Prevention of radiochemotherapy-induced toxicity with amifostine in patients with malignant orbital tumors involving the lacrimal gland: a pilot study

BACKGROUND: To use amifostine concurrently with radiochemotherapy (CT-RT) or radiotherapy (RT) alone in order to prevent dry eye syndrome in patients with malignancies located in the fronto-orbital region. METHODS: Five patients (2 males, 3 females) with diagnosed malignancies (Non-Hodgkin B-cell Lymphoma, neuroendocrine carcinoma) involving the lacrimal gland, in which either combined CT-RT or local RT were indicated, were prophylactically treated with amifostine (500 mg sc). Single RT fraction dose, total dose and treatment duration were individually adjusted to the patient's need. Acute and late adverse effects were recorded using the RTOG score. Subjective and objective dry eye assessment was performed for the post-treatment control of lacrimal gland function. RESULTS: All patients have completed CT-RT or RT as indicated. The median total duration of RT was 29 days (range, 23 - 39 days) and the median total RT dose was 40 Gy (range, 36 - 60 Gy). Median lacrimal gland exposure was 35.9 Gy (range, 16.8 - 42.6 Gy). Very good partial or complete tumor remission was achieved in all patients. The treatment was well tolerated without major toxic reactions. Post-treatment control did not reveal in any patient either subjective or objective signs of a dry eye syndrome. CONCLUSION: The addition of amifostine to RT/CT-RT of patients with tumors localized in orbital region was found to be associated with absence of dry eye syndrome

Clinical practice guideline on the optimal radiotherapeutic management of brain metastases

BACKGROUND: An evidence-based clinical practice guideline on the optimal radiotherapeutic management of single and multiple brain metastases was developed. METHODS: A systematic review and meta-analysis was performed. The Supportive Care Guidelines Group formulated clinical recommendations based on their interpretation of the evidence. External review of the report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from Cancer Care Ontario's Practice Guidelines Coordinating Committee (PGCC). RESULTS: One hundred and nine Ontario practitioners responded to the survey (return rate 44%). Ninety-six percent of respondents agreed with the interpretation of the evidence, and 92% agreed that the report should be approved. Minor revisions were made based on feedback from external reviewers and the PGCC. The PGCC approved the final practice guideline report. CONCLUSIONS: For adult patients with a clinical and radiographic diagnosis of brain metastases (single or multiple) we conclude that, • Surgical excision should be considered for patients with good performance status, minimal or no evidence of extracranial disease, and a surgically accessible single brain metastasis. • Postoperative whole brain radiotherapy (WBRT) should be considered to reduce the risk of tumour recurrence for patients who have undergone resection of a single brain metastasis. • Radiosurgery boost with WBRT may improve survival in select patients with unresectable single brain metastases. • The whole brain should be irradiated for multiple brain metastases. Standard dose-fractionation schedules are 3000 cGy in 10 fractions or 2000 cGy in 5 fractions. • Radiosensitizers are not recommended outside research studies. • In select patients, radiosurgery may be considered as boost therapy with WBRT to improve local tumour control. Radiosurgery boost may improve survival in select patients. • Chemotherapy as primary therapy or chemotherapy with WBRT remains experimental. • Supportive care is an option but there is a lack of Level 1 evidence as to which subsets of patients should be managed with supportive care alone. Qualifying statements addressing factors to consider when applying these recommendations are provided in the full report. The rigorous development, external review and approval process has resulted in a practice guideline that is strongly endorsed by Ontario practitioners

The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

TARGET POPULATION: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. RECOMMENDATION: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged

Homogeneous MGMT Immunoreactivity Correlates with an Unmethylated MGMT Promoter Status in Brain Metastases of Various Solid Tumors

The O6-methylguanine-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical reports on treating brain metastases with temozolomide describe varying effects. This may be due to the fact that MGMT promoter methylation of brain metastases has not yet been explored in depth. Therefore, we assessed MGMT promoter methylation of various brain metastases including those derived from lung (n = 91), breast (n = 72) kidney (n = 49) and from malignant melanomas (n = 113) by methylation-specific polymerase chain reaction (MS-PCR) and MGMT immunoreactivity. Fifty-nine of 199 brain metastases (29.6%) revealed a methylated MGMT promoter. The methylation rate was the highest in brain metastases derived from lung carcinomas (46.5%) followed by those from breast carcinoma (28.8%), malignant melanoma (24.7%) and from renal carcinoma (20%). A significant correlation of homogeneous MGMT-immunoreactivity (>95% MGMT positive tumor cells) and an unmethylated MGMT promoter was found. Promoter methylation was detected in 26 of 61 (43%) tumors lacking MGMT immunoreactivity, in 17 of 63 (27%) metastases with heterogeneous MGMT expression, but only in 5 of 54 brain metastases (9%) showing a homogeneous MGMT immunoreactivity. Our results demonstrate that a significant number of brain metastases reveal a methylated MGMT-promoter. Based on an obvious correlation between homogeneous MGMT immunoreactivity and unmethylated MGMT promoter, we hypothesize that immunohistochemistry for MGMT may be a helpful diagnostic tool to identify those tumors that probably will not benefit from the use of alkylating agents. The discrepancy between promoter methylation and a lack of MGMT immunoreactivity argues for assessing MGMT promoter methylation both by immunohistochemical as well as by molecular approaches for diagnostic purposes

Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a meta-analysis

To assess the early effect of epoetin beta on survival and tumour progression in anaemic patients with cancer, data were pooled from nine randomised clinical trials comparing epoetin beta with placebo or standard care. Studies were not primarily designed to assess these end points. Follow-up was for treatment duration plus 4 weeks following therapy completion. All adverse events (AEs) were retrospectively reviewed blinded, for progression. Thromboembolic events were also assessed. Data analysis involved standard statistical tests. Overall, 1413 patients were included (epoetin beta, n=800; control, n=613; 56% haematological, and 44% solid). Median initial epoetin beta dose was 30 000 IU/week. Overall survival during months 0–6 was similar with epoetin beta and control (0.31 vs 0.32 deaths/patient-year). No increased mortality risk was seen with epoetin beta (relative risk (RR) 0.97, 95% CI: 0.69, 1.36; P=0.87). There was a significantly reduced risk of rapidly progressive disease for epoetin beta (RR 0.78, 95% CI: 0.62, 0.99; P=0.042). Epoetin beta was associated with a slightly higher frequency of thromboembolic events vs control (5.9% vs 4.2% of patients) but thromboembolic-related mortality was identical in both groups (1.1%). Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic-related mortality

Whole brain radiotherapy with radiosensitizer for brain metastases

<p>Abstract</p> <p>Purpose</p> <p>To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment.</p> <p>Methods</p> <p>A meta-analysis of randomized controlled trials (RCT) was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently.</p> <p>Results</p> <p>A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84–1.25, p = 0.77). Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 – 1.03) and brain tumor progression (OR = 1.11, 95% CI 0.9 – 1.3) when the two arms were compared.</p> <p>Conclusion</p> <p>Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide), have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast) to have positive action in lung and breast carcinoma brain metastases in association with WBRT.</p

Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

Epoetin-β is used to treat patients with metastatic cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life. This meta-analysis of 12 randomised, controlled studies evaluated the impact of epoetin-β on overall survival, tumour progression and thromboembolic events (TEEs). A total of 2297 patients were included in the analysis (epoetin-β, n=1244; control, n=1053; 65% solid and 35% nonmyeloid haematological malignancies). A prespecified subgroup analysis assessed the effects in patients with a baseline Hb⩽11 g dl−1, corresponding to current European Organisation for Research and Treatment of Cancer (EORTC) guidelines. No statistically significant effect on mortality was observed with epoetin-β vs control, both overall (hazard ratio (HR)=1.13; 95% CI: 0.87, 1.46; P=0.355) and in patients with baseline Hb⩽11 g dl−1 (HR=1.09; 95% CI: 0.80, 1.47; P=0.579). A trend for a beneficial effect on tumour progression was seen overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb⩽11 g dl−1 (HR=0.80; 95% CI: 0.65, 0.99; P=0.041). An increased frequency of TEEs was seen with epoetin-β vs control (7 vs 4% of patients); however, TEEs-related mortality was similar in both groups (1% each). The results of this meta-analysis indicate that when used within current EORTC treatment guidelines, epoetin-β has no negative impact on survival, tumour progression or TEEs-related mortality

Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

The substantial augmentation of the radiation sequelae during chemo–radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo–radiotherapy scheme with Stealth® liposomal doxorubicin (Caelyx®) and Docetaxel (Taxotere®) in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere® was 20 mg m−2 week and of Caelyx® was 15 mg m−2 every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere®/Caelyx® was, thereafter, increased to 20/25 (five patients) and 30/25 mg m−2 (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The ‘in-field’ radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere®/Caelyx® chemo–radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the ‘in-field’ toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer

A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 × 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m−2 day−1 × 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3–752/4–433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3–399/4–228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment