End Of Combination Therapy Research Articles

Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN

Background: The influence of hepatitis C virus (HCV) treatment on the course of HCV cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) is controversial. Methods: Twenty-five patients with nephrotic-range proteinuria, mixed cryoglobulinemia, MPGN proved by renal biopsy, and HCV infection were studied for their response to antiviral treatment. Results: After first-line treatment with prednisone, furosemide, or plasmapheresis, antiviral therapy with standard or pegylated interferon alfa and ribavirin was introduced in 18 patients. These patients were compared with 7 patients who did not receive antiviral treatment. Mean duration of antiviral treatment was 18 ± 10 months, with a follow-up of at least 6 months after treatment withdrawal. HCV RNA clearance (sustained virological response) was achieved in 12 of 18 patients. Compared with values before antiviral therapy, a decrease in proteinuria was observed in sustained virological responders at the end of combination therapy, as well as at the end of follow-up (mean, 2.85 ± 2.2 [SD] versus 1 ± 1.4 and 0.4 ± 0.8 g/d, respectively; P < 0.05). In sustained virological responders, cryoglobulin levels at the end of treatment (0.29 ± 0.4 g/L) and end of follow-up (0.25 ± 0.4 g/L) were decreased (P < 0.05) compared with pretreatment values (1.38 ± 2.2 g/L). Conversely, no changes in serum cryoglobulinemia levels were observed in nonresponders or controls. Serum creatinine levels remained stable in the 18 patients with antiviral therapy, regardless of response to treatment. Conclusion: Anti-HCV treatment improved HCV-associated cryoglobulinemic glomerulonephritis.

Comparison of candesartan and felodipine alone and combined in the treatment of hypertension: a single-center, double-blind, randomized, crossover trial

Background: In the past decade, many studies have indicated that the combination of low doses of different classes of antihypertensive agents may be more efficacious than monotherapy while minimizing the likelihood of dose-dependent adverse effects (AEs). Objective: The aim of this study was to determine whether combination therapy with lower doses of candesartan and a calcium antagonist, felodipine, would be more effective and tolerable in controlling mild to moderate hypertension compared with either drug used alone. Methods: In this 18-week, single-center, double-blind, crossover study, patients with mild to moderate essential hypertension were randomized to 1 of 2 treatment groups after a 2-week placebo washout period. Patients in group 1 received candesartan 16 mg once daily and patients in group 2 received felodipine 5 mg once daily, for 6 weeks. All patients then received half-dose combination therapy (candesartan 8 mg plus felodipine 2.5 mg, once daily) for 6 weeks. Finally, patients received 6 weeks of monotherapy with the alternate medication (group 1 received felodipine 5 mg once daily and group 2 received candesartan 16 mg once daily). Results: Thirty patients (18 men, 12 women; mean [SD] age, 54.0 [4.9] years; range, 39–62 years) were included in the study. During both monotherapy periods, candesartan and felodipine significantly reduced blood pressure (BP) (both P<0.001). BP further decreased with combination therapy ( P<0.001 in both groups). Overall, 90.0% (27/30) of the patients achieved the target BP at the end of combination therapy. The incidence of AEs was similar with combination therapy compared with either monotherapy. Conclusions: In this study population, candesartan and felodipine had additive effects when used in combination, even at low doses, in the treatment of hypertension. Therefore, the combination of candesartan and felodipine is an effective alternative to that of candesartan and hydrochlorothiazide.

Hodgkin's disease in 35 patients with HIV infection: An experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF

The optimal therapeutic approach for patients with Hodgkin's disease and human immunodeficiency virus infection (HD-HIV) is unknown. In an attempt to improve the results previously obtained with EBV (epirubicin, bleomycin and vinblastine) without G-CSF (Cancer 1994; 73: 437-44), in January 1993 we started a trial using chemotherapy (CT) consisting of EBV plus prednisone (EBVP), concomitant antiretroviral therapy (zidovudine, AZT or dideoxinosyne, DDI), and G-CSF. Up to August, 1997, 35 (30 M/5 F) consecutive previously untreated patients (median age 34, range 21-53 years) with HD-HIV were enrolled in the European Intergroup Study HD-HIV. Their median performance status was 1 (range 1-3). At diagnosis of HD, 26% of the patients had AIDS, 90% had B symptoms at HD presentation and 83% had advanced-stage HD. Patients received E 70 mg/m2 i.v. on day 1, B 10 mg/m2 i.v. on day 1, V 6 mg/m2 i.v. on day 1 and P 40 mg/m2 p.o. from day 1 to day 5 (EBVP). Courses were repeated every 21 days for six cycles. AZT (250 mg x 2/day), or DDI (200 or 300 mg x 2/day) if AZT had been previously used, were given orally from the beginning of CT. G-CSF was given at the dose of 5 mcg/kg/day s.c. from day 6 to day 20 in all cycles. An overall response rate of 91% was observed. There were 74% complete responses (CR) and 17% partial responses (PR). Toxicity was moderate, with grade 3-4 leukopenia and thrombocytopenia in 10 (32%) and three (10%) patients, respectively. The median number of administered cycles was 6 (range 3-6). Twenty-three of 35 patients received AZT and nine patients received DDI. Three (8%) patients had opportunistic infections (OI) during or immediately after CT. The median CD4+ cell count was 219/mm3 (6-812) at HD diagnosis and 220/mm3 (2-619) after the end of combined therapy, and these numbers remained unchanged. Ten of 26 (38%) patients who achieved CR relapsed. Twenty-three patients died of HD progression alone or in association with OI, being the cause of death in 48% and 9% of patients respectively. The median survival was 16 months, with a survival rate of 32% and a disease-free survival of 53% at 36 months. The combined antineoplastic and antiretroviral treatment is feasible, but HD in HIV setting is associated with a more adverse prognosis than in the general population. Although the CR rate obtained was satisfactory, the relapse rate was high. Furthermore, comparison of the results of our two consecutive prospective studies demonstrated no overall improvement in the current trial with respect to the CR rate and survival.

Local hyperthermia and radiation therapy in the treatment of superficially located lymphomas and recurrent Hodgkin's disease

The combination of radiation therapy CRT) and hyperthermia (HT) has proved to be an effective treatment of a wide variety of superficially located recurrences of different tumors, particularly those arising in previously irradiated areas. Some studies have been reported with the use of this combined approach in the management of cutaneous lymphomas or recurrent previously irradiated sites of Hodgkin's disease (HD). We report a small series of five patients with six located sites of recurrent HD, and four patients with six superficially located sites of non Hodgkin's lymphomas (NHL), all of them being treated with combined HT and RT at our institution. Local control was obtained in each of combined treatment fields, and all patients are alive after a median follow-up of 24 months. All the patients tolerated the HT treatments well, and in all cases average intratumoral temperatures were >42 degrees C, with 8 out of 12 sites achieving the goal of average temperatures >42.5 degrees C. Two patients, one with recurrent HD and one with NHL, are free of disease after 20 and 21 months from the end of combined therapy. Our results thus seem to confirm previous experiences, suggesting a role of HT/RT not only for palliative purposes in cutaneous lymphomas, but also in the management of selected, heavily pretreated patients with superficially located recurrences of HD.

182 P - Epirubicin, bleomycin, vinblastine and prednisone (EBVP) chemotherapy (CT) in combination with antiretroviral therapy and primary use of G-CSF for patients (pts) with hodgkin's disease and HIV infection (HD-HIV)

