pirarubicin and Leukopenia

Pirarubicin tetrahydropyranyl adriamycin (THP-ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin-resistant cell lines. We performed a phase II study of biweekly THP-COP [50 mg/m(2) pirarubicin, 750 mg/m(2) cyclophosphamide, 1.4 mg/m(2) vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1-5] in patients with peripheral T-cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T-cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP-COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow-up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3-year progression-free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP-COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP-COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485).

Topics: Adolescent; Adult; Aged; Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Leukopenia; Lymphoma, T-Cell, Peripheral; Lymphopenia; Middle Aged; Neutropenia; Prognosis; Survival Analysis; Treatment Outcome; Vincristine; Young Adult

The safety of chemotherapy combining TS-1 and pirarubicin (THP) for treatment of recurrent or locally advanced gastric cancer was evaluated. THP was administered by intravenous drip infusion at a dose of 14 mg/m2 every other week. TS-1 was administered orally at a dose of 40 mg/m2 twice a day for 2 weeks followed by 2 weeks of rest (level 1), for 3 weeks followed by 2 weeks of rest (level 2), and for 4 weeks followed by 2 weeks of rest (level 3). Three patients were treated with the level 1 schedule. One patient with peritoneal dissemination received 22 courses of the treatment, and benefited from a long-term NC. However the remaining 2 cases were diagnosed as PD after 4 courses and were withdrawn from further treatment. Two patients in this group suffered from grade 2 adverse events according to the NCI-CTC. Only 1 patient who had liver metastasis was treated at level 2. Fourteen courses were administered, and a PR was achieved while grade 2 adverse events were observed. One of 3 patients who were treated with level 3 had grade 3 adverse events. Consequently, 3 more cases were added to this dose level, and no additional grade 3 adverse events were observed, while grade 2 adverse events were seen in 4 cases. Urinary urgency had completely disappeared in 1 patient with peritoneal recurrence. Myelosuppression, which was the main observed adverse event, was well controlled and of brief duration. The response, including alleviation of clinical symptoms, was confirmed in 3 of 5 chemo-naive patients.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Administration Schedule; Drug Combinations; Female; Humans; Leukopenia; Liver; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Vomiting, Anticipatory

Twenty-four eligible patients (23 of whom were evaluated) with advanced and metastatic breast cancer were treated at the Saitama Cancer Center every 4 weeks with pirarubicin (30 mg/m2 i.v., day 1 and 8), cyclophosphamide (200 mg/m2 div, day 1 and 8) and doxifluridine (800 mg/day po, day 1-14). The 23 evaluable patients had a median age of 49.7 years (range 35.3-72.1) and underwent a median number of 3 cycles (range 2-5). Grade 4 leukopenia (10/24 patients) was the dose-limiting factor and led to infection in one patient. Four complete responses and 7 partial responses with a median duration of 12.1 months (range 2.6-61.0) were achieved, resulting in an overall response rate of 47.8%. The 50% survival duration was 22.9 months.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Floxuridine; Humans; Leukopenia; Middle Aged; Neoplasm Recurrence, Local

We studied the remission rate and adverse effects in THP-COPBLM therapy consisting of pirarubicin (THP), which is said to be less cardiotoxic than doxorubicin. Subjects were 21 non-Hodgkin's lymphoma (NHL) patients older than 70 years of age. Of 21 patients, complete remission (CR) was achieved in 16 patients (76.2%) and partial remission in 2 patients (9.5%). Classified by stages, CR was achieved in 5 out of 6 patients in stage II, 7 out of 8 in stage III and 4 out of 7 in stage IV. Two-year survival rate was 61.5%. Adverse effects were observed in 7 patients (33.3%) with grade 3 or above leukocytopenia, 2 (9.5%) with thrombocytopenia and 1 (4.8%) with gastrointestinal symptoms. However, no abnormality in EKG was found, and the left ventricular ejection fraction in echocardiography did not differ before and after therapy. One patient each developed pneumonia and sepsis when they had granulocytopenia. THP-COPBLM therapy seemed useful in treatment of elderly patients with NHL. There were few adverse effects such as gastrointestinal symptoms or cardiotoxicity. However, leukocytopenia was observed in many patients despite combined use of G-CSF, suggesting the dose and administration method of THP should be studied further.

Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Female; Humans; Leukopenia; Lymphoma, Non-Hodgkin; Male; Prednisolone; Procarbazine; Remission Induction; Vincristine

A total of 50 patients were treated weekly with 5-fluorouracil (FU), leucovorin (LV), and 4'-O-tetrahydropyranyl-doxorubicin (THP) as first-line chemotherapy for advanced breast cancer (ABC). In phase I the doses of LV (500 mg/m2, day 1) and FU (350 mg/m2, day 1) were held constant, while the dose of THP (day 1) was escalated, from the initial dose of 10 mg/m2 up to the maximum tolerated dose (MTD). Twenty-eight patients entered phase I, and MTD for THP was defined as 35 mg/m2 in this combination. Dose-limiting toxicities were myelosuppression and hepatotoxicity. In phase II, another 22 patients were treated with THP at a dose level of 30 mg/m2. Including 4 patients already treated at this dose in the first part, 25 patients were evaluable for response: 1 patient obtained a complete response (CR) and 13 showed a partial response (PR), giving an objective response rate of 56%. The median duration of response was 9.1+ months and median survival, 15.5+ months. Side effects were generally mild, with ECOG grade I and II leukopenia in 51% of all cycles and grade III in 3% of the courses. Other toxicity included nausea and vomiting (54% and 8%, respectively) and alopecia (24%), all restricted to ECOG grade I and II. Our results suggest that weekly THP/LV-FU represents an active regimen for first-line treatment of ABC with relative low toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Middle Aged; Nausea

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Agents; Doxorubicin; Endometrial Neoplasms; Female; Humans; Leukopenia; Middle Aged; Ovarian Neoplasms; Thrombocytopenia; Uterine Cervical Neoplasms; Vomiting

A multi-institutional collaborative phase II study of (2"R)-4-O-tetrahydropyranyladriamycin (THP) was performed by intravenous administration to patients with advanced or recurrent gastric cancer. The administration schedules were (1) 40-60 mg/body every 3 or 4 weeks and (2) 20-40 mg/body once a week. Of 58 registered patients, 49 cases were eligible and 37 cases were evaluable for response. The therapeutic results were 1 CR, 4 PR, 14 NC and 18 PD. The response rate of the evaluable cases was 13.5%. The side effects were mainly bone marrow suppression and digestive symptoms. In particular, the frequency of leukopenia was a high 75.5%, while there was a decrease in hemoglobin in 38.8% and anorexia in 30.6%. The frequency and severity of alopecia, which is a known problem with anthracyclines, were slight, and no abnormal electrocardiograms were observed.

Topics: Adenocarcinoma; Adult; Aged; Anorexia; Bone Marrow; Doxorubicin; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Stomach Neoplasms

We present the response rate and adverse effects of our regimen of concurrent chemoradiotherapy with pirarubicin (THP) and 5-fluorouracil (5-FU) for oral and maxillary carcinoma.. Fifteen patients with oral (10 cases) or maxillary (5 cases) squamous cell carcinoma who underwent our concurrent chemoradiotherapy with the combination of intraarterial pirarubicin, intravenous continuous 5-fluorouracil, and radiation between March 2001 and February 2003 in our department were entered in this study. THP (5 mg/day) was infused into the lingual or maxillary artery one hour before radiation on days 1-5 and 8-12, while intravenous 5-FU (150 mg/m2/day) was instilled continuously on days 1-5, 8-12, 15-19, and 22-26 in accordance with the radiation schedule (2 Gy/day). Consequently, total doses of THP, 5-FU, and radiation were 50 mg, 3000 mg/m2 and 40 Gy, respectively. After the treatment series, response rate and adverse effects were evaluated.. Response rate achieved 100% (12 cases exhibited a complete response and the remaining 3 a partial response). Notably, all 10 patients with oral carcinoma exhibited complete response. The main adverse effects were leucopenia (6/15) and mucositis (6/15), both of which were acceptable.. This concurrent chemoradiotherapy is very useful for oral and maxillary carcinoma as a preoperative modality with remarkably high response rate and acceptable adverse events.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Humans; Immunosuppressive Agents; Inflammation; Leukopenia; Male; Maxillary Neoplasms; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Radiotherapy, Adjuvant; Tomography, X-Ray Computed; Treatment Outcome

