pirarubicin and Neoplasm-Metastasis

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Confidence Intervals; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Heart; Heart Failure; Humans; Incidence; Menopause; Middle Aged; Neoplasm Metastasis; Survival Analysis

Forty-seven patients with advanced non-small cell lung cancer (NSCLC) were treated in a multicentre phase II study with pirarubicin (THP), 4'-O-tetrahydropyranyl-doxorubicin using a dosage of 70 mg/m2 every 3 weeks. The median age of the patients was 59 years (range 45-70) and the performance status grade 0-2 (WHO). Thirty-eight patients had stage IV and 9 stage III (UICC). Twenty-six patients had an adenocarcinoma. 19 a squamous cell carcinoma, and 2 a polymorphocellular carcinoma. Six out of 45 evaluable patients achieved a partial remission leading to an overall response rate of 13%. Eighteen patients showed no change (NC), 12 were progressive (PD), 2 patients had early progression (EP), and 7 patients died during the first course with clinical signs of tumor progression (early death). The median survival time was 4.6 months. Leukocytopenia and thrombocytopenia (WHO grade 4) was experienced in 8.5% and 2.1%, nausea and vomiting (grade 2 and 3) by 32% of the patients. There was no cardiotoxicity or other severe side effects. Pirarubicin has only a moderate antineoplastic activity in patients with advanced NSCLC. Observed response rates are similar to those reported for doxorubicin, but the toxic side effects are milder.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis

Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

Topics: Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Follow-Up Studies; Humans; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Survival Rate

Biomimetic design has been extensively investigated. The only FDA-approved biomimetic albumin-bound paclitaxel may not be beneficial to some treated patients due to rapid dissociation upon intravenous infusion and no substantial improvement in the drug's pharmacokinetics or biodistribution. Herein, we developed an alternative and injectable preformed albumin-bound anticancer drug delivery. We combined HSA, Kolliphor HS 15 (HS15), and pirarubicin (THP) via purely physical forces in a thin-film hydration method to obtain an albumin-bound complex of HSA-THP. The lack of any chemical reactions preserves HSA bioactivity, in contrast to the destroyed secondary structure within AN-THP (albumin nanoparticle of THP) for the harsh manipulation during preparation. In vitro, HSA-THP showed a significantly higher cellular uptake efficiency than THP, and the complex was more cytotoxic. In vivo, HSA-THP showed longer half-life than THP. It also exhibited greater tumor accumulation and tumor penetration via gp60- and SPARC-mediated biomimetic transport than THP and AN-THP. As a result, HSA-THP showed strong antitumor and antimetastasis efficacy, with relatively little toxicity. These results suggest the clinical potential of biomimetic tumor-targeted drug delivery.

Topics: Albumins; Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Humans; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Stearates

A 13-year-old boy was referred to us for investigation of a giant liver mass, approximately 16 cm in diameter. Sonographically guided percutaneous needle biopsy was performed and histological examination revealed a fetal-type hepatoblastoma. After four courses of chemotherapy, we performed a left hepatic trisegmentectomy. Follow-up computed tomography, 55 months after the surgery, showed a 1-cm tumor on the route of the preoperative needle biopsy. A second laparotomy revealed a peritonealised tumor, which was excised. The histology of this tumor was identical to that of the primary hepatoblastoma. To our knowledge, this is only the second report of needle tract implantation of hepatoblastoma after percutaneous needle biopsy.

Topics: Adolescent; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy, Needle; Cisplatin; Combined Modality Therapy; Doxorubicin; Follow-Up Studies; Hepatectomy; Hepatoblastoma; Humans; Liver Neoplasms; Male; Neoplasm Metastasis; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

