Identifying pre-post chemotherapy differences in gene expression in breast tumours: a statistical method appropriate for this aim

Although widely used for the analysis of gene expression microarray data, cluster analysis may not be the most appropriate statistical technique for some study aims. We demonstrate this by considering a previous analysis of microarray data obtained on breast tumour specimens, many of which were paired specimens from the same patient before and after chemotherapy. Reanalysing the data using statistical methods that appropriately utilise the paired differences for identification of differentially expressed genes, we find 17 genes that we can confidently identify as more expressed after chemotherapy than before. These findings were not reported by the original investigators who analysed the data using cluster analysis techniques.     

Anaplastic thyroid carcinoma: three protocols combining doxorubicin,hyperfractionated radiotherapy and surgery

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gyx2 (A) and 1989-92 1.3 Gyx2 (B). Thereafter 1.6 Gyx2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) 'had a survival' exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005).     

Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group.

BACKGROUND: To determine the activity and safety of the combination of paclitaxel and pegylated liposomal doxorubicin (Caelyx) in patients with locally advanced breast cancer. PATIENTS AND METHODS: This was a multicenter phase II study. Thirty-five newly diagnosed patients with locally advanced breast cancer were included in the study. Histological or cytological diagnosis was necessary for inclusion. Median age was 54 years (range 26-73 years). Fifteen patients were premenopausal and 20 postmenopausal. Paclitaxel was administered at a dose of 175 mg/m(2) and pegylated liposomal doxorubicin 35 mg/m(2) every 3 weeks for six cycles. RESULTS: Twenty-five patients (71%) responded. Six (17%) had a complete response, 19 (54%) had a partial response, four remained stable, two progressed and four were not evaluated for response due to discontinuation of chemotherapy. Three patients had a pathologically complete response. A total of 173 cycles were administered. The primary toxicity observed was skin toxicity. Grade 3 skin toxicity was noted in four patients (11%). Palmar-plantar erythrodysesthesia (PPE) grade 3 was experienced by three (9%). Two patients presented with PPE and skin toxicity. Hematological toxicities included grade 3 leukopenia in four patients (3%). Other grade 3 toxicities were uncommon and included only alopecia in 29 patients (83%). Grade 3 or 4 neurotoxicity was not observed in any patient. Dose reduction was necessary in seven patients; in six due to skin toxicity and in one due to neutropenia. Four patients discontinued treatment due to skin toxicity. There were no treatment-related deaths. CONCLUSIONS: The combination of pegylated liposomal doxorubicin and paclitaxel was active in locally advanced breast cancer. The primary toxicity was cutaneous toxicity and it was manageable.     

Second malignant tumors following treatment during childhood and adolescence for cancer

Many pediatric and adolescent cancer patients are treated with carcinogenic chemotherapeutic agents and radiation therapy to achieve permanent control of their malignancy. These modalities may induce a new cancer in the successfully treated patient. To identify disease and treatment factors which increased the risk of occurrence of a second malignant tumor following modern treatment for cancer during childhood or adolescence, we reviewed the courses of 1,406 previously untreated patients who were less than 20 years of age at diagnosis and were treated at Roswell Park Cancer Institute between January 1, 1960 and December 31, 1989. Eighteen patients developed a second malignant tumor, including two meningiomas, 2.65-25.65 years after diagnosis of the first cancer. The actuarial risk of a second malignant tumor was 5.6% at 25 years after diagnosis. Using Cox proportional hazards modelling, we identified prior therapy with BCNU (P = 0.0055) and doxorubicin (P = 0.0254) as the only factors that were significantly associated with the risk of a second malignant tumor. Three second malignant tumors of the central nervous system occurred following treatment with a nitrosourea. Successfully treated patients must be carefully followed to identify treatment related malignant tumors at an early Stage. © 1994 Wiley-Liss, Inc.     

Multiple cutaneous acral metastases in a woman with breast adenocarcinoma treated with pegylated liposomal doxorubicin: incidental or aetiological association?

This paper reports the case of a 45-year-old female with histologically documented, multiple cutaneous metastases in the palmar and plantar surface of the fingers and toes originating from a breast adenocarcinoma after treatment with a docetaxel and pegylated liposomal doxorubicin regimen. The rarity of such a metastatic pattern from breast cancer and the eventual association with the chemotherapy administered are thoroughly discussed.     

Morphological manifestations of heart remodeling in anthracycline-induced dilated cardiomyopathy

The morphogenesis of anthracycline-induced dilated cardiomyopathy was studied after single sublethal dose of doxorubicin. Cardiomyocyte depopulation (up to 27%) and decrease in their regeneratory plastic reactions were the main mechanisms of cardiac failure development after anthracycline (doxorubicin) treatment, determining the type of heart remodeling by the dilatation variant. Cardiomyocyte elimination and atrophy during the development of anthracycline-induced regeneratory plastic cardiac insufficiency were paralleled by hypertrophy of remaining cardiomyocytes and diffuse and small focal sclerosis of the myocardium, which could be regarded as a correlated compensatory reaction of the connective tissue to the decrease in the number of muscle fibers.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 12, pp. 684–689, December, 2004This revised version was published online in April 2005 with a corrected cover date.     

Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.     

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.