The therapeutic efficacy of weekly coadministration of paclitaxel (TXL) and pirarubicin (THP) on docetaxel (TXT)- and epirubicin-resistant recurrent breast cancer, adverse reactions caused by this therapy, and the possibility of ambulatory treatment using it were evaluated. The present study was conducted in 11 patients with recurrent breast cancer with pretreatment with CEF and TXT. The site of recurrence was the lung in 9 patients, lymphnodes in 2, bones in 1, liver in 1 and local foci in 1. One cycle consisted of 20 mg/m2 of THP followed by 80 mg/m2 of TXL 4 h later, repeated three times every other week. Three to six cycles were conducted in each patient. An anti-emetic drug was administered before administration of THP as short premedication. Dexamethasone (16 mg; i.v.) and d-chlorpheniramine maleate (12 mg; p.o.) were administered 1 h before administration of TXL and ranitidine (100 mg; i.v.) was administered 30 min before administration of TXL. Ubidecarenone (30 mg/day; p.o.) was administered for 3 days. The response rate was 27.3% with a rating of PR in 3 patients, NC in 6, and PD in 2. Adverse reactions observed included transient facial hot flushes, alopecia grade 1 or milder grade 1 symptoms, and peripheral nerve damage. No adverse reactions such as myocardial disorders or congestive heart failure were noted. Grade 3 and grade 2 neutropenia occurred in 1 and 6 patients, respectively, and 4 patients were admitted for treatment of this. In conclusion, the short premedication was useful, and this was thought to make it possible to conduct ambulatory treatment with TXL + THP in some patients. The response rate of 27.3%, however, was not satisfactory. It will be necessary to clarify the characteristics of this therapy by administering it to a wider spectrum of patients.

Topics: Adult; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukopenia; Middle Aged; Nausea; Neoplasm Recurrence, Local; Paclitaxel

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Doxorubicin; Drug Administration Schedule; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Humans; Leukopenia; Middle Aged; Neutropenia; Ovarian Neoplasms; Paclitaxel; Retrospective Studies; Taxoids; Thrombocytopenia; Uterine Cervical Neoplasms

The objective of the present study was to evaluate the relationship between the pharmacokinetic parameters of pirarubicin and of its metabolite doxorubicin measured in plasma and whole blood, and the hematologic toxicity of this drug, in order to evaluate the predictability of changes in white blood cells (WBC) by single measurement of drug concentrations. This pharmacokinetic-pharmacodynamic relationship was studied in a total of 45 patients with different tumor types treated by combined chemotherapy containing pirarubicin, administered as short infusion (10+/-2 min) at doses ranging from 50 to 90 mg. In 45 courses performed in 24 patients, we established the relationship between the half-product of pirarubicin level in whole blood at the end of the infusion and the duration of this infusion, which represents an estimate of the area under the time x concentration curve (AUC(PIRA,wb,ei) = C(PIRA,wb,ei) x duration of infusion/2), the age of the patients and the relative fall in WBC counts. These results allowed us to establish a predictive formula in order to anticipate the number of WBC that the patient will obtain about 12 days after treatment, at the nadir of the counting. WBCnadir = 0.032404 x Age + 2.005 + WBCinitial x e(-0.009316 x AUC(PIRA,wb,ei) + 4.202265), WBC being expressed as x 10(3) cells/microl and AUC(PIRA,wb,ei) in ng/ml x h. In a second step, the validation of the prediction was carried out in 43 courses from 21 patients treated in the same conditions, for which WBC(predicted nadir) was compared by linear regression to WBCcounted. We obtained a highly significant correlation: r = 0.656; p<0.0001). Therefore, we show in this paper that the hematological toxicity, especially the WBC nadir count, can be predicted from single-sample blood HPLC analysis. This rapid and easy prediction of leukopenia can help the clinician in anticipating important hematological toxicities and in deciding to start early prophylactic treatment with hematopoietic growth factors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Doxorubicin; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neoplasms

We treated 8 patients of Stage III and IV breast cancer preoperatively with THP-ADR intra-arterial infusion chemotherapy. The median dose was 200 mg with a range from 150 to 310 mg. The response rate of THP was 75.0% compared to 66.7% of ADR. Leucopenia was observed during THP treatment with a lower frequency of alopecia.

Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukopenia; Middle Aged; Preoperative Care

In a phase II study, 35 patients with advanced breast cancer were treated with 4'-O-tetrahydropyranyl-doxorubicin (THP-DXR) (70 mg/m2 i.v. on day 1); treatment was repeated every 3 weeks. Eight patients had failed prior chemotherapy for advanced disease. A total of 34 patients were evaluable for response. After a median of 10 treatment courses (range, 3-15), objective tumor response was seen in 59% (20 of 34 patients) (95% confidence limits, 42%-75%). In all, 17 partial remissions and 3 complete remissions were observed; stable disease occurred in 13 patients. The median duration of response was 42+ weeks (range, 21 - 77+ weeks). The dose-limiting side effects were leukopenia (26 patients, WHO grade III-IV) and thrombocytopenia (9 patients, WHO grade II-IV). Nausea/vomiting was experienced by 34 patients; in 18, it reached WHO grade II-III. Other treatment-related side effects included alopecia (WHO grade II-III) in 26 patients and stomatitis and diarrhea (WHO grade I-III) in 9 patients. At cumulative doses of THP-DXR of at least 700 mg/m2 (range, 700-1,050 mg/m2), no signs of congestive heart failure were observed. We conclude that THP-DXR is effective for first- and second-line chemotherapy in advanced breast cancer and that side effects are manageable.

Topics: Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Platelet Count; Survival Analysis

In a phase II study, 77 patients with metastatic breast cancer were treated with pirarubicin, 70 mg/m2 iv every 3 weeks. Most of them had received prior hormonal (n = 39) and/or chemotherapeutic drug treatment for advanced disease, including anthracycline-containing regimens in 17. After a median of 5.5 treatment cycles (range 1-14), objective tumor response was seen in 22/71 (31%) evaluable patients (4CR, 18 PR). Stable disease occurred in 34 (48%) patients, whereas the tumor progressed in 15 (21%). Significant hematologic toxicity (WHO grade III-IV) requiring interval and/or dose adjustments was observed in 41 (58%) patients. Other treatment-related side effects were generally mild, and included alopecia in 52 (73%), nausea and/or emesis in 50 (70%), and stomatitis and diarrhea in 3 patients each. There was no treatment-related death, nor was there any evidence of cardiac toxicity thus far. In summary, the early results of this trial suggest that pirarubicin is an active and rather well tolerated drug in pretreated patients with advanced breast cancer.

Topics: Adult; Aged; Alopecia; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Humans; Infusions, Intravenous; Leukopenia; Male; Menopause; Middle Aged; Nausea; Vomiting

Thirty-five non-pretreated patients (29 male, six female) with malignant pleural mesothelioma, median age of 68.5 years (range, 29 to 78 years) and a median performance status of 80% (range, 60% to 100%) were treated with 70 mg/m2 Pirarubicin. The treatment was repeated every 3 to 4 weeks (median duration per cycle, 23 days) up to progression or severe toxicity. The median cumulative dose given was 294 mg/m2, or 4.5 cycles. All patients were evaluable regarding response. Three partial remissions were achieved, leading to a remission rate of 8.6%. The median duration of remission was 6 months. Five patients achieved minor response, and a further 14 patients were stable under treatment with Pirarubicin. The median survival time was 10.5 months. Leukocytopenia was the main dose-limiting factor and 20% of the patients experienced World Health Organization (WHO) Grades III and IV. Anemia and thrombocytopenia were mild. Nausea and vomiting, WHO Grades I and II, were observed in 46% of all patients. Alopecia, Grades I and II, was seen in 47% and Grade III in 6%. No signs of cardiac dysfunction were detectable, except for cardiac arrhythmia in four patients (11%). Pirarubicin is an active drug in the treatment of pleural mesothelioma with fewer severe side effects than doxorubicin.

