Temozolomide in combination with fotemustine in patients with metastatic melanoma

Purpose  Temozolomide and fotemustine are both active drugs for treating metastatic melanoma. The present study was designed to assess the efficacy and safety of combination therapy with temozolomide + fotemustine in patients with metastatic melanoma. Methods  Forty patients (median age 50.5 and 22 males) with pathologically confirmed, unresectable, AJCO stage IV melanoma were enrolled into the study. The primary endpoints were tumor response and safety. Patients received oral temozolomide 125 mg/m² on days 1–7 and intravenous fotemustine 80 mg/m² on day 3 every 3 weeks. Results  Fourteen (35%) patients achieved an objective response, including 3 (7.5%) complete and 11 (27.5%) partial responses. Median overall survival time was 6.7 months and 6-month survival rate was 57.4%. Myelosupression, particularly thrombocytopenia, was the primary toxicity. Conclusion  The regimen, temozolomide combined with fotemustine, is an active and moderately safe first-line chemotherapy regimen with acceptable and easily manageable toxicities in patients with metastatic melanoma.     

Docetaxel in combination with dacarbazine in patients with advanced melanoma

OBJECTIVES: The number of agents that are active in patients with metastatic melanoma is limited and cure is not a realistic objective for treatment at this stage. The aim of the study was to evaluate the efficacy and safety of new combination regimen cosisting of docetaxel and dacarbazine (DTIC), as first-line chemotherapy, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with advanced melanoma (including cerebral metastases) were eligible. Docetaxel 80 mg/m(2), i.v. over 1 h infusion on day 1, and DTIC 400 mg/m(2), i.v. over 45 min on days 1 and 2, were given every 21 days, for six cycles. All patients were premedicated, prior to each course, with methylprednisolone per os. RESULTS: Forty-one patients entered the study. Thirty-nine were assessable for response and 40 for toxicity. Objective responses were seen in 10 patients (24% of the eligible; 95% CI = 12.4-40.3%, 26% of the assessable and 28% of patients with cerebral metastases were excluded). Three of them achieved a complete response (7%; 95% CI = 1.5-19.9) and 7 a partial response (17%; 95% CI = 7.1-32.0), while 8 patients demonstrated stabilization of their disease (20%; 95% CI = 8.8-34.9). After a median follow-up of 20 months, the median time to progression was 7 months (range 0.5-22) and the median survival was 10 months (1-24+). The main toxicity (G3-4) was neutropenia which occurred in 8/40 (20%) patients. Additional patients had reversible G3-4 toxicities including alopecia, nausea and vomiting and fatigue; 3 of them presented mild to moderate hypersensitivity reactions to docetaxel. No toxic death was noted. CONCLUSIONS: The combination of docetaxel and DTIC is active and well tolerated in patients with advanced melanoma. While this combination is at least as effective as various combination regimens, it does not differ from that reported for single-agent DTIC.     

Preoperative treatment with bevacizumab in combination with chemotherapy in patients with unresectable metastatic colorectal carcinoma

Purpose

This prospective observational study assessed the efficacy of bevacizumab in combination with chemotherapy as preoperative treatment to downsize tumours for radical resection in patients with unresectable metastatic colorectal cancer (mCRC).

Patients/methods

Patients with mCRC initially unresectable according to predefined criteria were included. Preoperative treatment consisted of bevacizumab (5 mg/kg) combined with oxaliplatin- or irinotecan-based chemotherapy, which was followed by surgery in patients showing clinical benefit. Resection rate was the primary endpoint. Response rate (RR) and clinical benefit of preoperative chemotherapy, and overall survival (OS) were secondary endpoints.

Results

A total of 120 eligible patients were included and received preoperative treatment. Chemotherapy was irinotecan-based in 73 (61 %) patients, oxaliplatin-based in 25 (21 %) and 22 (18 %) patients received more than one line. A RR of 30 % and a clinical benefit rate of 73 % were observed with preoperative chemotherapy. Metastatic resection was possible in 61 (51 %) patients. Median OS was 33 months (95 % CI 31–NA months) for patients undergoing surgery, and 15 months (95 % CI 11–25 months) in non-operated patients. Thirty-five patients experienced 59 postoperative complications (morbidity rate 57 %).

