Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors

Background: Pneumocystis carinii pneumonia (PCP) is an opportunistic infection with rather adverse outcomes. An unexpected increase in cases of PCP was noted in the brain tumor population at the Johns Hopkins Hospital (JHH) in 2000. This prompted the present review of the clinical features and risk factors for PCP in the human immunodeficiency virus (HIV) negative brain tumor population. Methods: The study was located at the JHH. A retrospective review of medical records was done to identify patients with discharge diagnosis of PCP from 1980 to 2001. Patients who were HIV positive were excluded. A detailed analysis was done of patients with brain tumors. Results: From 1980 to 2001, 468 cases of PCP were identified, diagnosed histologically or clinically, of which 110 were patients with an underlying malignancy. Of the 110 cases 15 were seen in the brain tumor population. Of these, 6 patients were seen in 2000 and one in early 2001. Three of these had primary central nervous system (CNS) lymphoma (PCNSL) on high dose methotrexate. Eight of the fifteen episodes (53.3%) were fatal despite institution of antibiotics and supportive therapy. Conclusion: The incidence and mortality due to Pneumocystis carinii among the brain tumor population is increasing. While corticosteroids are known immunosupressants, prescribing patterns for these medications has not changed lately. However, high dose methotrexate is now being used in PCNSL and could be a complicating factor. Since effective prophylaxis exists, it should be considered in patients with brain tumors receiving high dose steroids, high dose methotrexate or with lymphopenia.     

Treatment of acute myeloid leukemia and blastic phase of chronic myeloid leukemia with combined eflornithine (alpha difluoromethylornithine) and methylglyoxal-bis-guanyl hydrazone (methyl-GAG)

Summary A combined eflornithine-MGBG treatment was studied in patients with acute myeloid leukemia (AML) or blastic transformation of chronic myeloid leukemia (BT CML). The first ten patients (5 AML, 5 BT CML) received i.v. or p.o. eflornithine 6 g m^-2 day-1 and i.v. MGBG 500 mg/m² once a week. The duration of treatment was 5–37 days (median 15) with one to five MGBG infusions (median 2). The results were complete response (CR) in one patient, partial response (PR) in four, minimal response (MR) in one and failure (F) in four. Pronounced side effects, including severe mucositis, gastrointestinal disturbances and skin infiltration, were observed in eight patients. As the four PRs were achieved in patients with BT CML, it was decided also to study ten patients with this indication. In attempts to decrease the incidence and severity of unwanted effects, lower doses of eflornithine-MGBG were used, i.e., eflornithine 4 g m^-2 day-1 and MGBG 200 mg m^-2 once a week. The duration of treatment was 9–110 days (median 46), with 2–14 MGBG infusions (median 6). Responses observed were CR in two patients (in one of whom it was only transient), transient PR in two, transient MR in four, and F in two. Treatment at lower doses was better tolerated, thus allowing a longer duration of treatment. Five of ten patients had moderate or severe gastrointestinal disturbances and one patient had a severe subjective hearing loss. The eflornithine-MGBG combination may prove to be a useful alternative treatment for AML and BT CML, but comparative trials will ultimately be necessary for a more definitive assessment of the combination.     

Phase II trial of 5-fluorouracil,adriamycin and cisplatin (FAP) in advanced gastric cancer

Summary Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m² IV on days 1–5, adriamycin 50 mg/m² IV on day 1, cisplatin 20 mg/m² IV on day 1–5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patients showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2×10⁹/l (range 0.7–4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).     

NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94).

Purpose:We conducted a phase II multicentre study of gemcitabinein patients with anaplastic astrocytoma and glioblastoma multiforme at firstrelapse. Patients and methods:Patients with anaplastic astrocytoma orglioblastoma multiforme receiving a stable dose of steroids and ECOGperformance status 3 were eligible for this study at the time of firstrelapse. One adjuvant chemotherapy regimen was permissible. Patients receivedgemcitabine 1000 mg/m² i.v. weekly × 3, repeated on afour-weekly cycle. Results:Of 20 patients enrolled, 15 were evaluable for response,19 for non-hematological toxicity and 18 for hematological toxicity. Sevenpatients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme(GBM). Age ranged from 28–71 years (median 50). Fifteen patientsdiscontinued therapy due to disease progression. The median number of cyclesadministered was 1 (range 1–11); only two patients received more thanthree cycles. Hematologic toxicity was acceptable and no grade 4 toxicity wasseen. One patient developed Pneumocystispneumonia and eventualpulmonary embolism; one died of gastric hemorrhage related to steroid therapy.No objective responses were seen. Nine patients had stable disease (medianduration 2.7 months, range 0.9–11.2). Conclusions:Gemcitabine given in this dose and schedule seemswell tolerated but is not active in patients with recurrent high-gradegliomas.     