Topics: Adult; Aged; Alopecia; Arrhythmias, Cardiac; Doxorubicin; Drug Evaluation; Female; Humans; Leukopenia; Male; Mesothelioma; Middle Aged; Nausea; Pleural Neoplasms; Remission Induction; Survival Rate

In 34 patients with primary advanced breast cancer, intra-arterial administration of ADR (50 mg X 3, total dose 150 mg, 10 cases), 4' epi ADR (50 mg X 3, 150 mg, 8 cases; 70 mg X 3, 210 mg, 10 cases) and THP-ADR (50 mg X 3, 150 mg, 6 cases) was performed, and its effects and side effect were analyzed. The clinical and histological response rate were superior in the ADR (150 mg) regimen and 4'-epi-ADR (150 mg) regimen. Signs of systemic toxicity such as gastrointestinal disorders, leukocytopenia and thrombocytopenia were the side effects in patients treated with THP-ADR, but the frequency of alopecia was lower. No cardiotoxicity was recorded in any of the patients. These results indicated that 4'-epi-ADR given the total dose of 150 mg in a single dosage of 50 mg was the most effective agent in intra-arterial infusion chemotherapy for advanced breast cancer.

Topics: Alopecia; Antineoplastic Agents; Breast Neoplasms; Doxorubicin; Epirubicin; Female; Humans; Infusions, Intra-Arterial; Leukopenia; Lymphatic Metastasis; Remission Induction; Thrombocytopenia

A phase II study of a new anthracycline, (2"R)-4'-O-tetrahydropyranyladriamycin (THP), was conducted in 110 patients with various head and neck cancers in a multi-institutional cooperative study. The response rate was 20.3% (PR 12) in an intravenously injected group and 52.3% (CR 8, PR 15) in an intraarterially injected group. In the former cases, the response rate according to primary sites was 19.2 to 27.3% for the maxilla, pharynx, oral cavity and larynx. In the latter cases, it was 40.9 to 64.3% for the maxilla, pharynx and oral cavity, and 100% for the external auditory meatus (CR 1, PR 1). According to histology, the response rate was 37.5 % in squamous cell carcinoma. Partial response was observed in two cases of undifferentiated carcinoma. The predominant toxicity was myelosuppression. Leukocytopenia (less than 3,000/mm3) was noted in 44 cases (41.9%). Loss of hair and stomatitis were observed in 13 (12.6%) and 12 (11.7%) respectively. However, these were mild and recovered quickly on discontinuation of THP. We concluded that THP therapy was markedly effective for various head and neck cancers.

Topics: Alopecia; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Head and Neck Neoplasms; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Leukopenia; Stomatitis

A Phase II clinical trial of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was performed in 137 patients with urological malignancies. Out of them, 111 patients were evaluated for tumor responses and 125 patients were evaluated for adverse effects. In cases of intravenous administration, overall response rate was 18.5% (22.2% for bladder cancer, 30.0% for tumors of the renal pelvis and ureter, and 6.7% for prostatic cancer). In the case of intra-arterial administration, overall response rate was 42.9% (50.0% for bladder cancer). For 50 patients with superficial bladder cancer intravesical chemotherapy with THP was performed. Sixteen patients showed complete disappearance of the tumor, 2 patients showed more than 90% tumor regression and 12 patients showed more than 50% tumor regression, respectively. Overall response rate was 60%. Cardiotoxicity was minimal. Alopecia was noted in a total of 16 patients, but this was minimal. Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration. In conclusion, THP was most effective against transitional cell carcinoma of the urinary tract.

