A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study

The Canadian Cancer Society requested that the Centre for Behavioural Research and Program Evaluation of the National Cancer Institute of Canada evaluate Reach to Recovery and CanSurmount, 1-on-1 peer-support programs that provide information and support to individuals with cancer and their families. Key informant interviews (with program participants and volunteer visitors) were conducted to gather qualitative data and to help us develop a framework and tools to evaluate these programs. We found that 1) there are program objectives from the perspective of volunteers and participants in addition to those outlined in the program materials; 2) there are variations in how the programs are delivered and how patients or family members are recruited into the program; and 3) there is evidence that Reach to Recovery and CanSurmount volunteers are in a unique position to deliver the programs, either because they have personally experienced cancer or have family members who have had cancer. We describe the key informant exercise developed for this evaluation project and present the results of preliminary data-gathering activities.     

A combination of ifosfamide and mitoxantrone as salvage therapy in patients with advanced ovarian cancer

Ifosfamide (IFX) and mitoxantrone (MXN) have been found to be effective against advanced epithelial ovarian cancer. The combination of these two agents has not yet been tested in this setting but seems to be rational, given the different action mechanisms of these drugs and their not completely overlapping side effects. Between June 1987 and November 1991, 37 patients with advanced ovarian carcinoma recurrent or refractory to primary cisplatin-based chemotherapy entered the study. Therapy consisted of MXN, given i.v. at 10 mg/m2 on day 1 and IFX given i.v. at 2,000 mg/m2 per day on days 1-3 with mesna. The cycles were repeated every 3 weeks. Four patients achieved a complete remission and three achieved a partial remission, for response rates of 18.9% [95% confidence interval (CI) 6.3-31.5%] in the whole sample and 38.8% (95% CI 16.3-61.3%) in the subset of 18 patients responding to first-line cisplatin. No response was obtained in the remaining patients, whose disease was refractory to primary platinum-based chemotherapy. Clinically significant toxicity (WHO grades 3-4) included leukopenia in 46% of the patients and anemia in 32.5%. The non-hematologic toxicity was mild, except for reversible alopecia (57%) and nausea and vomiting (48.5%). This regimen seems attractive for patients who have either failed or not received platinum retreatment, especially when limiting neurotoxicity occurs. Further studies are warranted to establish the relative impact of both of these agents.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

A phase II study of topotecan administered five times daily in patients with advanced gastric cancer

CASE REPORT: Arginine hydrochloride is used both diagnostically to test for growth hormone deficiency and therapeutically for treatment of metabolic alkalosis. We describe a 21-month-old girl who developed cardiopulmonary arrest following an accidental overdose of arginine hydrochloride. The patient developed acute metabolic acidosis and transient, but severe, hyponatremia. Thirty-six hours after successful resuscitation, she developed fatal central pontine and extrapontine myelinolysis. Unlike previous reports of arginine-toxicity, our patient showed no evidence of hyperkalemia. This case illustrates a previously unreported mechanism of arginine hydrochloride toxicity.     

M-VAC combination in locally advanced, locally recurrent or metastatic breast carcinoma. A phase II study

A 54-year-old woman presented a lesion on the dorsum of the right hand. Routine laboratory tests were normal or negative. Histological examination revealed mucin deposits in the reticular dermis. The lesion cleared within 1 year without any treatment but biopsy. This case does not fit the diagnostic criteria of any known cutaneous mucinoses.     

Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer

We performed a phase I trial to evaluate the toxicity and the maximum tolerated dose of high dose epirubicin on a three-consecutive-day schedule on Japanese patients with advanced non-small cell lung cancer. Fourteen patients were entered in the study. At least three patients were assigned to each different dose level. Epirubicin was given intravenously daily for three day by bolus injection. The dose was started at 60 mg/m2/course and escalated by 30 mg/m2/course. Granulocytopenia was found to be the dose limiting toxicity with a maximum tolerated dose of 150 mg/m2/course. Thrombocytopenia and non-hematological toxicities were mild and well tolerated. The maximum tolerated dose was lower than that in Europe and Canada. Partial responses were observed in two out of five patients on 150 mg/m2/course. The recommended phase II dose for high dose epirubicin was demonstrated to be 120 mg/m2/course. A further dose-escalating study of epirubicin in conjunction with the administration of granulocyte colony stimulating factor is scheduled for the determination of its antitumor activity in non-small cell lung cancer.     

