Standard dose cisplatin with rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer

We have investigated the feasibility of a program of autologous peripheral blood stem cell (PBSC) harvesting and transplantation in patients with ovarian cancer. From four patients, PBSC was collected during hematopoietic recovery following aplasia induced by standard dose cisplatin 70 mg m⁻² with etoposide 500 mg m⁻² or adriamycin 40 mg m⁻² and cyclophosphamide 500 mg m⁻² plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) at a dose of 75 µg day⁻¹ given intracutaneously. In apheresed patients, we harvested an average of 2.31 × 10⁵ kg⁻¹ colony-forming unit granulocyte/macrophage (range 0–5.22) per cycle. Low hematologic toxicity was observed during the hematopoietic reconstitution of the four patients subjected to PBSC support with G-CSF (5 µg kg⁻¹ day⁻¹ given by continuous infusion) after high-dose chemotherapy (carboplatin 900 mg m⁻² and etoposide 900 mg m⁻²). The patients were not evaluable for a response because we performed consolidated high-dose chemotherapy. However, no evidence of recurrence has been observed 11.8 months (range 2–19) after high-dose chemotherapy. We can conclude that standard dose cisplatin in combination with etoposide or adriamycin and cyclophosphamide plus rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer.     

Salvage chemotherapy with a combination of paclitaxel, ifosfamide, and cisplatin for the patients with recurrent carcinoma of the uterine cervix

The aim of this study was to assess the efficacy and toxicities of a combination of paclitaxel, ifosfamide, and cisplatin (TIP) for recurrent carcinoma of the uterine cervix. Fifty-three patients with recurrent cervical carcinoma were treated with ifosfamide 1500 mg/m(2) intravenously over 3 h on days 1-3, paclitaxel 135 mg/m(2) as a 3-h intravenous infusion, and cisplatin 50 mg/m(2) intravenously over 30 min on day 1. The chemotherapy was repeated every 3 weeks until there was disease progression or unacceptable toxicity. Forty-five patients received at least three courses of treatment and were evaluable for their response. Twenty-one patients (46.7%) showed objective responses, including 4.4% complete responses and 42.2% partial responses. The median time to progression and the overall survival for all the patients were 8.0 months (95% confidence interval [CI], 7.1-8.9 months) and 19.0 months (95% CI, 11.9-26.1 months), respectively. The median duration of response was 9.0 months. Patients who had previously been treated with another chemotherapy after tumor recurrence showed a moderate response rate (29.4%) but a shorter time to progression (6 vs 8 months, P= 0.0421) and a shorter survival (11 vs 39 months, P= 0.0018). Patients with good performance status showed a higher response rate (63.6% vs 30.4%, P= 0.026) and a longer time to progression (9 vs 7 months, P= 0.0049). Patients with recurrent disease only outside the previous radiotherapy (RT) field exhibited a slightly higher response without statistical significance (60.0% vs 36.0%, P= 0.109). Grade 3 or 4 toxicities included neutropenia in 13% of patients and neurotoxicity in 5%. Three deaths during treatment were observed, but two of them were due to disease progression. We conclude that the combination chemotherapy with TIP yields a high response rate with acceptable toxicity for patients with recurrent cervical carcinoma, including those patients who have failed to respond to prior platinum-based chemotherapy.     

Circulating CD34+ cells to predict the adequate harvest of peripheral blood progenitor cells in platinum-based chemotherapy

Objective: The aim of this study was to clarify the appropriate timing for peripheral blood progenitor cells (PBPC) harvesting after platinum-based mobilization chemotherapy by measurement of the circulating CD34⁺ cell concentrations. Patients and Methods: PBPC were collected for autotransplantation via a total of 68 leukaphereses in 16 patients with gynecological cancer. Circulating CD34⁺ cell concentrations were measured by CD34-side scatter parameter analysis. Results: Data could be fitted into a linear regression line described by the equation y=0.33+4.14×x (R ²=0.256), where y=the number of harvested colony-forming unit granulocyte macrophage (CFU-GM (×10⁵/kg) and x=the percentage of circulating CD34⁺ cells and y=1.747+44.53×x (R²= 0.475), where y=the number of harvested CD34⁺ cells (×10⁶/kg) and x=the percentage of circulating CD34⁺ cells. Failure to mobilize sufficient CFU-GM numbers (>1×10⁵/kg) occurred in 29 of 31 leukaphereses when the percentage of circulating CD34⁺ cells was less than 0.10%. Conclusions: Harvesting procedure may be avoided when circulating CD34⁺ cells showed less than 0.10% after platinum-based mobilization chemotherapy. Received: 20 December 2000 / Accepted: 5 May 2001     