To evaluate the effect of anthracycline pirarubicin-based regimen in association with different ways of fluorouracil (5-Fu) as neoadjuvant and adjuvant chemotherapy for primary breast cancer.. Two hundred and eighty-nine primary breast cancer patients who were to be operated, two to eight cycles of pirarubicin in association with cyclophosphamide and 5-Fu (CTF or CTFci regimen) were given before operation. The pathological response rate, effect and its relation with the infusion routes of 5-Fu were analyzed.. The overall pathological complete remission (pCR) rate was 28.4%. The median follow-up period was 39 months. The 5-year DFS was 87.6% (95% CI:82.1% to 92.7%), 5-year DDFS was 89.9% (95% CI:84.0% to 95.8%), and overall survival was 99.6%. CTFci (5-Fu, continuous infusion) regimen was superior to CTF regimen in pCR rates (32.3% vs. 20.2%, P = 0.037), and 5-year DDFS were 92.9% and 80.1%, respectively (P = 0.015). The pCR group was superior to non-pCR group in 5-year DDFS (92.4% vs. 85.6%, P = 0. 033). The pCR rate of patients with ER/PR-positive tumor was significantly lower than those of ER/PR-negative (P = 0.004). The 5-year DDFS rates of HER-2 (+) and HER-2(-) groups were 75.0% and 91.9%, respectively (P = 0.043). In the ER/PR-positve group, the 5-year DDFS of CTFci regimen was superior to those of CTF regimen, 91.4% vs. 81.4% (P = 0.047).. CTF/CTFci regimen as neoadjuvant and adjuvant chemotherapy is effective for primary breast cancer. CTFci regimen is superior to CTF regimen in pathological complete response rate and 5-year DDFS. CTFci regimen may do better to ER/PR (+) patients' benefits compared with CTF regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Remission Induction; Retrospective Studies; Survival Rate

Three pediatric patients with infratentorial metastatic non-epithelial malignant brain tumors were successfully treated by radical surgical resection followed by aggressive radiochemotherapy. One patient with neuroblastoma and two with rhabdomyosarcoma were successfully treated by first line multimodal treatments, but developed infratentorial metastasis after several months of remission. All patients revealed intracranial metastases manifesting as rapidly progressing neurological symptoms caused by mass effect in the posterior fossa. Radical surgical resection was performed without morbidity. The patients were then treated by adjuvant radiochemotherapy with or without autologous peripheral blood stem cell transplantation, resulting in complete remission. Two patients developed extracranial recurrences 4 months after the treatments for intracranial metastases. One patient was treated by second high-dose chemotherapy with allogeneic cord blood transplantation, again resulting in complete remission. Another patient was treated by second chemotherapy and maintaining stable disease. The other patient maintained complete remission. All three patients were alive without neurological deficit for 8, 11, and 12 months after diagnosis of brain metastasis. Patients with infratentorial brain metastases of highly malignant pediatric non-epithelial tumors are in a severe clinical state, but still can have longer and useful lives with aggressive multimodal treatments combined with radical surgical resection.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Carboplatin; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Dactinomycin; Doxorubicin; Etoposide; Humans; Ifosfamide; Infant; Infratentorial Neoplasms; Irinotecan; Melphalan; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma; Thiotepa; Topotecan; Vincristine

We present the outcome of treatment with preoperative concurrent chemoradiotherapy and surgery for resectable lingual squamous cell carcinoma more than 3 cm in its greatest dimension. Twenty patients were enrolled in this study between June 2001 and August 2004. Concurrent chemoradiotherapy included intraarterial pirarubicin (THP) (5 mg/day), intravenous continuous 5-FU, and radiation, usually followed by surgery. Complete response rate was 100%. Notably, 8 of 12 patients who underwent surgery exhibited pathologically complete response, though three patients developed recurrence or distant metastasis. The main adverse effects were mucositis (13/20) and leucopenia (9/20), both of which were acceptable. Although long-term results should be considered, our treatment method appears very useful for lingual squamous cell carcinoma greater than 3 cm, with a remarkably high rate of pathological local control and acceptable adverse events.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Preoperative Care; Tongue Neoplasms; Treatment Outcome