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.     

A phase II study of 13-cis-retinoic acid in patients with advanced renal cell carcinoma

We describe a new patient with type IV 3-methylglutaconic aciduria who presented with a clinical picture simulating a primary hepatic disorder subsequently followed with progressive neurologic impairment and an magnetic resonance imaging picture of Leigh syndrome.     

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.     

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer

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.     

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.     

A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are major complications associated with total knee arthroplasty. The American College of Chest Physicians recommends twice-daily, fixed-dose low-molecular-weight heparin (LMWH) as routine prophylaxis in this patient population. This study represents a cost analysis of ardeparin and enoxaparin, the two LMWHs currently available for this indication in the United States. Costs for treating DVT, PE, and major bleeding episodes were derived from values reported in the literature. Both ardeparin and enoxaparin were found to produce significant cost savings when used routinely as DVT prophylaxis after knee replacement surgery compared with no prophylaxis. Based on the currently available data, enoxaparin 40 mg once daily appears to be the least costly LMWH for routine pharmacoprophylaxis of DVT in patients undergoing knee replacement surgery.     

Dexrazoxane cardioprotection in advanced breast cancer patients undergoing high-dose epirubicin treatment

PURPOSE: We performed a randomized trial to evaluate the cardioprotective effect of dexrazoxane (DEX) in advanced breast cancer patients (ABC) treated with high single-dose epirubicin (EPI). A secondary objective was to determine the role of radioimmunoscintigraphy (RIS) in the assessment of epirubicin cardiotoxicity. PATIENTS AND METHODS: Ninety-five patients with ABC were treated with EPI 160 mg/m2 by i.v. bolus every 3 weeks with or without DEX, 1,000 mg/m2 i.v. Cardiac monitoring included multigated radionuclide (MUGA) scan with determination of resting left ventricular ejection fraction (LVEF), and RIS with 111-Indium antimyosin monoclonal antibodies. RESULTS: The overall response rate was 69% in the EPI arm and 67% in the EPI + DEX arm; median time to response and median time to progression were identical in both arms, being 2 and 8 months, respectively. Median survival was 19 months versus 29 months (p 0.21), respectively. DEX did not appear to contribute to extracardiac EPI toxicity. Congestive heart failure occurred only in the EPI arm (2 instances). LVEF significantly decreased from baseline only in the EPI group. An abnormal tracer uptake at RIS was observed early in both arms, but the increase in heart to lung ratio was much more evident in the control group. CONCLUSIONS: DEX significantly protects against the development of high dose epirubicin cardiotoxicity apparently without evidence of an adverse impact on antitumor activity and non cardiac toxicity. RIS is a very sensitive technique in detecting anthracycline cardiac damage, but its specificity is low and cannot be considered alone a primary test for guiding anthracycline treatment.     

A phase II study of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) with G-CSF for breast cancer patients with visceral metastases or hormone-independent tumors: a trial of the Japan Clinical Oncology Group

In a previous study, we found that oral chromium nicotinate overcame sucrose-induced hypertension in spontaneously hypertensive rats (SHR). Accordingly, we examined more chromium compounds to determine if others were more or less effective in regulating blood pressure (BP) of SHR. Since chromium is postulated to be an antioxidant, we also assessed the ability of different chromium compounds to alter free radical formation measured by determining thiobarbituric acid reactive substances (TBARS). The control group of SHR ingested a diet low in chromium, and 5 other groups ate the same diet with various chromium compounds added at 5 ppm-chloride, acetate, nicotinic acid-glycine-cysteine-glutamic acid (NA-AA), picolinate, and nicotinate. Following this, the rats were challenged with drinking water containing 5% and 10% w/v sucrose. Except for NA-AA, all chromium compounds inhibited the sucrose-induced elevation of systolic BP; and acetate, picolinate, and nicotinate chromium compounds lowered HbAIC below control. Only chromium acetate and nicotinate significantly lowered both hepatic and renal TBARS. Chromium picolinate lowered hepatic TBARS, and chromium chloride and NA-AA lowered neither. We conclude that chromium, rather than a specific ligand, plays a major role in ameliorating sucrose-induced BP elevations and can act as an antioxidant.     