A pharmacokinetic and clinical evaluation of thio-TEPA in combination with cisplatin as first-line chemotherapy for advanced epithelial ovarian carcinoma

The purpose of the study was to explore the combination of thio-TEPA with cisplatin in first-line chemotherapy of epithelial ovarian cancer with special reference to pharmacokinetic and pharmacodynamic relationships. Ten women with advanced disease were included. Pharmacokinetics of thio-TEPA were similar to those in previous studies of single drug therapy with rapid first order elimination of the parent drug and substantial intra- and interindividual variation of the area under the concentration–time curve (AUC). No effects of the drug sequence or repeated treatments were seen on the pharmacokinetics of thio-TEPA, indicating no significant influence from the coadministration of cisplatin on the distribution, metabolism or excretion of thio-TEPA. Pharmacokinetic--pharmacodynamic relationships were less pronounced compared to previous studies, probably due to the influence from cisplatin. Prolongation of treatment intervals, dosage reduction, and withholding of thio-TEPA were required due to myelosuppression, which was the dominating toxicity. Non-hematological toxicity was moderate and easily manageable, cisplatin-related toxicity did not seem to be aggravated. Response rate based on CA 125 fluctuations was 80%, overall median survival was 18 months. In conclusion, the pharmacokinetics of thio-TEPA does not seem to be significantly influenced by concomitant administration of cisplatin in female patients. Manageable toxicity, largely restricted to myelosuppression, and high response rate justify further evaluation of the current regimen.     

Cervical non-squamous carcinoma: an effective combination chemotherapy of taxane, anthracycline and platinum for advanced or recurrent cases

Objective

An effective salvage chemotherapy for advanced and recurrent non-squamous carcinoma of the uterine cervix has not yet been established. The aim of the present study was to analyze the safety and efficacy of a combination chemotherapy for this disease using taxane, anthracycline, and platinum.

Study design

This was a retrospective analysis of advanced and recurrent non-squamous cervical cancers treated at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases during a 10 year study period from 2000 to 2009. Single agent chemotherapies and combination chemotherapies for advanced and recurrent cervical cancer cases of non-squamous histology which were reported in the English literature were also reviewed.

Results

Salvage chemotherapy, using taxane, anthracycline and platinum, was performed for 5 advanced and 14 recurrent cases. Prior to the salvage chemotherapy, 15 (79%) of the 19 patients had already received either radiation or chemotherapy. A complete or partial tumor response was achieved in 8 (42%) of the 19 cases. The response rate for recurrent disease in a previously irradiated field was 40%. The median progression-free survival (PFS) and overall survival (OS) were 8 months (1–108) and 13 months (5–108), respectively. Grade 4 and febrile grade 3 neutropenia was observed in 6 cases (32%), but there was no case in which salvage chemotherapy had to be cancelled due to toxicity. According to previous reports, the cumulative response rate of combination chemotherapy (35%) was significantly higher than that of single agent chemotherapy (17%) (p < 0.001). OS tended to be longer in the combination chemotherapy cases (8.7 months to 18 months) than that of single agent chemotherapy cases (7.3+ months to 9.1+ months).

Conclusion

Combination chemotherapy of taxane, anthracycline, and platinum was found to have a survival benefit for advanced and recurrent cervical cancer patients of non-squamous carcinoma histology, with a tolerable toxicity.     

