a wide spectrum of diffusion and proliferation rates suggests that while partial or subtotal resections generally do not provide a survival advantage, complete resection significantly improves patient outcomes. Furthermore, our model predicts a tumor‐specific quantitative threshold below which EOR has no effect on patient survival and demonstrates that this threshold increases with tumor aggressiveness, particularly with the rate of proliferation. Thus, this model may serve as an aid for determining both when surgical resection is indicated as well as the surgical margins necessary to provide clinically significant improvements in patient survival. In addition, by assigning relative benefits to radiation and surgical resection based on tumor invasiveness and proliferation, this model confirms that (with the exception of the least aggressive tumors) the survival benefit of radiation therapy exceeds that of surgical resection.     

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6–7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.     

吉西他滨联合顺铂或卡铂治疗晚期非小细胞肺癌的近期疗效

目的 :观察吉西他滨 (gemcitabine)联合顺铂与吉西他滨联合卡铂治疗晚期非小细胞肺癌的疗效和毒性反应。方法 :10 6例经病理组织学或细胞学证实的晚期非小细胞肺癌患者分为GP和GC两组 ,GP组应用吉西他滨 10 0 0mg/m2 ,静滴 ,第 1、8天 ;顺铂 30mg/m2 ,静滴 ,第 1～ 3天。GC组应用吉西他滨 10 0 0mg/m2 ,静滴 ,第 1、8天 ;卡铂ACU =5 ,静滴 ,第 1天。 2 1天为 1个周期 ,连用 2个周期评价疗效。结果 :GP组和GC组有效率 (CR PR)分别为 4 8.1%和 4 4 .2 % (P >0 .0 5 ) ;中位疾病进展时间分别为 6 .8个月和 6 .2个月 (P >0 .0 5 ) ;毒性反应中GP组消化道毒副反应较GC组大 ,差异有显著性 ;骨髓毒性两组相当 ,差异无显著性。结论 :吉西他滨联合顺铂及吉西他滨联合卡铂两方案治疗晚期非小细胞肺癌疗效均较好 ,毒性反应轻微 ,患者耐受良好 ,尤其吉西他滨联合卡铂的消化道反应轻 ,患者易于接受 ,值得临床进一步研究。     

Ototoxicity and cancer therapy

Ototoxicity is a well‐established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemotherapy, radiation or surgery involving the ear and auditory nerve, and supportive care agents such as aminoglycoside antibiotics and loop diuretics. The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges from 4% to 90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques. The impact of ototoxicity on subsequent health‐related and psychosocial outcomes in these patients can be substantial, and the burden of morbidity related to ototoxic agents is particularly high in very young children. Considerable interindividual variability in the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting genetic susceptibility as a risk factor. The development and testing of otoprotective agents is ongoing; however, to the author's knowledge, no US Food and Drug Administration‐approved otoprotectants are currently available. Prospective monitoring for ototoxicity allows for comparison of auditory outcomes across clinical trials, as well as for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss. Cancer 2016;122:1647‐58 . © 2016 American Cancer Society.     

High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: Final results of a phase II study

Purpose:to analyse toxicity and response to a new scheme ofneoadjuvant chemotherapy (CT) and concomitant radiochemotherapy (RT–CT)for locally advanced anal canal squamous-cell carcinoma (ACC). Patients and methods:Eighty patients with an ACC >40 mm and/orwith lymph node involvement were included (1 T₁, 52 T₂,14 T₃, 13 T₄, 18 N₀, 30 N₁, 32N₂–N₃). Two cycles of 5-fluorouracil (5-FU) andCDDP were delivered as neoadjuvant CT and two during RT–CT. Pelvic(± inguinal) RT delivered 45 Gy in 25 fractions of 1.8 Gy. Involvedfields were boosted after a one to two month gap (15–20 Gy). The medianfollow-up was 29 months. Results:One patient died of a pulmonary embolism on day 4. Allpatients received the entire treatment, with reduced 5-FU doses in 27%of the cases because of acute toxicity. Sixty-four grade 3 and five grade 4toxicities were observed. No toxic death occurred.Complete response (CR) and partial response (PR) rates were, respectively,10% and 51% after neoadjuvant CT, 67% and 28%after RT–CT and 93% and 5% after treatment completion(including 4 abdomino-perineal resections).The three-year actuarial overall, tumour-specific, colostomy-free,relapse-free, disease-free and event-free survivals were 86%,88%, 73%, 70%, 67% and 63%,respectively. Conclusions:Tolerance was good. After neoadjuvant CT, most of thepatients were objective responders. After treatment completion, all but fiveachieved CR. The long-term results confirm the durability of local control andlow toxicity on the sphincter. An ongoing phase III intergroup trial analysesthe impact of neoadjuvant CT, and the benefit of a high-dose boostirradiation, on local control and colostomy-free survival.     