Topics: Adult; Aged; Alopecia; Anorexia; Carcinoma, Transitional Cell; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Kidney Neoplasms; Leukopenia; Male; Middle Aged; Urinary Bladder Neoplasms; Urologic Neoplasms

A Phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was conducted in 162 patients with various hematological malignancies in a multi-institutional cooperative study. THP was given intravenously at a dose of either 10-30 mg/body for 3-5 consecutive days or 40-60 mg/body at 3-week intervals. Of 22 patients with AML, complete remission (CR) was observed in 2 patients and partial remission (PR) in 2. Of 18 patients with ALL, CR was observed in 5 and PR in 3. Of 68 patients with NHL, CR was observed in 11 and PR in 22. Of 8 patients with HD, CR was observed in 4 and PR in 2. One CML case showed CR and one ATL case showed PR. PR was noted in one of 2 patients with mycosis fungoides. Overall remission rate was 43.1% (CR 23 cases and PR 33 cases). The predominant toxicity was myelosuppression. Leukopenia (less than 4,000/mm3) was noted in 67 (77.6%) and thrombocytopenia (less than 10 X 10(4)/mm3) in 24 (27.0%). Nausea/vomiting and anorexia were common, and were observed in 61 (43.3%) and 65 (46.1%) cases, respectively. Hair loss and cardiotoxicity were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for various hematological malignancies including acute leukemia and malignant lymphoma.

Topics: Acute Disease; Adolescent; Adult; Aged; Anorexia; Antineoplastic Agents; Child; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia; Leukopenia; Lymphoma; Male; Middle Aged

A Phase II Study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with various solid tumors was carried out by 44 cooperative study institutions. Seven hundred fifty-six patients administered the drug intravenously were entered into this study. Of these, 499 patients were evaluated for objective responses. THP was given mainly at a dose of 40 to 60 mg/body every 3 to 4 weeks or 20 to 30 mg/body once a week. Response rates were 18.8% for head and neck cancer, 13.1% for stomach cancer, 21.4% for breast cancer, 22.2% for bladder cancer, 30% for renal pelvic and urinary tract tumor, 26.8% for ovarian cancer and 24.2% for uterine cancer. Overall response rate was 15.4% including 10 complete responses and 67 partial responses. Adverse reactions were similar to those previously reported in the phase I study, including gastrointestinal toxicities and myelosuppression. Alopecia and stomatitis, which are major side effects of other anthracyclines, were rather mild. Incidence of ECG changes was 2.8% and no congestive heart failure was observed.

Topics: Adult; Aged; Alopecia; Anorexia; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukopenia; Male; Middle Aged; Nausea; Neoplasms

A phase I trial of a new anthracycline derivative, 4'-O-tetrahydropyranyldoxorubicin (THP), was conducted in 54 patients with various advanced solid tumors and malignant lymphomas. Starting dose was 5 mg/m2 i.v. and dose escalations were made by a modified Fibonacci search scheme. There were 40 evaluable courses. The dose-limiting toxic effect was leukopenia which was dose-related and reversible. The maximum tolerated dose for a single i.v. injection was estimated to be 55 mg/m2. The median nadir day for leukopenia was day 12 with recovery occurring 13 days (median) after reaching the nadir. Thrombocytopenia was less commonly observed than leukopenia. Other toxic effects were mild gastrointestinal disturbances, fever and general malaise. Ventricular extrasystole was observed in a case of pancreatic cancer who received 5 mg/m2 of the drug. There were no cases with alopecia, or with hepatic or renal dysfunction. With regard to objective tumor response, CR was observed in 2 cases with NHL, and MR in 2 cases with lung cancer, and 1 case each with breast cancer and NHL. Response occurred at a dose of more than 35 mg/m2. The recommended dose schedule for phase II trial is 35-45 mg/m2 by single i.v. injection at 3-4-week intervals.

Topics: Aged; Anorexia; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukopenia; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nausea; Neoplasms; Stomach Neoplasms; Thrombocytopenia

A phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP) was performed on 37 patients with gastrointestinal cancer in 6 co-operative study institutions. Twenty-five patients out of 37 were evaluable for response according to the Koyama-Saito's criteria. THP was administered weekly at doses of 10 to 30 mg/body or every 3 to 4 weeks at doses of 40 to 60 mg/body intravenously. Of the 14 patients with gastric cancer, we obtained one complete response and 3 partial responses (response rate 28.6%), and of the 6 patients with rectal cancer, we obtained one partial response (16.7%). Leukopenia of less than 3 X 10(3)/mm3 and erythrocytopenia of less than 300 X 10(4)/mm3 were seen in 48% and 26% of cases. Neither cardiotoxicity nor hair loss were seen. These results suggest that THP is useful in the treatment of patients with gastrointestinal cancer.