Interferon-gamma in combination with carboplatin and paclitaxel as a safe and effective first-line treatment option for advanced ovarian cancer: results of a phase I/II study

We have previously shown that interferon-gamma 1b (IFN-gamma) in combination with cyclophosphamide and cisplatin significantly prolongs progression-free survival in ovarian cancer. In this phase I/II study, we examined if administration of IFN-gamma is also safe in combination with the current standard treatment, paclitaxel and carboplatin. Thirty-four patients with newly diagnosed advanced epithelial ovarian cancer, FIGO stage III/IV, were treated for six to nine cycles with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve [AUC] 5) every 3 weeks. IFN-gamma was administered in an escalating dose from 6 days/cycle with 0.025 mg sc up to 9 days/cycle with 0.1 mg sc. As expected, administration of IFN-gamma was associated with flu-like symptoms. Grade 3/4 neutropenia was observed in 74% (25 out of 34) of patients. Other side effects, in particular peripheral neuropathies, were within the previously observed ranges for the paclitaxel plus carboplatin combination. Overall response rate (complete or partial response) in patients who received either six or nine doses (0.1 mg) of IFN-gamma/cycle (n = 28) was 71%. IFN-gamma is safe in combination with carboplatin and paclitaxel for first-line treatment of patients with advanced ovarian cancer. This combination should be further evaluated as an immunotherapeutic treatment option for ovarian cancer.     

Radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in cervical carcinoma limited to the pelvis: a phase I/II study of the Gynecologic Oncology Group

OBJECTIVES: To determine the maximum tolerated dose (MTD) of weekly paclitaxel and cisplatin chemotherapy concurrent with whole pelvic irradiation in women with locally advanced cervical cancer. METHODS: Consenting patients with stage IB2, IIA, IIB, IIIB and IVA carcinoma of the cervix (all cell types) were eligible for this phase I/II trial. Chemotherapy agents were administered in escalating doses to cohorts of three patients at each dose level, pending evaluation of toxicities from the previous dose level. RESULTS: Thirty-five eligible women were enrolled on this study, of whom 13 comprised the phase I component. The MTD was determined to be cisplatin 40 mg/m2 and paclitaxel 40 mg/m2 administered weekly for six cycles with external beam radiation therapy. An additional 21 patients were enrolled in the phase II component at the previously determined MTD, yielding a total of 22 patients at the MTD, of whom 19 were evaluable. Among the evaluable patients treated at the MTD, two had grade 3 or 4 gastrointestinal (GI) toxicities (representing 5 of 113 cycles administered to this cohort) and seven experienced grade 3 or 4 neutrophil toxicity, none occurring prior to the fourth cycle. Thrombocytopenia was rare. Radiation therapy was successfully completed in 52% of patients at 8 weeks and in 79% of patients at 9 weeks, with a median of 59 days. CONCLUSIONS: Paclitaxel and cisplatin combination chemotherapy concurrent with whole pelvic irradiation can be safely administered at the described MTD.     

子痫前期患者血管内皮祖细胞数量及生物学功能的变化

目的:观察子痫前期患者血管内皮祖细胞(endothelial progenitor cells,EPCs)数量与功能的变化。方法:选取孕28~40周子痫前期孕妇、健康孕妇各20例,抽取外周静脉血20m l,经密度梯度离心法分离单个核细胞,通过CD133/CD34双荧光标记及Ⅷ因子鉴定细胞;用流式细胞仪检测细胞数量,用MTT比色法、改良Boyden小室法、黏附能力测定实验,分别观察EPCs的增殖、迁移及黏附功能的变化。结果:与健康孕妇相比,子痫前期患者外周血EPCs数量明显减少(4.29%±1.21%vs15.32%±2.00%,P<0.01),其增殖能力(增殖率13.45%±1.68%vs 18.45%±1.67%)、迁移能力[迁移细胞(37.25±7.28)个/视野vs(67.10±9.55)个/视野]、黏附能力[黏附细胞(20.65±5.19)个/视野vs(34.40±6.72)个/视野]明显受损。结论:子痫前期患者外周血EPCs数量减少、生物学功能减退。     

Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with mullerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2 followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3-12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2 is warranted for further evaluation.     