逐步递量加速超分割放射治疗联合化疗治疗ⅢB期非小细胞肺癌

目的 研究逐步递量加速超分割放射治疗（EHART）对ⅢB期非小细胞肺癌（NSCLC）的近期疗效和急性放射反应。方法 1998年至2001年间，112例符合纳入标准的患者进入本研究，非随机分为常规放疗组（CFRT65例）和EHART组（47例）。CFRT组：1.8-2Gy／次／天，5天／周，肿瘤中心总剂量54－70Gy/27-40次／37－85天，中位剂量60Gy／30次／43天；EHART组：第1、2周为1.2Gy／次，2次／天，间隔6h以上，第3、4、5周分别为1.3、1.4、1.5Gy/次，2次／天，均5天／周，总剂量为60－66Gy/46-50次／30－45天，中位剂量66Gy/50次／34天。照射野均包括胸部CT可见的病灶及周围1.5cm的正常组织。放疗前化疗1－2个周期，放疗结束后继续化疗，共计4－6个周期，所用方案多数为MVP方案（M：丝裂霉素，V：长春地辛，P：顺铂）。患者均随访满1年。结果 EHART组和CFRT组各有7例和12例患者未完成治疗计划。在按计划完成治疗的93例患者，两组的有效率分别为72.5%和64.2%，1年生存率分别为60.0%和47.2%，局控率分别为67.5%和52.8%，两组间比较均无显著性差异（P＞0.05）。EHART组急性放射性食管炎发生率及严重度高于CFRT组（P＝0.025）。结论 EHART联合化疗治疗ⅢB期NSCLC近、远期疗效较好，局控率较高，急性放射反应能为大多数患者耐受；长期生存和晚期放射损伤有待进一步研究。     

局部后程加速超分割放疗同期配合长春瑞滨加顺铂治疗Ⅲb期非小细胞肺癌

目的 :探讨Ⅲb期非小细胞肺癌 (NSCLC)局部小野放疗与长春瑞滨加顺铂联合化疗 (NP方案 )同步进行的临床疗效、生存质量和毒副反应。方法 :1996年 6月～ 1999年 3月 ,2 3例Ⅲb期NSCLC患者行同步放、化疗。化疗方案 :长春瑞滨 (NVB) 2 5mg/M2d1,d8;顺铂 (DDP) 30mg/M 2d1- 3,2 8天为一周期。放疗采用针对局部病变小野放疗 ,后程加速超分割方式 ,总剂量达 6 1～ 70Gy。结果 :全组病例总有效率达 86 96 % ,中位生存期 (MST) 16个月 ,1、3、5年生存率分别为 6 5 2 2 %、30 4 3%、4 35 %。骨髓抑制是主要的限制性毒副作用 ,放疗前后检测肺功能无明显改变。结论 :NP方案联合化疗加同期局部小野放疗治疗Ⅲb期NSCLC可提高疗效 ,延长中位生存期而不降低生存质量。     

Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer

Background:

This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.

Methods:

Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).

Results:

Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.

Conclusion:

Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.     

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma

BackgroundTo determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM).MethodsEligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs).ResultsA total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02).ConclusionsIn this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.     

Invasive bladder carcinoma: a pilot study of conservative treatment with accelerated radiotherapy and concomitant cisplatin.

