Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma.

PURPOSE: In the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens. METHODS: This bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment. RESULTS: Hematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy. CONCLUSIONS: This analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.

Achievable Central Nervous System Concentrations of the Green Tea Catechin EGCG Induce Stress in Glioblastoma Cells in Vitro.

The polyphenolic compounds present in green tea are preventative against cancer in several animal tumor models. However, direct cytotoxic effects on cancer cells have also been reported. In order to determine whether drinking of green tea has chemopreventive or cytotoxic effects on brain cancer cells, we investigated the effect of the major green tea polyphenol EGCG as a pure substance and as tea extract dietary supplement on primary human glioblastoma cell cultures at the CNS-achievable concentration of 100 nM reported in the literature. We compared this with the effect of the cytotoxic concentration of 500 µM determined to be specific for the investigated primary glioblastoma cultures. After treatment with 500 µM EGCG, strong induction of autophagy and apoptosis was observed. Under treatment with 100 nM EGCG, glioblastoma cells proliferated over the entire observation period of 6 days without any detectable signs of cell death. Only within the first 12 h of treatment was increased accumulation of autophagic vacuoles and increased reactive oxygen species production as a stress response demonstrated. Mild forms of stress, such as treatment with 100 nM EGCG, activate different endogenous repair mechanisms to protect cells. Our data imply that drinking of green tea may have chemopreventive effects, but no direct cytotoxic properties.

Clinical benefit in recurrent glioblastoma from adjuvant NovoTTF-100A and TCCC after temozolomide and bevacizumab failure: a preliminary observation.

The NovoTTF-100A is a device that emits alternating electric fields and it is approved for the treatment of recurrent glioblastoma. It works by perturbing tumor cells during mitosis as they enter anaphase leading to aneuploidy, asymmetric chromosome segregation and cell death with evidence of increased immunogenicity. Clinical trial data have shown equivalent efficacy when compared to salvage chemotherapies in recurrent disease. Responders were found to have had a lower dexamethasone usage and a higher rate of prior low-grade histology. We treated a series of patients with NovoTTF-100A and bevacizumab alone (n = 34) or in combination with a regimen consisting of 6-thioguanine, lomustine, capecitabine, and celecoxib (TCCC) (n = 3). Compared to the former cohort, the latter cohort exhibited a trend for prolonged overall survival, median 4.1 (0.3-22.7) months versus 10.3 (7.7-13.6) months respectively (P = 0.0951), with one experiencing an objective response with a 50% reduction in tumor size on magnetic resonance imaging despite possessing a larger tumor size at baseline and more severe neurologic dysfunction than the median for either group. These observations illustrate the possibility of improving survival and achieving a response in patients with end-stage recurrent glioblastoma by biasing the tumor toward anti-tumor immunologic response with a combination of NovoTTF-100A and TCCC, as well as the continuation of bevacizumab in order to limit dexamethasone use due to its global immunosuppressive effect on the patient.

Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials.

BACKGROUND: Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials. METHODS: We assessed 14,611 patients (1218 black and 13,393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan-Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided. RESULTS: Black patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively. CONCLUSIONS: Black patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients' adjuvant colon cancer treatment.

Monitoring individual response to brain-tumour chemotherapy: proton MR spectroscopy in a patient with recurrent glioma after stereotactic radiotherapy.

Since antineoplastic activity varies, sensitive methods for individual assessment of efficacy are needed. We demonstrate the clinical value of MR spectroscopy in monitoring chemotherapy in a patient with recurrent glioma after stereotactic radiotherapy. Diagnostic imaging before and after chemotherapy included contrast-enhanced MRI, single-voxel proton MR spectroscopy ((1)H MRS), (1)H MR spectroscopic imaging ((1)H SI), and fluorodeoxyglucose (FDG) positron-emission tomography (PET). A significant decrease in choline signal intensity was observed 2 months after chemotherapy indicating tumour chemosensitivity, in line with tumour shrinkage on MRI and decreased uptake of FDG. Assessment of early response by MRS may help to improve treatment protocols in other patients.