Lymphopenia associated with adjuvant anthracycline/ taxane regimens

BackgroundWe observed 2 cases of Pneumocystis carinii pneumonia (PCP) occurring in HIV-negative patients during treatment with dose-dense chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T). These represent the first case reports of PCP occurring during dose-dense chemotherapy for breast cancer. Because lymphocyte depletion is thought to predispose patients to PCP, we explored whether the shortened intervals between cycles during dose-dense chemotherapy might place patients at risk for lymphocyte depletion and thereby a potentially increased risk of opportunistic infection.Patients and MethodsThree cohorts of patients were analyzed. Cohort 1 involved 135 patients receiving dose-dense AC → T on a phase II study. Cohort 2 included 64 patients who received treatment with dose-dense AC → albumin-bound paclitaxel on a phase II clinical trial. Cohort 3 consisted of 59 patients who received AC → T given every 3 weeks who were identified from the Clinical Research Information System database at Dana-Farber Cancer Institute. For cohorts 1 and 3, the electronic medical record was reviewed to determine absolute lymphocyte counts (ALCs) and absolute neutrophil counts (ANCs) for day 1 of each of the 8 cycles of treatment. For cohort 2, data was prospectively collected and entered into an electronic database. The lowest ALC obtained by each patient on day 1 of any cycle was termed the nadir.ResultsPatients experienced grade 3 (ALC < 500 cells/mm³) or grade 4 (ALC < 200 cells/mm³) lymphopenia in all 3 cohorts: 63% with dose-dense AC →T, 23.4% in dosedense AC → albumin-bound paclitaxel, and 69% with dose-dense AC → T every 3 weeks. Patients experienced their lowest median ALC count at cycle 5 of treatment in all 3 cohorts, with a median nadir of 400 cells/mm³ in cohort 1, 690 cells/mm³ in cohort 2, and 400 cells/mm³ in cohort 3.ConclusionThe majority of patients receiving AC → T every 2 or 3 weeks experience grade 3/4 lymphopenia. Median lymphocyte counts appear to be lowest around cycle 5, the point at which we observed 2 cases of PCP. Lymphocyte counts appear to be reaching a low enough level to place patients at risk for opportunistic infection during treatment with dosedense AC → T and with AC → T given every 3 weeks.     

High-dose epirubicin as primary chemotherapy in advanced breast carcinoma: a phase II study

Summary A total of 40 patients with metastatic breast cancer were treated with 120 mg/m² i.v. epirubicin every 3 weeks for a maximum of 10 cycles. Nine achieved a complete response and 17 showed a partial response, for an objective response rate of 65% (95% confidence interval, 47%–83%); the median duration of response was 7 months (range, 1–15 months) and median survival amounted to 13 months (range, 2–20 months). Leucopenia (grade 2 or 3) was seen in 14 patients on day 21 of the cycle. A subset of nine patients underwent blood counts on day 10, when all had marked neutropenia (<1×10⁹/l). Other toxicity was frequent and included nausea/vomiting (80%), alopecia (95%) and stomatitis (35%). Five patients showed a significant fall in cardiac output, but this reverted to normal after treatment. Epirubicin should have a role in the development of high-dose regimens for the treatment of advanced breast cancer.     

Salvage chemotherapy in metastatic breast cancer: An experience with the combination of mitoxantrone, 5-fluorouracil,and L-leucovorin