Are herbal medicines alone or in combination for diabetic peripheral neuropathy more effective than methylcobalamin alone? A systematic review and meta-analysis

Background and purposeIn Asian countries, herbal medicines have been used to treat diabetic peripheral neuropathy (DPN) as an adjunctive therapy. This review aims to assess the effectiveness and safety of herbal medicines for the treatment of DPN.MethodsA literature search was conducted on PubMed, Embase, CENTRAL, Scopus, CINAHL, CNKI, DBPIA, and OASIS for randomized controlled trials that evaluated the effects of herbal medicines on DPN. The oral methylcobalamin administered group was selected as the control. The primary outcome measure was nerve conduction velocity (NCV), and the secondary outcome measure was the total efficacy rate (TER). The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. A meta-analysis was conducted using Review Manager 5.4.1 software.ResultsSeventy-two RCTs with a total of 6260 patients were included. The meta-analysis showed that herbal medicine and co-administration of herbal medicine and methylcobalamin (CHM) treatment for DPN significantly increased the sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of the median and common peroneal nerves than methylcobalamin treatment alone. Herbal medicine and CHM treatment for DPN also significantly improved the TER compared to the control group. Herbal medicine and CHM treatment was found to be relatively safe.ConclusionOur study suggests that herbal medicine and CHM might be more effective than methylcobalamin alone in the management of DPN. Further rigorous studies should be conducted to make more definite conclusions.     

High dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in ovarian cancer

Abstract. Ledermann JA. High dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in ovarian cancer.
Ovarian cancer is a very chemosensitive tumor, but survival is poor due to the emergence of drug resistance. It may be possible to overcome resistance by using high dose chemotherapy supported by peripheral blood stem cell transplantation. A review of retrospective studies of dose-intensity and phase I/II high dose chemotherapy trials, and an analysis of the EBMT registry data is used as evidence to support the case for dose-intensification in ovarian cancer. As a result of this analysis there are now prospective randomized trials of high dose chemotherapy in ovarian cancer.     

Radiotherapy is effective for metastatic spinal cord compression in patients with epithelial ovarian cancer

Ovarian cancer patients developing metastatic spinal cord compression (MSCC) are extremely rare and account for only 0.4% of MSCC patients. Only very few case reports are available in the literature. This analysis evaluates seven ovarian cancer patients treated for MSCC with radiotherapy alone. Data of 1,852 MSCC patients irradiated between 1992 and 2005 were retrospectively reviewed. Seven patients were identified with epithelial ovarian cancer. These seven patients were evaluated for functional outcome, ambulatory status, local control of MSCC, and survival. The patients received either short-course radiotherapy (1 x 8 Gy or 5 x 4 Gy, n= 2) or long-course radiotherapy (10 x 3 Gy, 15 x 2.5 Gy, or 20 x 2 Gy, n= 5). Improvement of motor function occurred in three of the seven patients, in three of the five patients after long-course radiotherapy, and none of the two patients after short-course radiotherapy. Two of the five nonambulatory patients regained the ability to walk after radiotherapy. No further deterioration of motor function was seen in another three of the seven patients, in two of the five patients after long-course radiotherapy, and one of the two patients after short-course radiotherapy. Deterioration occurred in one of the seven patients, in none of the five patients after long-course radiotherapy, and one of the two patients after short-course radiotherapy. Patients died after a median interval of 4 months (range 1-7 months) following radiotherapy. A recurrence of MSCC did not occur. Radiotherapy alone is effective in improving or maintaining motor function in MSCC patients with ovarian cancer and should be administered if decompressive surgery is not indicated.     

Optimized sequence of drug administration and schedule leads to improved dose delivery for gemcitabine and paclitaxel in combination: a phase I trial in patients with recurrent ovarian cancer