We have determined whether sequential molecular detection of minimal residual disease (MRD) in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma (NB).. Bone marrow samples from 19 patients over 12 months of age with stage 4 neuroblastoma were sequentially examined for tumor cell contamination by detecting tyrosine hydroxylase (TH) mRNA using reverse transcription-polymerase chain reaction (RT-PCR). All patients received repetitive multi-drug chemotherapy including cisplatin, cyclophosphamide or ifosphamide, adriamycin, and etoposide or vincristine. Seventeen patients received myeloablative therapy with hematopoietic stem cell transplantation after achieving complete remission.. All but one patient were histologically positive for tumor cells in BM samples at diagnosis, and they became negative for tumor cells within 3 months histologically. By the RT-PCR analysis, all patients were positive for TH mRNA in BM samples at diagnosis, and they became negative for TH mRNA 1 to 13 months after the start of chemotherapy. Six patients whose BM samples became negative for TH mRNA within 4 months after the start of chemotherapy remained alive without evidence of disease (median 61 months, range 20-76). In contrast, 12 of 13 patients whose BM samples remained positive at that time developed relapse and 10 of them died of disease (median 24 months, range 13-43). There was a statistically significant difference in survival between the two groups (P < 0.05). No significant difference of clinical characteristics by the MRD positivity at 4 months after the start of chemotherapy.. Persistence of MRD in BM at 4 months after the start of chemotherapy could predict poor prognosis in advanced neuroblastoma.

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow Examination; Bone Marrow Transplantation; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Life Tables; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Staging; Neoplasm, Residual; Neuroblastoma; Prognosis; Retroperitoneal Neoplasms; RNA, Messenger; RNA, Neoplasm; Survival Analysis; Treatment Outcome; Tyrosine 3-Monooxygenase; Vincristine

Sixteen heavily pretreated patients (pts) (4 surgery + chemotherapie + radiotherapy; 4 chemotherapy + radiotherapy: 6 surgery + radiotherapy; 2 chemotherapy) and one previously untreated patient, who refused surgery and or radiotherapy, all with progressive disease, with advanced squamous cell carcinoma of the head and neck were included in a phase II study with pirarubicin 60 mg/m2 i.v. day 1 every 3-4 weeks (CT). All pts received at least one course of CT. 15 pts were evaluable for response, all 17 pts were evaluable for toxicity. Female (male ratio 1/16; mean age 56 (42-68) yrs, mean performance status 70% (50-70). Seventeen pts received a mean of 3 (1-8) courses, 2 pts had received only one course of CT. Response and toxicity were assessed according to WHO classification. Results after 1-8 courses of CT: 1 (7%) complete remission; 1 (7%) partial remission; 9 (60%) no change; 4 (26%) progressive disease. No toxicity of grade IV was observed. Mean duration of remission 16 weeks. Median survival time 7 (1-10) months. 9 pts died and 8 pts are alive; six of them had progressive disease.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Doxorubicin; Drug Evaluation; Female; Humans; Hypopharyngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oropharyngeal Neoplasms; Palliative Care; Pharyngeal Neoplasms

Fourteen patients with metastatic breast cancer previously treated with one chemotherapy regimen received Pirarubicin at a dose of 70 mg/m2 at 3-week intervals. In 7 patients the dose had to be reduced, in 1 patient to 40 mg/m2 and in 6 patients to 50-60 mg/m2. There were 1 complete and 2 partial remissions. These objective responses were observed in soft tissue, lung and pleural areas and lasted 1+; 4+ and 5+ months. Grade 3 and 4 leukopenia was found in 42%, grade 3 thrombocytopenia in 2%, grade 3 nausea/vomiting in 29% of the cycles. Grade 1 and 2 alopecia occurred in 64% of the patients, the remaining 36% of the patients did not suffer from any alopecia. No cardiotoxic side effects were observed in 13 patients. In 1 patient with severe coronary heart disease extrasystoles and reduction in left ventricular ejection fraction occurred. Pirarubicin has antitumor activity in previously treated metastatic breast cancer patients.

Topics: Adult; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Humans; Middle Aged; Neoplasm Metastasis

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

Topics: Adult; Aged; Blood Cell Count; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Heart Diseases; Humans; Middle Aged; Neoplasm Metastasis