Summary From January 1992 to July 1993, 28 patients with metastatic breast cancer were entered in a phase II trial to assess the activity and toxicity of the combination of mitoxantrone, 5-fluoruracil, and leucovorin. Patients were eligible if they had progressive disease after either adjuvant (2 patients) or previous chemotherapy for metastatic disease (26 patients). Twenty-five patients (89.2%) had received previous anthracycline-based therapy. Predominant site of metastatic disease was visceral in 22 patients, bone in 2 patients, soft tissue in 4 patients, and the majority of patients (89.2%) had two or more sites of disease. The regimen was administered according to the following schedule: Mitoxantrone 9–12 mg/m² i.v. on day 1; L-Leucovorin 150 mg i.v. over 1 hour before 5-Fluorouracil 350 mg/m² i.v. push days, 1, 2 and 3. Courses were repeated every 21 days. Twenty-six patients were evaluable for response. We observed 2 complete responses, 5 partial responses with a median duration of 38 weeks (range 23–68). The objective response rate was 27% (95% C.I., 10% to 44%). Myelo-suppression was the most frequent toxicity, but it was mild in the majority of patients. Nine episodes of fever and neutropenia occurred in six patients but none of these episodes was fatal. No clinical evidence of cardiotoxicity was observed.At a median follow-up of 78 weeks, the median time to progression was 20.5 weeks and the median overall survival was 48 weeks.We conclude that this regimen is well tolerated and in our experience the objective response rate is similar to other salvage chemotherapy regimens.     

Small cell lung cancer: Results of a phase II study of 1,2,4 triglycidylurazol

Summary Fourteen patients with small cell lung cancer (SCLC) received treatment with 1,2,4 triglycidylurazol (TGU) 600 mg/m² or 800 mg/m² as an IV bolus every 4 weeks. Twelve patients had received previous chemotherapy consisting of a five-drug regimen given for the short duration of only 9 weeks. All had measurable disease. Following TGU 11 patients had progressive disease and 3 patients had stable disease. The most frequent toxicity was nausea and vomiting, which occurred in all patients but was generally mild. Myelosuppression was common with a median white blood count nadir of 2.5×10⁹/l (range 0.9–7.4×10⁹/l) and median platelet count nadir of 76×10⁹/l (range 5–173×10⁹/l). Alopecia, thrombophlebitis, and hepatic or renal toxicity were not observed.In this study, TGU had no activity in SCLC, and the dose-limiting toxicity was myelosuppression.Funded by the Cancer Research Campaign     

Ifosfamide plus oral etoposide salvage chemotherapy for platinum-resistant paclitaxel-pretreated ovarian cancer

Background:The prognosis of platinum resistant ovarian cancer isvery poor and the treatment of choice has not been clearly defined. Patients and methods:We conducted a phase II study with thecombination of ifosfamide i.v. at 2.25 g/m² (days 1, 2) andetoposide per os at 100 mg daily (days 1–10) every four weeks. To beeligible for the study patients had to be resistant to platinum and paclitaxelpretreated. Results:Forty-one patients entered the study. The median intervalfrom the previous chemotherapy was 3.9 months. The median number of previouschemotherapeutic regimens was 2. Severe toxicities included neutropenia(41% of patients), leukopenia (29%) and thrombocytopenia(13%). Thirty-five patients are assessable for response. Nine patientsresponded (22% of the eligible, 26% of the assessable), four ofthemdemonstrated complete response to chemotherapy (10% and 12%,respectively), while three patients demonstrated stabilization of theirprogressive disease. After a median follow-up of 18 months, time toprogression is 3 months (range 0.9–14.4), duration of response is 9months (2.5–11) and median survival is 13 months (2.5–37.4+). Conclusions:The combination of ifosfamide with oral etoposideappears to have significant but manageable toxicity and encouraging efficacyin platinum resistant ovarian cancer.     

GR38032F,a 5HT3 receptor antagonist,in the prophylaxis of acute cisplatin-induced nausea and vomiting

Summary A total of 28 patients receiving cancer chemotherapy with cisplatin-containing regimens (70–120 mg/m²) participated in an evaluation of the efficacy and safety of GR38032F for the prevention of acute nausea and vomiting. GR38032F, a 5HT₃ receptor antagonist, was given 30 min prior to cisplatin as an 8-mg loading dose by i.v. infusion over 15 min, followed by continuous infusion at a rate of 1 mg/h for 24 h. Efficacy was assessed by measurement of the number of episodes of retching and vomiting occurring in the 24 h after cisplatin administration and by an assessment of nausea during the same period. In all, 26 patients were evaluable for efficacy: overall, complete control was achieved in 12 patients (46%), major control (1–2 emetic episodes), in 6 (23%); minor control (3–5 episodes), in 1 (4%); control could not be achieved (failure; >5 episodes) in 7 patients (27%). GR38032F was well tolerated, with no significant drug-related adverse events. These encouraging results should be confirmed in compariative trials.     