Acute diarrhea during adjuvant therapy for rectal cancer: a detailed analysis from a randomized intergroup trial.

PURPOSE: During adjuvant radiotherapy (RT) for rectal cancer, patients receiving 5-fluorouracil (5-FU) by protracted venous infusion have a higher risk of diarrhea than have patients receiving bolus 5-FU. Toxicity from a previously reported randomized clinical trial was analyzed to quantify the difference in this risk. Additionally, the persistence of diarrhea after RT was analyzed. METHODS AND MATERIALS: A total of 656 patients were eligible. Patients with T3-4 N0-2 M0 or T1-2 N1-2 M0 resected, high-risk rectal cancer were randomly allocated to receive 5-FU by either protracted venous infusion or bolus during RT (50.4-54.0 Gy). Two cycles of bolus 5-FU were given before and after RT. One-half of the first 445 patients were also randomly allocated to receive lomustine in conjunction with the bolus 5-FU. The incidence and severity of diarrhea in relation to patient and treatment characteristics were evaluated. RESULTS: The rate of diarrhea was significantly greater in patients receiving 5-FU by protracted venous infusion than in patients receiving bolus 5-FU; the difference was most pronounced for Grade 3 (severe) diarrhea (21% versus 13%, p = 0.007). The incidence and magnitude of diarrhea before and after RT were similar. Patients treated with an anterior resection had a higher rate of severe or life-threatening diarrhea than did patients treated with an abdominoperineal resection (31% vs. 12%, p < 0.001). CONCLUSIONS: During pelvic RT, patients who receive 5-FU by protracted venous infusion rather than by bolus have a higher risk of severe or life-threatening diarrhea during RT. This risk does not appear to persist during chemotherapy after completion of pelvic RT.

Adults with newly diagnosed high-grade gliomas.

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.

Optimal control of cyclophosphamide-induced emesis.

Cyclophosphamide induces moderate to severe emesis. The severity of emesis is dependent on the dose of cyclophosphamide and on the addition of other cytotoxic drugs. A review of the literature dividing studies according to the dose of cyclophosphamide and the specific cytotoxic combination shows that ondansetron plus dexamethasone provides optimal antiemetic therapy in patients receiving standard or high-dose cyclophosphamide (> or = 450 mg/m2). These studies also show that it is important to give antiemetic therapy to cover the prolonged duration emesis and nausea induced by these regimens, e.g. intravenous CMF/(F)AC/(F)EC. For continuous 'oral' (low-dose) CMF chemotherapy, oral ondansetron or oral metoclopramide plus intravenous (or possibly oral) dexamethasone are effective antiemetic therapies.

[Adjuvant treatment of colonic carcinoma]. / Adjuvante Behandlung des Kolonkarzinoms.

After many years of negative trials of adjuvant chemotherapy in colon cancer, two studies in the years 1989 and 1990 of the NCCTG and the Intergroup Trial, respectively showed a significant reduction of relapse and improved survival in patients treated with 5-FU and levamisole in an adjuvant setting. The absolute and relative reductions in 5-year-relapse and death rates were approximately 35% and 17%, respectively. Intraportal perfusion of the liver in an adjuvant perioperative setting seems to be of similar benefit. Preliminary data of the adjuvant therapy with 5-FU and folinic acid also show that this combination seems to have at least the same efficacy as the current standard 5-FU/levamisole in the adjuvant therapy of colon cancer. At the current time, patients with colon cancer of Dukes stage C should be offered adjuvant chemotherapy with 5-FU/levamisole outside of clinical studies.

Cardiorespiratory decompensation following methylprednisolone administration.

A 2-year-old white female receiving multidrug chemotherapy for treatment of a primitive neuroectodermal tumor developed acute hypotension, bradycardia, and shock following administration of ondansetron and high-dose methylprednisolone. The subsequent clinical course is described, and cardiovascular reactions to ondansetron and methylprednisolone are reviewed. While the etiology of this severe reaction is uncertain, it is possible that it represents an idiosyncratic reaction to the rapid administration of high-dose adrenal corticosteroids. Patients receiving high-dose corticosteroid therapy should be closely monitored, and slow rates of infusion are recommended.