From November 1992 to December 1997, 25 patients (inoperable or refusing cystectomy) were included in a prospective study to assess the feasibility, tolerance, and curative potential of accelerated radiotherapy (RT) and concomitant cisplatin. Median age was 74 years (range 49-86). Stage distribution was as follows: 1 T1, 10 T2, 8 T3, and 6 T4. Two patients had clinically positive pelvic nodes. The goal was to deliver a total dose of 40 Gy to the whole pelvis and bladder in 4 weeks using a concomitant boost of 20 Gy to the tumor or to the whole bladder during the third and fourth weeks (total dose 60 Gy), with daily cisplatin (6 mg/m(2)) before RT for patients with creatinine clearance > 50 ml/min. All but one patient completed the RT protocol. Daily cisplatin was successfully delivered in 18 patients. One patient presented with grade III ototoxicity. Diarrhea was scored grade III in two and grade IV in two patients. Acute urinary toxicity was scored grade III in one patient. Posttreatment late effects included bladder grade II and grade III in two patients and one patient, respectively; large bowel grade III in one; urethral grade III in one; and femoral head radionecrosis in one. Four-year overall and disease-specific survival rates were 23% and 35%, respectively. The latter was 60% for patients with T2 tumors. The 4-year actuarial locoregional control rate for all patients was 61%. In summary, accelerated RT and concomitant cisplatin is feasible with acceptable tolerance even in relatively old patients. Although outcome was better for patients with low-stage tumors, local control and survival rates appeared similar to those of standard RT schedules for a similar patient population.     

紫杉醇脂联合顺铂与替吉奥联合顺铂在晚期非小细胞肺癌患者中的应用效果对比

目的 探讨紫杉醇脂联合顺铂与替吉奥联合顺铂在晚期非小细胞肺癌患者中的应用效果.方法 选取肺癌晚期患者70例,按照随机数字表法分为观察组36例,对照组34例.观察组采取紫杉醇酯联合顺铂的治疗方法,对照组采取替吉奥联合顺铂的治疗方法.对比两组患者的生存时间以及1年内的生存率、并发症发生情况以及患者治疗后的疗效.结果 观察组患者的平均生存时间为(8.2±0.3)个月,1年生存率为44.4％;对照组患者的平均生存时间为(10.3±0.5)个月,1年生存率为47.1％,差异无统计学意义(P＞0.05).观察组患者出现肾功能异常率为22.2％,血小板减少率为11.1％,严重脱发率为27.8％;对照组患者出现肾功能异常率为38.2％,血小板减少率为17.6％,严重脱发率为41.2％,观察组均低于对照组,差异有统计学意义(P＜0.05).观察组患者用药后完全缓解、部分缓解以及稳定的百分比分别为0.0％,72.2％,27.8％;对照组患者用药后完全缓解、部分缓解以及稳定的百分比分别为0.0％,41.7％,58.3％,差异具有统计学意义(P＜0.05).结论 紫杉醇脂联合顺铂治疗晚期非小细胞肺癌在降低患者并发症以及治疗效果方面优于替吉奥联合顺铂的治疗方案.     

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed,inoperable glioblastoma

We report on a phase II clinical trial to determine the effect of a concurrent ultra‐fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m² for 7 days a week. After a 4‐week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5‐day regimen. Tolerance and toxicity were the primary endpoints; survival and progression‐free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra‐fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long‐term survivors were noted. Concurrent ultra‐fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.     

Radiation therapy combined with radiosensitizing agents for cerebral glioblastoma in adults

We analyzed our treatment results of 71 operated patients with cerebral glioblastoma treated by conventional external radiation therapy (mean dose 60.2 Gy) combined with radiosensitizing agents. More than 50% reduction of tumor volume was obtained in 20 patients (28.2%). A response rate of at least 40% was obtained in patients treated with combined ACNU-vincristine-nicardipine, ACNU-5FU-hydroxyurea, or cisplatin alone. The combination of ACNU and vincristine with or without nicardipine resulted in significantly longer survival. The median survival in this group was 101.1 weeks and the two-year survival rate was 45.9%; these results were significantly better than those achieved with other ACNU combinations or other combinations without ACNU. In the analysis of survival, factors correlated to longer survival were a patient age of younger than 45 years, wide resection of the tumor, a good postoperative performance status (KS 70%), a radiation dose of 68–72 Gy, small postoperative tumor remnants (< 20 cm³), no visible tumor after radiation therapy, and the administration of adjuvant chemotherapy. Maximum resection of the tumor and localized irradiation with a dose of 70 Gy combined with ACNU and vincristine appears to be the most effective treatment at present.     

Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons

BackgroundWe investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM).MethodsPatients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis.ResultsRates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79–0.94) for the final G3+L prediction model.ConclusionsSex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.