The effect of food on oral melphalan absorption

Summary Fifteen patients receiving oral melphalan (4.2–5.3 mg/m²) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m²) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95–336) ng · h · ml^-1, and when taken with food, 122 (47–227) ng · h · ml^-1, the median reduction being 39% (P0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38–71) was no different from its oral half-life [55 (27–104) min fasting; 55 (30–72) min with food] (P>0.1). In these patients bioavailability was 85% (26–96)% when the drug was taken fasting and 58% (7–99)% when taken with food (P0.025). Median clearance following IV administration was 362 ml/min/m² (range 104–694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (r_s=0.915, P0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.     

Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy

The purpose of this retrospective study was to evaluate the influence of axillary disease on patients' survival after neoadjuvant chemotherapy and to assess patient and tumor characteristics associated with post-chemotherapy axillary involvement.After six induction cycles, 277 patients with operable breast cancer (stage II–III) underwent surgery with axillary dissection, followed by radiotherapy (n = 267) or additional chemotherapy (n = 63) and adjuvant tamoxifen therapy (n = 138). At a median follow-up of 8.5 years, overall survival (OS) and disease-free survival (DFS) were analyzed as a function of node involvement.The differences in OS and DFS according to the number of positive nodes were highly statistically significant with a decreased survival associated with the increasing number of nodes (p = 5 × 10^–6 and 9 × 10^–7, respectively). Upon multivariate analysis, the node number after chemotherapy appeared as the most significant prognostic factor (p = 7 × 10^–4 for OS and p = 3 × 10^–5 for DFS). All the other classical prognostic factors were insignificant, except post-chemotherapy Scarff–Bloom–Richardson (SBR) grading for OS (p = 8 × 10^–4) and adjuvant hormonotherapy for DFS (p = 1 × 10^–2).Although constituting a different parameter from primary surgery data, the number of positive nodes after chemotherapy could still remain a valuable prognostic factor at secondary surgery, raising the question for high risk patients of a second non-cross-resistant adjuvant regimen, or high dose chemotherapy with peripheral blood stem cells support.     

Primary Care Continuity and Wait Times to Receiving Breast Cancer Chemotherapy: A Population-Based Retrospective Cohort Study Using CanIMPACT Data

(1) Background: Wait times to chemotherapy are associated with morbidity and mortality in breast cancer patients; however, it is unclear how primary care physician (PCP) continuity impacts these wait times, or whether this association is different in immigrants, who experience cancer care inequities. We assessed the association between PCP continuity and the contact-to-chemotherapy interval (wait time from when a patient first presents to healthcare to the first day of receiving breast cancer chemotherapy), with a specific look at the immigrant population. (2) Methods: Population-based, retrospective cohort study of women who were diagnosed with stage I–III breast cancer in Ontario who received surgery and adjuvant chemotherapy. We used quantile regression at the median and 90th percentile to quantify the effect of PCP continuity on the contact-to-chemotherapy interval, performing a separate analysis on the immigrant population. (3) Results: Among 12,781 breast cancer patients, including 1706 immigrants, the median contact-to-chemotherapy interval (126 days) was 3.21 days shorter (95% confidence interval (CI) 0.47–5.96) in symptom-detected patients with low PCP continuity, 10.68 days shorter (95% CI 5.36–16.00) in symptom-detected patients with no baseline PCP visits and 17.43 days longer (95% CI 0.90–34.76) in screen-detected immigrants with low PCP continuity compared to the same groups with high PCP continuity. (4) Conclusions: Higher PCP continuity was not associated with a change in the contact-to-chemotherapy interval for most of our study population, but was associated with a marginally longer interval in our symptom-detected population and a shorter contact-to-chemotherapy interval in screen-detected immigrants. This highlights the importance of PCP continuity among immigrants with positive screening results. Additionally, having no PCP visits at baseline was associated with a shorter contact-to-chemotherapy interval in symptom-detected patients.     