Hypofractionated radiotherapy with concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced colorectal cancer. A phase II study

In a pilot study we treated 19 patients suffering from recurrent or locally advanced inoperable colorectal cancer, with concurrent hypofractionated radiotherapy (4-5 Gy/fraction, 2 fractions per week) and 5-fluorouracil bolus, 1 hour before RT at doses of 300 mg/m2. For 16 patients treated with radical intent the Normalised Total Dose for alpha/beta = 10 Gy ranged between 56-74 Gy (median 62 Gy). The schedule used was very well tolerated. Moderate grade II haematological toxicity was observed in 11% of cases and diarrhoea grade II/III resulting in 2-4 weeks treatment delay was observed in 26% of cases. One case with bowel perforation and one with painful subcutaneous fibrosis was observed during 12-27 months of follow-up. Out of 16 patients treated with radical intent 4 (25%) showed complete response and the overall response rate was 56% (9/16). The one-year symptom-free survival was obtained in 11/16 (69%) radically treated patients. It is concluded that hypofractionated radiochemotherapy with 5-fluorouracil for recurrent or locally advanced colorectal cancer is an effective regimen and has acceptable acute and late toxicity. Further investigation is required.     

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience

BACKGROUND: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m2, three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum. PATIENTS AND METHODS: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response. RESULTS: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P < or = 0.0001). No serious toxicity was registered. CONCLUSION: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses can be induced in a significant number of patients, the survival figures remain poor.     

Control of emesis by intravenous granisetron in breast cancer patients treated with 5-FU, epirubicin and cyclophosphamide

Granisetron, a potent and selective 5-hydroxytryptamine receptor (5-HT3) antagonist was reported to be an effective antiemetic agent both in animal studies and in patients given highly emetogenic chemotherapy. A sample of 43 patients with breast cancer was accrued from September to November 1992 in a phase II study to assess the efficacy of granisetron in patients receiving FEC (5-FU, epirubicin, cyclophosphamide). Each patient received 3 mg intravenous granisetron as a single dose just prior to chemotherapy. Oral metoclopromide was prescribed to each patient as a rescue anti-emetic. The emetic episodes and degree of nausea were evaluated on a daily basis. Good control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) was in the range 77%-98% and 77%-93% respectively. There was a complete response (no emetic episodes throughout the 6-day period) in 16 patients (37.2%). Onset of emesis tends to occur on day 1 and tend to subside after day 3; 85% of patients had onset of emesis in the first 2 days after chemotherapy. Control of emesis and nausea tends to improve after day 3, which could be the result of the reduced emetogenicity of the combination FEC with time. Altogether, 77% had good control of acute emesis; control of delayed emesis was better with 84% achieving a major response on day 2 after chemotherapy, which improved to more than 90% after day 4. Granisetron was generally tolerated with headache being the most common side-effect followed by constipation and flushing. This study suggests that granisetron is an effective and well-tolerated anti-emetic agent, which deserves randomised trials to elucidate its efficacy further.     

Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study

The aim of the study was to define the maximum tolerated dose (MTD) of vinorelbine given as one or two weekly doses in combination with epirubicin 60 mg/m2 every third week. The MTD was defined as the dose resulting in a WHO grade III or IV leucopenia exceeding 50% of patients. Patients were treated in groups of 10 at escalating doses of vinorelbine. The number of patients at the final dose level was expanded to 20. The dose of epirubicin was kept constant at 60 mg/m2 every third week. At dose level 1, 15 mg/m2 vinorelbine was given on day 1 at level 2, 20 mg/m2 was given on day 1 and at level 3, 20 mg/m2 was given on days 1 and 8. The MTD was reached at dose level 3. WHO haematological toxicity grade IV occurred in 0, 10 and 45% and grade III at 60, 30 and 30% of patients at dose levels 1, 2 and 3, respectively. Despite the common occurrence of grade IV haematological toxicity, only two serious infections were noted. Non-haematological toxicity of vinorelbine included neurotoxicity, manifesting as muscle weakness, constipation and paresthesias in the majority of patients. Neurotoxicity was usually mild and did not require treatment discontinuation. Phlebitis at the injection site was troublesome in many patients. Alopecia and nausea, probably due to epirubicin, occurred in most patients. The response rates were 22% (95% CI (confidence interval) 3-60%), 40% (12-74%) and 60% (36-81%) at levels 1, 2 and 3, respectively (non-significant).