Conclusion

Preoperative bevacizumab-based chemotherapy offers a high surgical rescue rate in patients with initially unresectable mCRC.     

再放疗并同步使用Docetaxel在鼻咽癌放疗后复发病人中的应用

目的:不能手术切除的鼻咽癌放疗后再复发的病人,其治疗困难,化疗疗效差,而单独再放疗只能挽救一小部分病人,本文探讨再放疗并同步使用多西紫彬醇(Docetaxel)在鼻咽癌首次放疗后复发病人中可行性及毒副反应,并评价其疗效。方法:对11例鼻咽癌足量放疗后经组织病理学证实复发、而无法行手术及腔内放疗的患者进行了同步放化疗。放疗采用三维适形放疗,外照射鼻咽部,分次量为1.8Gy,总剂量为36Gy-39.6Gy。化疗采用Docetaxel,15mg/m2,每周一次,静脉滴注。结果:10%、33%的患者分别出现Ⅲ度、Ⅳ度皮肤反应,18%、10%的病人分别出现Ⅲ度、Ⅳ度黏膜反应,18%患者出现Ⅲ度恶心呕吐,27%的患者出现Ⅲ度-Ⅳ度白细胞下降,10%患者出现Ⅲ度血小板下降。1例患者因严重的黏膜反应致使治疗延迟2周。治疗结束后,9例(82%)患者达到CR,2例(18%)达到PR,反应率为100%。结论:对于放疗后局部复发的鼻咽癌患者,采用同步放化疗,3D-CRT同时每周使用Docetaxel是可行的,其毒性反应在可以接受的范围内,短期疗效显著。     

Concomitant radiotherapy with chemotherapy in patients with glioblastoma

Glioblastomas are the most frequent and the most aggressive primary brain tumors in adults. Therapeutic strategy is challenging because of radioresistance and chemoresistance explaining the poor prognosis (median survival of 12 months). Standard therapy consisted until recently of surgery and postoperative radiotherapy while the impact of chemotherapy (investigated as adjuvant, neo adjuvant therapy or concomitant with irradiation) was a matter of debate. However a recent phase III study has concluded to the benefit of adjuvant temozolomide administered during and after radiotherapy. This strategy is yet to become a standard.     

Adherence with surveillance schedule in patients with invasive melanoma

BackgroundSeven percent of patients develop melanoma recurrence after successful treatment, and 4–8% develop a second primary melanoma. This study aimed to assess how providing Survivorship Care Plans (SCPs) to patients may improve adherence to surveillance visits.MethodsAll patients treated for invasive melanoma at our institution between 8/1/2018-2/29/2020 were included in this retrospective chart review. SCPs were delivered in-person to patients and sent to primary care providers and dermatologists. Logistic regression was performed to assess influences on adherence.ResultsOf 142 patients, 73 (51.4%) received SCP regarding their follow-up care. Reception of SCP (p = 0.044) and shorter distance from clinic (p = 0.018) significantly improved rates of adherence. Seven patients developed melanoma recurrences, five were physician-detected. Three patients had primary site recurrence, six had lymph node recurrences, and three had distant recurrences. There were 5 second primaries, all physician-detected.ConclusionOur study is the first to investigate the impact of SCPs on patient adherence in melanoma survivors and the first to reveal a positive correlation between SCPs and adherence in any type of cancer. Melanoma survivors require close clinical follow-up, as demonstrated by our study finding that even with SCPs, most recurrences and all new primary melanomas were physician-detected.     