Fludarabine and mitoxantrone: Effective and well-tolerated salvage therapy?in relapsed indolent lymphoproliferative disorders

Background:Prior studies of the combination of fludarabine,mitoxantrone and dexamethasone have yielded high response rates but areassociated with a significant risk of opportunistic infections,predominantly Pneumocystis Carinii pneumonia (PCP) requiring routineprophylaxis. Patients and methods:We evaluated thecombination of fludarabine (25 mg/m²/day × 3) andmitoxantrone (10 mg/m² × 1) withoutcorticosteroids or PCP prophylaxis in 29 patients with relapsed orrefractory indolent lymphoproliferative disorders; median age 56 years,62% refractory to preceding chemotherapy. Results:A median of four cycles was administered without cumulativemyelosuppression. Neutropenia <0.5 × 10⁹/l was seenin 16% of cycles. Infections complicated 10.4% of cycles,with impaired performance status (ECOG 2) and increased age (>56years) significant risk factors (P 0.01). Nocases of PCP were encountered. The response rate was 90%, medianremission duration 11.9 months and the median survival 57 months.Peripheral blood progenitor cell mobilization was attempted in 11patients and yielded 2 × 10⁶ CD34+ cells/kg in only5 cases (45%). Conclusions:High response ratescan be attained with fludarabine and mitoxantrone in combination withoutcorticosteroids, and routine PCP prophylaxis can safely be omitted.Peripheral blood progenitor collections are problematic in these heavilypretreated patients.     

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas

Background: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions.Patients and methods: We examined the feasability and safety of a CD34-selection followed by purging with anti-B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophosphamide, BCNU and etoposide with retransfusion of autologous HPC's.Results: A mean number of 340 × 10⁸ mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%–4.5%) to a mean of 68% (range 49%–87%) with a mean recovery of 27% (range 15%–43%). The mean number of retransfused CD34+ cells was 1.2 × 10⁶/kg (range 0.6–2.2 × 10⁶/kg) body weight with a median of 11 days (range 10–13 days) to neutrophil recovery of 0.5 × 10⁹/l and 17 days (range 13–25 days) to platelet recovery of 50 × 10⁹/l. Mean number of intravenous antibiotics and inpatient days were 8 (range 0–14) and 22 (range 19–26) respectively. Major toxicity consisted in four septicemias.Conclusions: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphomas.     

A clinical and pharamcological study of high-dose mitozolomide given in conjunction with autologous bone marrow rescue

Summary In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i. v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m² over 1 h. Neutropaenia occurred consistently at 300 mg/m², and three trivial infective episodes were recorded. Thrombocytopaenia occurred consistently at 150 mg/m², and three patients experienced episodes of minor bleeding. The death of one subject was attributable to pulmonary thromboembolism during the bone marrow reinfusion. Transient emesis and mild alopecia were the only other toxicities. Three of six evaluable patients receiving 300 mg/m² exhibited measurable reductions in tumour dimensions, although these failed to fulfil the criteria for a partial response. Mitozolomide was undetectable in plasma at 12 h after drug administration. The plasma pharmacokinetic data fitted mono- or biexponential models in all patients. Model-independent pharmacokinetic parameters were: peak plasma drug concentration, 3.4–46 mg/l; AUC, 8–82 mg h l^–1; clearance, 7.6–45 l/h; steady-state volume of distribution, 11–85 l; and plasma elimination half-life, 1.4–2.8 h. Dose-dependent pharmacokinetics were not observed, and only a small percentage of the delivered dose was eliminated unchanged in the urine. The maximally tolerated dose of mitozolomide given with autologous bone marrow rescue was >400 mg/m². At this dose myelosuppression was the only major toxicity, and the plasma drug levels and AUC values were comparable to those obtained after therapeutic doses in experimental models.     

The combination of gemcitabine and vinorelbine is an active regimen as second-line therapy in patients with metastatic breast cancer pretreated with taxanes and/or anthracyclines: a phase I-II study

Purpose. To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes. Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m² and vinorelbine was given at the fixed dose of 25 mg/m², both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m² per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30–70) and median performance status (PS, ECOG score), 1 (range 0–2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively. Results. The optimal schedule for the combination was gemcitabine 800 mg/m² and vinorelbine 25 mg/m². The maximum tolerated dose of gemcitabine was 1000 mg/m², with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3–9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28–57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone. Conclusions. The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline – based schedules or with combinations of anthracyclines and taxanes.     