Topics: Adult; Anorexia; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukopenia; Male; Middle Aged; Nausea; Rectal Neoplasms; Stomach Neoplasms

A statistically significant circadian rhythm in tolerance of 226 male B6D2F1 mice synchronized with LD 12:12 for 4'-O-tetrahydropyranyl-adriamycin (THP) was demonstrated. Four intravenous dosages (18, 25, 32 and 40 mg/kg) and six different dosing times (3, 7, 10, 14, 19 and 23 hr after light onset-HALO) were compared. Survival rate, body weight loss and leukopenia depended on both the dose and time of injection. The overall survival rate varied between 83% (light-rest span) and 56% (dark-activity span) (chi2 = 17; d.f. = 2; P less than 0.001). Maximal body weight loss occurred 4-5 days after drug injection. Total leukocyte counts were determined on these days. Both body weight loss and leukopenia were reduced by approximately 100% in those mice injected in their late rest span (7-10 HALO) as compared to those treated in the middle of their activity span (19 HALO). Circadian rhythms in day-60 survival rate, body weight loss and leukopenia were statistically validated by cosinor analysis, with estimated peak times (acrophases) occurring respectively at 7:30, 9:20 and 8:40 HALO. Minor cardiac lesions consisting of diffuse vacuolization and loss of muscular striation were observed in histologic sections from 3/32 hearts (16 controls, 16 treated). All three corresponded to THP given at 19 (2/2 mice) or 23 HALO (1/4 mice). Thus lethal, hematologic and possibly cardiac tolerance for THP were largely optimized by administering the drug to mice in their late span (7-10 HALO).

Topics: Animals; Body Weight; Circadian Rhythm; Dose-Response Relationship, Drug; Doxorubicin; Drug Tolerance; Leukocyte Count; Leukopenia; Male; Mice; Mice, Inbred Strains; Myocardium

THP-adriamycin was administered in a dose of 5 to 20 mg, 3 times a week, and the results showed 4 cases of CR, 5 cases of PR, 3 cases of MR and 2 cases of NC with the accumulated total dose of less than 100 mg. Histological effects were slight in a total dose of less than 50 mg, while the effects appeared in a total dose of 60 to 70 mg and further effects were obtained after about 1 week of the termination of the therapy. Leukopenia occurred in 6 of 14 cases. The side effects of THP-adriamycin were milder than those of ADM.

Topics: Aged; Carcinoma, Squamous Cell; Doxorubicin; Female; Humans; Infusions, Intra-Arterial; Leukopenia; Male; Maxillary Sinus Neoplasms; Middle Aged; Mouth Neoplasms; Paranasal Sinus Neoplasms

Of 3 patients with adult ALL and 23 patients with NHL treated with intravenous administration of 10 mg/M2 of THP for 5 consecutive days, complete remission was observed in 3 patients and partial remission in 14. The antitumor spectrum of THP seemed to be similar to that of Adriamycin from evidence that THP was effective in patients with NHL of diffuse large and mixed cell type. Neither cardiotoxicity nor alopecia was noticed. Anorexia, nausea or vomiting was mild but granulocytopenia and thrombocytopenia were severe in the patients with ALL and leukemic type NHL. Further studies are required for determining cross resistance to other anthracyclines and an optimal dose schedule.

Topics: Adult; Aged; Anorexia; Antibiotics, Antineoplastic; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma; Male; Middle Aged; Naphthacenes; Nausea; Stomatitis; Thrombocytopenia

The phase I study of a new anthracycline, 4'-o-tetrahydropyranyl adriamycin, was performed. A dose-limiting factor was leukopenia while thrombocytopenia was less frequent and a maximum tolerated dose was determined as 54 mg/m2. Mild gastrointestinal toxicities including anorexia, nausea and vomiting occurred in about half of the patients, while very minimal alopecia was seen in only one patient. A recommended dose for phase II study was established: 40 mg/m2 at 3-week intervals.

Topics: Adult; Aged; Alopecia; Digestive System; Doxorubicin; Drug Evaluation; Female; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Thrombocytopenia