Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen

This study's objectives were to determine the maximum tolerated dose (MTD) of 9-aminocamptothecin (9-AC), given as a prolonged continuous infusion (CI) for 7-21 days, when formulated in dimethylacetamide/polyethylene glycol 400 (DMA) and then later as a colloidal dispersion (CD), and to determine the steady-state pharmacokinetics of 9-AC. Patients with solid tumors refractory to standard therapy were enrolled on this study. Total dose/cycle of 9-AC/DMA was initially escalated by duration (7-21 days), while keeping the dose rate constant at 6.2 microg/m/h (1.04-3.12 mg/m/4-week cycle). Then, the dose rate was escalated from 6.2 to 21.1 microg/m/h (3.12-10.6 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days. CD formulation was escalated from 14.1 to 25 microg/m/h (7.11-12.60 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days and then escalated from 28.1 to 37.5 microg/m/h (9.44-12.60 mg/m/3-week cycle) while keeping the infusion duration constant at 14 days. Sixty-two patients were evaluable for toxicity; 61 received prior chemotherapy (median 3 regimens/patient). No consistent dose-limiting toxicity (DLT) was encountered with the DMA formulation until dose level 10.60 mg/m/cycle, when two patients experienced DLTs. With the 21-day CD formulation, the MTD was 12.60 mg/m/cycle with three DLTs out of five patients. When 9-AC was given on the 14-day schedule, DLT was seen at 9.44, 11.20 and 12.60 mg/m/cycle, with consistent DLT at the two highest dose levels. All DLTs for both formulations were grade 4 hematologic toxicities (neutropenia and/or thrombocytopenia), while non-hematologic toxicities were relatively mild (including gastrointestinal toxicities and fatigue). One patient with ovarian cancer had a complete response and three had partial responses (PRs). One patient each with non-Hodgkin's lymphoma and cancer of unknown primary had a PR. Pharmacokinetic studies of both formulations of 9-AC revealed a linear relationship between increasing plasma 9-AC lactone concentration and dose. The median plasma 9-AC lactone concentration for 9-AC/CD was approximately twice that achieved by 9-AC/DMA for the same dose level. Both 9-AC formulations, given as a 21-day CI, were well tolerated with dose-limiting myelosupression at the MTD. This dose intensity exceeds that of other 9-AC phase I/II schedules. The recommended phase II dose (RPTD) is 9.42 mg/m/4-week cycle, given as a 21-day infusion. The 14-day schedule of 9-AC/CD was equally myelosuppressive with the RPTD of 9.44 mg/m/3-week cycle, although two heavily pre-treated patients (one with pelvic radiotherapy) could not tolerate this dose. Objective responses were observed in six out of 57 heavily pre-treated patients, most of which had ovarian cancer.     

Integrating Social Marketing Into Fijian HIV/AIDS Prevention Programs: Lessons From Systematic Review

Social marketing techniques have been tested and proven useful within the health sector worldwide. In Fiji, social marketing was introduced in the early 1990s, and more rapidly during the last decade to improve national response to an increasing incidence of sexually transmitted infections (STIs) such as human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). Given the limited amount of research in the area of program evaluation in Pacific Island Countries and Territories (PICTs), this study systematically analyzes five Fijian HIV/AIDS prevention programs through Andreasen’s benchmark criteria, in order to identify gaps in program design that ultimately impact program effectiveness. Assessment results unveil some interesting trends regarding the focus and applications of past Fijian HIV/AIDS prevention programs in the past decade. This article discusses these findings and other valuable lessons for future HIV/AIDS prevention strategies in Fiji and elsewhere.     

Tattoo allergy in patients receiving adjuvant radiotherapy for breast cancer

Tattooing is routinely employed prior to radiotherapy treatment but allergies to tattoos are rare. New information on the incidence of tattoo allergy at St George Hospital is presented with details of two clinical cases. The literature on tattoo allergy has been unable to estimate the incidence of allergic reaction to tattoos because the total number of patients treated is unknown and not all patients were followed up. Our radiation oncology population for the first time has provided a known denominator, but wide confidence intervals prevent an accurate estimate of the incidence. Salient issues about tattoo allergy are highlighted based on a review of the published literature from 1966 to 1998.     

Phase II study of paclitaxel and vinorelbine (Pacl‐Vin) in hormone‐refractory metastatic prostate cancer: double tubulin targeting

Background: Androgen ablation is the standard treatment for advanced prostate cancer. However, most patients will eventually develop progressive hormone‐refractory prostate cancer (HRPC). The aim of the Pacl‐Vin study was to determine the efficacy and safety of paclitaxel in combination with vinorelbine in patients with HRPC, following from a phase I trial. Methods: Thirty castrate patients with progressive, metastatic prostate cancer were enrolled. Patients were treated with paclitaxel 40 mg/m², vinorelbine 20 mg/m² intravenously on day 1 and day 8 of a 21‐day cycle. Results: Two patients demonstrated a partial response and seven patients had stable disease from a cohort of 10 patients with measurable disease. Of 30 patients assessable for prostate‐specific antigen (PSA) response, 19 showed stable disease, which was maintained for at least 4 weeks, while six (20%) experienced ≥50% decline in PSA levels. Median overall survival was 7.3 months (interquartile range (IQR): 4.7–9.9 months). Median progression‐free survival was 3.3 months (IQR: 2.5–7.0 months). Improvement in quality of life measures was noted after three cycles of therapy. Grade 3 and 4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anaemia 3%, lethargy 1% and somnolescence 1%. One patient died as a result of neutropenic sepsis. Conclusion: In a poor prognostic cohort of patients paclitaxel and vinorelbine is a tolerable regimen, with a 20% PSA and objective response rate. The majority of patients achieved PSA stability. Furthermore, quality of life parameters, such as pain, were improved. However, the low level of activity of this regimen precludes its further testing.     

A phase I study of paclitaxel,estramustine phosphate and vinorelbine (Pacl-E-Vin) in advanced malignancies: triple tubulin targeting

Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.     

Resection of right atrial metastatic large-cell neuroendocrine carcinoma

The incidence of cardiac metastases is rising due to increasingly sensitive diagnostic investigations and longer patient survival as a result of improved treatment for malignancies. We report a rare case of right atrial metastasis from a large cell neuroendocrine carcinoma successfully resected with cardiopulmonary bypass. The surgical management of advanced cardiac malignancy is discussed. In appropriately selected cases surgical resection of cardiac metastases can be beneficial, allowing improvement in quality of life, and prolongation of life.     

Phase I study of amifostine as a cytoprotector of the gemcitabine/cisplatin combination in patients with advanced solid malignancies

Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance.     

Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer

We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T ⋝3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m²) with cisplatin (25 mg/m²) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival. Presented at the Forty-Second-Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001. Supported in part by Pharmacia Oncology and grants NCI/NIH CA 16087 and GCRC M01RR00096.