Abdominal pain with anorexia in patients with breast carcinoma

Breast cancer is the second commonest primary tumour responsible for gastrointestinal metastases after malignant melanoma. The real incidence of gastrointestinal metastases in breast cancer patients is probably underestimated owing to the non-specific presenting symptoms and death of patients caused by other more obvious metastases. The predominant histological subtype of gastrointestinal metastases of breast cancer is invasive lobular carcinoma and the median interval from diagnosis of primary breast cancer to gastrointestinal metastases is five years. We report two cases of disseminated breast cancer with gastrointestinal involvement with a rather long survival.     

Compliance with guidelines and correlation with outcome in patients with advanced germ-cell tumours

PurposeTo evaluate prior compliance with guidelines in patients treated with salvage chemotherapy for advanced germ-cell tumours (GCT).Patients and methodsData concerning the initial management of patients requiring salvage chemotherapy for GCT at Institut Gustave Roussy between 2000 and 2010 were obtained and correlated with recommendations for treatment. Criteria of non-compliance were defined based on guidelines. Compliance with guidelines, predictive factors for non-compliance and the impact on outcome were analysed.ResultsAmong 82 patients treated in the salvage setting, guidelines to initial treatment were followed in only 41 cases (50%). The most common non-compliance criteria were non-adherence to the planned dose (16%), an inappropriate interval between first-line chemotherapy cycles (16%), the lack of post-chemotherapy surgery (16%) and a long interval to post-chemotherapy surgery (48%). Compliance with standard care was better in cancer centres than in other hospitals (private or public) (Odd Ratio (OR): 6.9, P = 0.001). A poor-risk status according to the International Germ Cell Cancer Collaborative Group (IGCCCG) was also predictive of compliance in univariate but not in multivariate analysis. No significant difference in outcome after salvage chemotherapy was observed. Patients relapsing after non-compliant first-line therapy tended to be more easily salvaged, which is consistent with the fact that their initial treatment was inadequate. Some of these relapses were therefore probably not due to true biologically refractory disease.ConclusionGuidelines for first-line treatment are adhered to in only half the patients requiring salvage chemotherapy. As the only predictive factor for non-compliance was the treating centre, centralisation of patients with GCT in well-trained hospitals should be recommended.     

Leukoencephalopathy associated with intra-arterial ACNU in patients with gliomas

Summary Thirty cases of gliomas treated by surgery, radiotherapy and intra-arterial (IA) ACNU were reviewed with a focus on the late side-effect known as leukoencephalopathy. All cases were classified into three groups; remission (10 cases), regrowth (15 cases) and leukoencephalopathy (5 cases) from their outcome. The average total doses of IA ACNU were 49.8 mg/sqm body surface area in the remission group, 157.3 mg/sqm in the regrowth group and 203.1 mg/sqm in the leukoencephalopathy group. There were significant differences in the total IA ACNU doses between the remission group and both regrowth and leukoencephalopathy groups, while no significant differences were noticed in the dose of radiation given. There was a correlation between the total dose of IA ACNU and the occurrence of leukoencephalopathy. An autopsy of a typical case of leukoencephalopathy revealed various degrees of myelin breakdown and thickening of arterial walls, which probably manifested progressive dementia accompanied by urinary incontinence and gait disturbance.     

羟基喜树碱合并放射治疗鼻咽癌的疗效分析

目的探讨DNA拓扑异构酶抑制剂在鼻咽癌联合治疗中的应用价值.方法59例无远处转移的鼻咽癌患者随机分为两组单放组放疗DT64～70Gy/6～7周;综合组放疗同单放组,分别在放疗最初和最后2周每日放疗后加用HCPT6mg/m2.结果3年生存率和局部复发率单放组为76.7%(23/30)和26.7%(8/30),综合组为82.8%(24/29)和17.2%(5/29),P＞0.05.综合组和单放组肿瘤消退率分别为96.6%(28/29)和80%(24/30),P＜0.05,差异有显著性.综合组毒副反应未增加.结论羟基喜树碱是一种安全的抗癌药,与放疗联合应用能增效.     