Oxaliplatin and paclitaxel combination in patients with platinum-pretreated ovarian carcinoma: An investigator-originated compassionate-use experience

Purpose: Compassionate-use oxaliplatin–paclitaxel was assessed for toxicity and efficacy according to clinical platinum resistance status in cisplatin–carboplatin-pretreated advanced ovarian cancer patients.Patients and methods: Thirty-seven patients, retrospectively grouped into four oxaliplatin–paclitaxel dose levels (mg/m²): (DL1: 100/135; DL2: 130–135/135; DL3: 100/160–175; DL4: 130–135/160–175), received oxaliplatin and paclitaxel every three to four weeks.Results: Thirty-one of thirty-seven treated patients were evaluable for activity, with 1 complete and 14 partial responses, (objective response rate: 48%, 95% CI: 31–66). Of 18 platinum-resistant patients 6 responded, and of 13 platinum-sensitive patients, 9 responded. One patient (3%) had two febrile neutropenia episodes, and eight (22%) and eleven patients (30%) had grades 3 and 4 neutropenia, respectively. Six patients (16%) experienced grade 3 peripheral neuropathy. The median response duration was 10.8 months, with a 23-month (range 8–54) median follow-up. Median progression-free and overall survivals were 9 months (95% CI: 7–12), and 25.2 months (95% CI: 12–39), respectively.Conclusions: The antitumour activity of oxaliplatin–paclitaxel in platinum-resistant ovarian cancer patients accords with experimental data on the agents' lack of cross-resistance. Time-related progression parameters confirm it as a promising salvage treatment option.     

A new rat brain tumor model: Glioma disseminated via the cerebral spinal fluid pathways

Summary A rat brain tumor model has been developed with the clinical and pathological features of dissemination via the cerebral spinal fluid (CSF) pathways. A precise number of 9L gliosarcoma cells (5 × 10² to 5 × 10⁵) is stereotactically injected into the CSF of the lateral ventricle. The interval until the onset of neurological symptoms and then death is reproducible and dependent upon the number of cells injected. The median survival of three groups of rats receiving 5 × 10⁵ cells in three different experiments was 17, 18 and 19 days respectively. For three groups receiving 5 × 10⁴ cells, the median survival was 23, 24 and 25.5 days respectively and for two groups receiving 5 × 10³ cells the median survival was 28 and 30 days respectively. The animals developed multiple tumor implants along the CSF pathways usually resulting in hydrocephalus. This tumor model was developed to simulate dissemination via CSF pathways as seen with medulloblastoma and other primitive neuroectodermal tumors of the central nervous system. It will be used to evaluate the therapeutic efficacy of intra-ventricularly administered anti-neoplastic drugs against small implants and malignant cells in the CSF pathways.     

A randomized EPOCH vs. CHOP front-line therapy for aggressive non-Hodgkin's lymphoma patients: Long-term results

Background: The value of continuous-infusion chemotherapy (EPOCH) vs. the standard CHOP combination was evaluated in 78 patients with previously untreated aggressive non-Hodgkin's lymphoma in a randomized phase III clinical trial.Patients and methods: The EPOCH regimen given to 38 patients consisted of the drugs etoposide (50 mg/m²), vincristine (0.4 mg/m²), and doxorubicin (10 mg/m²), all given in a continuous infusion on days 1–4. Cyclophosphamide (750 mg/m²) was administered on day 6 as i.v. bolus, while prednisone was given orally 60 mg/m² on days 1–6. Courses were repeated every three weeks. CHOP was given to 40 patients as routinely prescribed.Results: Forty-eight patients were males and thirty were females. Their ages ranged from 19–75 years (median 45 years). Forty-three (55%) had grade 2 and thirty-five (45%) had grade 3 pathologic subtype. Nine patients (12%) presented with stage I, fourteen (18%) with stage II, forty (51%) with stage Ill, and fifteen (19%) with stage IV disease. The different clinico-pathologic characteristics, including international index categories, were comparable in the two groups. The number of courses given ranged between 3 and 9 (median 6) for both the EPOCH and CHOP regimens. Complete remission (CR) was achieved in 19 (50%), and 27 (67%) of the 38 and 40 patients for both the EPOCH and CHOP combinations, respectively. After a median observation time of 27 months, the four-year overall and failure-free survival rates were 42% and 30% for the EPOCH and 71% and 54% for the CHOP regimen (P = 0.006 and 0.1 for the overall and FFS rates, respectively). Toxicities were comparable and were mostly of grades 1 and 2, except for hair loss, hematologic toxicities, and infectious episodes which were more common in the EPOCH group. In the EPOCH group, overall survival rates were 55% vs. 22% (P < 0.04) at four years for the low-risk (2 prognostic factors) and high-risk (>2 factors) groups, respectively.Conclusions: Thus, it may be concluded that continuous-infusion (EPOCH) chemotherapy did not improve treatment outcome over that of the CHOP regimen for aggressive non-Hodgkin's lymphoma patients.