We examined appropriate sequence, schedule, and doses of gemcitabine (G) and paclitaxel (T) in patients with persistent or recurrent epithelial ovarian cancer. Patients received a maximum of six cycles of gemcitabine on days 1 and 8 (starting 1000 mg/m(2)), and paclitaxel (starting 135 mg/m(2)) on day 8 (groups A and B) or day 1 (group C). Drug sequences (G-->T and T-->G) were tested in group A. In group A, changing sequences of gemcitabine and paclitaxel infusion were evaluated. Sequence G-->T raised grade 3 alanine transaminase in two of three patients leading to use of T-->G sequence for remainder of study. In group B, maximum tolerable dose was reached at gemcitabine 1000 mg/m(2) and paclitaxel 175 mg/m(2). Reducing paclitaxel to 150 mg/m(2) allowed escalation of gemcitabine to 1250 mg/m(2), but neutropenia-related treatment delays occurred. Giving paclitaxel on day 1 (group C) enabled administration of paclitaxel 175 mg/m(2) and gemcitabine 1250 mg/m(2) with minimal dose adjustments. The overall response rate was 41.0%, with 2 complete responses and 14 partial responses in 39 eligible patients. The schedule of paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1250 mg/m(2) (days 1 and 8), with sequence of T-->G, appears most suitable with tolerable toxicity and promising activity.     

Concurrent ganirelix and follitropin beta therapy is an effective and safe regimen for ovulation induction in women with polycystic ovary syndrome

OBJECTIVE: To evaluate controlled ovarian stimulation cycles using the GnRH antagonist ganirelix in combination with the recombinant FSH, follitropin-beta, in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, nonrandomized clinical study. SETTING: Hospital-based infertility practice. PATIENT(S): Twenty women with PCOS planning to undergo ovarian stimulation. INTERVENTION(S): Fasting glucose and insulin levels were used to calculate insulin resistance ratios (FG/I). After pretreatment with oral contraceptives, serum LH levels were determined, and 250 microg ganirelix was administered on cycle day 2. Upon suppression of LH, concurrent ganirelix and follitropin-beta therapy (morning ganirelix and evening follitropin-beta) was started and continued until the day of hCG. MAIN OUTCOME MEASURES: Days of stimulation, dose of follitropin-beta, pregnancy, and ongoing pregnancy were compared based on FG/I ratios. RESULTS: One dose of ganirelix effectively suppressed LH levels in all patients. All patients ovulated as documented by a rise in progesterone. Significant differences were observed between the insulin-resistant and non-insulin-resistant groups for both days of stimulation and dose of follitropin-beta. The overall clinical pregnancy rate was 44.4%, with an ongoing pregnancy rate of 27.8%. CONCLUSIONS: In this preliminary study, we demonstrate the effectiveness of a concurrent ganirelix and follitropin-beta therapy for ovarian stimulation in women with PCOS.     

Phase III double-blind randomized trial of radiation therapy for stage IIIb cervical cancer in combination with low- or high-dose Z-100: treatment with immunomodulator, more is not better

BACKGROUND: To evaluate the efficacy of low or high-dose immunomodulator, Z-100, in combination with radiotherapy for cervical cancer. METHODS: Between 1995 and 1999, 221 patients with stage IIIb squamous cell carcinoma of the cervix were randomly assigned to treatment with Z-100 either at 0.2 microg or 40 microg in a double-blind manner in combination with radiotherapy. RESULTS: The 5-year survival of patients with high-dose and low-dose Z-100 was 41.5% (95% CI: 31.7-51.3%) and 58.2% (95% CI: 48.7-67.7%), respectively, showing a 30% reduction in the death rate (hazard ratio: 0.670 [95% CI: 0.458-0.980], P = 0.039). Survival of high-dose group was equivalent to the 4-year survival of the radiotherapy plus hydroxyurea arm (49.7%) of GOG120 study, and that of low-dose group was similar to the survival of the cisplatin-based chemoradiation arm. The progression-free survival was also significantly improved in favor of low-dose group (hazard ratio: 0.667 [95% CI: 0.447-0.997], P = 0.048). The survival of low-dose group was similar to the survival of the cisplatin-based chemoradiation arms of the GOG120 study. CONCLUSIONS: Unexpectedly, the survival of patients with advanced cervical cancer treated by lower dose of Z-100 in combination with radiotherapy was significantly better than those treated with higher dose Z-100, which was equivalent to the survival with radiotherapy alone. The hypothesis that lower dose of Z-100 enhances the efficacy of radiation therapy is now being tested by placebo-controlled randomized trial.