Enhanced cytotoxicity with methotrexate in conjunction with hypoxanthine in L1210 cells in culture

Summary By inhibiting dihydrofolate reductase, methotrexate (MTX) depletes cellular stores of reduced folates, resulting in the inhibition of DNA and RNA synthesis. Inhibition of RNA synthesis arrests cells in the G₁ phase of the cell cycle, preventing these cells from entering S phase and rendering them insensitive to MTX. Because MTX cytotoxicity can be enhanced by concurrent administration of hypoxanthine (HX), we examined the hypothesis that this modulation can allow normal rates of RNA synthesis and cell cycle progression from G₁ to S phase. For L1210 cells exposed to MTX for 12 h or 24 h, the addition of HX enhanced the cytotoxicity of MTX; however, no enhancement was observed with a 6-h exposure. Inhibition of RNA synthesis by MTX was prevented by concurrent administration of HX. The effect of HX on cell cycle progression was first examined using flow cytometry, which indicated that MTX treatment alone or with concurrent HX caused a buildup of cells with aG₁ content of DNA. Because this technique may fail to distinguish between cells in late G₁ phase, the G₁/S border, or early S, the method of premature chromosome condensation was used to determine cell cycle position based on chromatin morphology. A shift to a higher degree of chromatin decondensation was observed when HX was coadministered with MTX during a 12-h exposure, suggesting progression from G₁ towards S. This correlated with the enhancement of MTX cytotoxicity by HX after 12 h exposure. The results of these studies suggest that HX potentiates MTX cytotoxicity by maintaining RNA synthesis, allowing cells that mightordinarily be arrested in G₁ to progress into the cytotoxic S phase.This research was supported by USPHS Training Grant 5T-32-CA09223.From a dissertation by CRF presented to the department of Pharmacology, the George Washington University School of Arts and Sciences, in partial fulfillment of the requirements for the PhD. Predoctoral support was provided by Grant 5T-32-CA09223; present address: Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, Bldg. 10, Rm.6N116, Bethesda, MD 20892.     

乳腺癌化疗脑发生机制的研究进展

目前,有关乳腺癌化疗脑的研究发现其存在显著的异质性,而乳腺癌可通过其基因表达谱的不同区分不同分子亚型。通过文献综述发现乳腺癌化疗脑的行为学表现复杂多变,分子生物学机制与DNA损伤、APOE、COMT基因多态性有关。事件相关电位中N400和P600的变化及前额叶、海马等脑区功能及脑网络功能连接改变的差异与乳腺癌化疗脑存在明显的关系。但是乳腺癌化疗脑发生的特异性生物学机制,不同分子亚型乳腺癌化疗脑的特征目前尚不明确。     

Weekly docetaxel in combination with capecitabine in patients with metastatic gastric cancer

Docetaxel (T) and capecitabine (X) are active agents against gastric cancer with synergistic antitumor effects. We conducted the current phase II study to assess the response rate and toxicity of combination TX regimen in patients with metastatic gastric cancer. Eligible patients were treated with docetaxel (36 mg/m2 intravenously) on days 1 and 8 and capecitabine (1000 mg/m2 orally twice a day) on days 1-14 of a 3-week schedule until progression occurred. From December 2001 to May 2003, 55 patients with median age of 54 years (range, 22-73 years) were enrolled; 47 patients had measurable lesions. A total of 358 courses of treatment were given, with a median of 5 (range, 1-22+) per patient. Objective responses were documented in 19 of 47 patients with measurable lesions (response rate, 40.4%; 95% confidence interval [CI], 25.9-54.9), with the median response duration of 5.6 months (range, 2.1-13.6+). At a median follow up of 15.9 months for all of 55 study patients, the median time to progression and survival were 4.5 months (95% CI, 3.4-5.6) and 12.0 months (95% CI, 7.5-16.6), respectively. Hematologic toxicities were mild to moderate, and the observed grade 3 nonhematologic toxicities, the most frequent of which was stomatitis, were generally manageable. Four patients experienced pneumonitis, but all of them responded to steroid treatment. The TX regimen was relatively well tolerated and effective against metastatic gastric cancer, with the added advantage of being an outpatient regimen.