[Medulloblastomas--the results after postoperative radiotherapy with and without adjuvant chemotherapy]. / Medulloblastome--Ergebnisse nach postoperativer Radiotherapie mit und ohne adjuvante Chemotherapie.

Between 1975 and 1991, 40 patients with newly diagnosed medulloblastoma were treated at the authors' institutions. After aggressive surgical resection 39/40 (98%) received craniospinal radiation therapy with a local boost to the posterior fossa and other macroscopically involved areas. A group of 29 patients was treated with adjuvant chemotherapy. The five-year actuarial survival and event-free survival were 75% and 65%, respectively. Survival was significantly better for patients treated after 1981 as compared to those treated between 1975 and 1980 (p = .02). Younger age (two to four years) was associated with a better prognosis (p = .02). The extend of resection, Chang-stage, radiation dose to posterior fossa and the use of chemotherapy did not significantly impact on survival and relapse-free survival.

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

Adjuvant therapy for adenocarcinoma of the rectum.

Surgical resection continues to be the primary curative modality for patients with adenocarcinoma of the rectum. However, local tumor recurrence in the pelvis and/or distant metastasis may occur in spite of complete excision of grossly visible malignant disease. Surgical and pathologic staging can identify a subset of surgically treated rectal cancer patients at high risk for tumor relapse and death. Irradiation and chemotherapy have been used as adjuvant therapy in conjunction with surgery as single modalities and in combination for patients with high risk rectal cancer. Evidence from controlled clinical trials indicates a significant decrease in local tumor recurrence, and a significant improvement in disease-free and overall survival with the use of combined postoperative irradiation and chemotherapy in this setting. A current national clinical trial in the United States of America is studying whether irradiation can be combined with new chemotherapy regimens which have shown significant therapeutic benefit as surgical adjuvant therapy for patients with high risk colon cancer (5FU + levamisole) and for patients with metastatic colorectal cancer (5FU + leucovorin) to further improve the efficacy of surgical adjuvant therapy for adenocarcinoma of the rectum.

The value of adjuvant therapy after radical surgery for colorectal cancer.

Extensive efforts to improve survival for patients with colorectal cancer using adjuvant treatments in addition to radical surgery have long been tried but without success. Recent data from several controlled trials have, however, shown positive results. The collected information from several trials using different chemotherapy schedules indicate that overall survival is improved. The extent of this improvement is not properly known although several centres have considered it to be sufficiently large to merit routine use in certain stages. Likewise, the collected information from several trials using perioperative radiotherapy indicates that the proportion of local recurrences are reduced by about 50% but without any major influence on survival. Most evidence favours additional radiotherapy before surgery rather than after. If proper dose planning is utilized, sufficiently high doses can be given preoperatively without increasing postoperative mortality.

Brachytherapy of brain tumors.

Temporary implants of high-activity 125iodine sources have been used in the treatment of brain tumors since December 1979 at the University of California, San Francisco. For previously untreated patients who underwent external beam radiation therapy followed by implant boost, median survival from the date of diagnosis was 88 weeks for 34 patients with glioblastoma multiforme (GM) and 157 weeks for 29 patients with nonglioblastoma gliomas (NGM). For recurrent tumors treated with brachytherapy only, median survival from the date of the implant was 54 weeks for 45 patients with GM and 81 weeks for 50 patients with NGM. Finally, in 48 patients with recurrent tumors treated with combined hyperthermia and brachytherapy, median survival from the date of the implant was 46 weeks for 25 patients with GM and 44 weeks for 7 patients with metastases; 18-month survival was 65% for 16 patients with NGM. Brachytherapy appears to be a useful technique for the treatment of selected recurrent brain tumors and selected primary glioblastomas.

New approaches to the chemotherapy of melanoma.

Several new investigational agents have shown some promise in the treatment of patients with disseminated melanoma. While earlier studies of combination chemotherapy led to increased toxicity without improved anti-tumor effect, more recent combination regimens have produced responses up to 50%. One of these is a dose-intensification regimen using high-dose cisplatin and the chemoprotective drug WR-2721. Other treatments under study include autologous bone marrow transplantation plus thiotepa, a combination regimen of chemotherapy and interferon, and newer agents such as taxol, tauromustine, and detrorubicin.

Adjuvant chemotherapy with 5-fluorouracil, vincristine and CCNU for patients with Dukes' C colorectal cancer. The Swedish Gastrointestinal Tumour Adjuvant Therapy Group.

A prospective controlled randomized trial testing adjuvant postoperative combination chemotherapy (5-fluorouracil, lomustine (CCNU) and vincristine) versus no adjuvant therapy in patients operated on for Dukes' C colorectal cancer is reported. In total 334 patients aged less than 70 years were recruited: 205 patients with colonic and 99 with rectal cancer, but there were three protocol violations and these cases are excluded from further consideration. Twenty-seven patients had a limited resection of their cancer. After 5 years' follow-up there was no significant difference in the tumour-free survival rate or in the survival rate between the treated and control groups. Twenty-nine of the 147 patients who started chemotherapy discontinued this treatment because of side-effects, mainly from the gastrointestinal tract. In 30 patients treatment was discontinued because of recurrent disease. The conclusion is that systemic administration of combination chemotherapy for colorectal cancer after operation is not worthwhile in routine clinical practice.

Adjuvant chemotherapy with fluorouracil and CCNU in colon cancer. Results of a multicentric randomized study.

To establish the effectiveness of adjuvant chemotherapy in patients with colon cancer after radical surgery, from 1980 to December 1983, 263 patients were randomized in a multicentric study to no further treatment (131 patients) or to a combination of fluorouracil (5-FU) (400 mg/m2 i.v., days 1-5) and lomustine (CCNU) (100 mg/m2 per os on day 5) every 6 weeks for 9 cycles (132 patients). The two groups were well balanced for age, sex, histology, tumor and nodal extent. Chemotherapy was not given to 30 of the 132 randomized patients, and of 98 treated patients only 38 completed the entire protocol. Analysis, as intention to treat, at 54 months did not show any significant difference between the two treatment groups in terms of relapse-free survival (surgery alone, 74.5%; surgery + adjuvant chemotherapy, 70.9%; p = 0.91). In contrast, a significant difference was observed in overall survival (surgery alone, 78.8%; surgery + adjuvant chemotherapy, 60.8%; p = 0.04). The sites of relapse were identical in the two treatment arms. In conclusion, from this study it appears that adjuvant chemotherapy with 5-FU and CCNU seems to have no efficacy in the cure rate of colon cancer patients.

Adjuvant chemoimmuno- and immunotherapy in Dukes' stage B2 and C colorectal carcinoma: a 7-year follow-up analysis.

A prospectively randomised controlled clinical trial of adjuvant therapy was undertaken, at a single-centre, population-based cancer institute, in patients with Dukes' stages B2 and C colorectal carcinoma after curative surgery. Between 1976 and 1983, 253 patients were randomised to either control (no further therapy after surgery), immunotherapy (oral bacille Calmette-Guérin [BCG] 120 mg once a month) for 5 years or chemoimmunotherapy (oral BCG as above with methyl-cyclohexyl-chloroethyl nitrosourea [meCCNU] 130 mg/m2 on day 1 and 5-fluorouracil [5-FU] 325 mg/m2/day on days 1-5 and 375 mg/m2/day on days 36-40) repeated every 10 weeks for 8 cycles. The median follow-up of patients is now 6.95 years. Of the control, immunotherapy, and chemoimmunotherapy groups 22.35%, 39.28%, and 28.57%, respectively, have relapsed. The log-rank analysis of results shows no disease-free or overall survival advantage for patients receiving adjuvant therapy compared with the control group. Patients receiving adjuvant immunotherapy for stage B2 appear to have a significantly inferior disease-free survival compared with other groups, but their overall survival is similar. There are no significant differences in disease-free or overall survival in the three groups of patients with stage C tumour. Of 82 patients dying, 78.05% died of progressive colorectal carcinoma, 13 patients developed a second malignancy; the remainder died of seemingly unrelated causes.