Objective The optimal therapeutic opproach for pts with HD-HIV is unknown, In an attempt to improve the results that we obtained in a previous prospective study with EBY without G-CSF (Cancer, 73: 437–44, 1994). in January 1993 we started a second trial consisting of CT, concomitant antiretroviral therapy (AZT or DDI), and G-CSF. Methods Up to October 1995, 27(23M/4F)consecutive previously untreated pts (median age 33, range21–49 years) with HD-HIV were enrolled. Median performence status was 1 (range 1–3). At diagnosis of HD, 7 (26%) of pts had AIDS, 3(11%) ARC, and 17 (63%) were asymptomatic. Eighty-five per cent of pts had B symptoms at HD presentation. Pts received E 70 mg/m2 i.v. on day I, B 10 mg/2i.v. on day 1, V6 mg/m2 i.v. on day 1 and P 40 mg/m2p.o. from day 1 today 5. Courses were repeated every 21 days for six cyclcs. AZT (250 mg x 21/day) or DDI (200 or 300 mg × 2/day), when AZT w previously used, were given orally from the beginning of CT. G-CSF was given at the dose of 5 mcg/kg/day s.e. from day 6 to day 20 in all cyeles. Results Clinico-pathologic characteristics of pts and response 10 therapy are shown in the table: Table # pts CD4+at diagnosis Subtype Stage Response DFS entered/evaluable median # (range) MC & LD III & IV OR CR at 2 yrs 27/21 * 187 (6–812) 18(66%) 22(82%) 90% 71% 43% * pts are still on treatment Toxicity was moderate with grade 3–4 leukopenia and thrombocytopeni in 7 (33%) and in 2 (10%) pts respectively. Fifteen out of 21 pts received AZT and 2 pts received DDI. Only 6 (28%) pts had opportunistic infections (OI), during or after CT (median follow-up. 14 months). No change of CD4+ cell count was seen, being the median number 171/mm3 (2–529) after the end of combined therapy. Six out of 15 (40%) pts who achieved a CR relapsed. Overall, HD progression alone and in assciation with OI was the cause of death in 46% and in 15% of pts respectively. The median survival was 14 months with an actuarial survival rate of 33% at 24 months. Conclusions The combined treatment was feasible. However, although the CR rate obtained was satisfactory, the number of relapsed pts was high and overall median survival was not different from our previous experience or from literature, Taking in consideration the moderate toxicity, we are currently considering higher doses of CT at shorter interval with the support by G-CSF. Supported by A1RC 95 and ISS ‘95.

Fluvastatin in familial hypercholesterolemia: A cohort analysis of the response to combination treatment

A recent randomized, double-blind, double-dummy trial revealed differences in the response of patients with heterozygous familial hypercholesterolemia to combination therapy with the new, wholly synthetic 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor fluvastatin, 20 mg/day and then 40 mg/day, plus the fibric acid analogue bezafibrate, 400 mg/day, vs combination therapy wtth fluvastatin, 40 mg/day, plus the bile acid sequestrant (resin) cholestyramine, 8 g/day. The main purpose of the present cohort analysis was to determine whether these differences in lipid response were related to imbalances in the patients' prior responses to up to 42 weeks of fluvastatin monotherapy, 20 mg/day, 40 mg/day, and, in some patients, 60 mg/day, in 2 earlier studies. For the present analysis, we identified 18 patients in the fluvastatin plus bezafibrate group (cohort 1) and 16 patients in the fluvastatin plus cholestyramine group (cohort 2) for whom complete dose-response data were available for the full 56-week duration of all 3 studies. Subsets of 7 patients in cohort 1 and 8 patients in cohort 2 had received the 60 mg/day fluvastatin dose during a previous monotherapy study. In cohort 1, low density lipoprotein cholesterol (LDL-C) decreased by 19% with 20 mg/day fluvastatin, by 27% with 40 mg/day fluvastatin, by 31% with 20 mg/day fluvastatin plus bezafibrate, and by 35% with 40 mg/day fluvastatin plus bezafibrate, and the LDL-C/high density lipoprotein cholesterol (HDL-C) ratio had fallen by 46% at the end of combination therapy. In cohort 2, LDL-C declined by 19% with 20 mg/day fluvastatin, by 23% with 40 mg/day fluvastatin, and by 31% with fluvastatin plus cholestyramine, and the LDL-C HDL-C ratio was lowered by 38% at the combination therapy endpoint. Thus, the LDL-C response was similar in both cohorts, except for the enhancement of the effect on the LDL-C HDL-C ratio seen with the combination of fluvastatin plus bezafibrate, compared with the combination of fluvastatin plus cholestyramine. That is, the addition of either bezafibrate or cholestyramine lowered LDL-C levels by an additional 9–10% relative to the decreases achieved with 40 mg/day fluvastatin alone. According to the findings of the cohort analysis, some of the differences in efficacy observed between the 2 combination regimens were related to prior response to monotherapy, which, in turn, may have reflected patient gender and/or compliance with therapy. No clinically meaningful abnormalities in aspartate aminotransferase, alanine aminotransferase, or creatine kinase levels were noted with either combination regimen, which suggests that the regimens were equally safe. Although both combinations were effective, fluvastatin plus bezafibrate appeared to be superior, since it lowered triglyceride levels by 24%, in contrast to the 8% increase seen with fluvastatin plus cholestyramine. We conclude that the combination of fluvastatin with bezafibrate is a good alternative for the treatment of severe familial hypercholesterolomia when a fluvastatin-resin combination is poorly tolerated and/or does not achieve goal lipid levels. However, careful monitoring is recommended in light of reports of the development of myopathy and rhabdomyolysis with the use of fibrates alone or in combination with other fungally derived HMG-CoA reductase inhibitors.

Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas.

A single-center, prospective, nonrandomized trial was conducted to evaluate therapeutic results of a short-term program of chemotherapy followed by locoregional radiotherapy in stage I or II intermediate/aggressive non-Hodgkin's lymphoma (NHL). From 1985 to 1990, 183 consecutive patients with a diagnosis of NHL (Working Formulation [WF] E through J excluding Burkitt's type), Ann Arbor stage I or II, and no more than three sites of disease involvement were treated with four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (six cycles in partial responders). Radiation therapy to initial sites of disease involvement (40 to 44 Gy) and to proximal uninvolved nodal region (36 Gy) was delivered shortly after completion of the chemotherapy program. The complete remission (CR) rate was 98% at the end of combined therapy. Diagnostic excision of all measurable disease was performed in 33% of patients. In the remaining patients, 87% achieved CR with chemotherapy and 11% with radiation therapy, while three patients failed to achieve CR. After a median follow-up of 51 months, 26 patients have relapsed and 25 have died. The 5-year relapse-free and total survival rates were 83%. Aside from age older than 60 years, no other factor such as histology, stage, extranodal disease, bulky lymphoma, or abnormal lactic dehydrogenase (LDH) could predict for treatment outcome. There was a trend toward higher relapse rate for patients achieving CR at the time of radiation therapy (31%) as opposed to patients achieving CR with chemotherapy (15%) or with initial surgery (10%). Treatment was well tolerated and no deaths due to acute toxicity were observed. For patients who present with limited-stage, aggressive NHL, a short course of CHOP chemotherapy followed by locoregional irradiation is safe, highly effective, and curative for most. Therefore, at the present time this approach can be regarded as standard therapy for these patients.

Radical radiation alone versus radical radiation plus microwave hyperthermia for N 3 (TNM-UICC) neck nodes: a prospective randomized clinical trial

Between September 1985 and December 1986, 44 N 3 (TNM-UICC) metastatic squamous cell cervical lymphnodes were randomized to receive conventionally fractionated radical irradiation (RT) to a total dose of 64–70 Gy, or conventionally fractionated radical irradiation plus twice a week local microwave hyperthermia (Ht). The two major end points of this study were (a) local control rates evaluated at 3 months after the end of combined therapy and (b) incidence of acute local toxicity. Thirty-six nodes (82%) were evaluable as of December 1986, at which time there was a premature closure of this study due to ethical reasons. An interim analysis had revealed a statistically significant difference in complete response rates in favor of the combined arm ( p = 0.0152). The complete response rates were 82.3% ( 14 17 ) for the combined treatment arm versus 36.8% ( 7 19 ) for the control irradiation arm, leading to an iso-dose thermal enhancement ratio (TER) value of 2.23. Both arms are comparable in average total RT dose delivered (RT: 67.05 Gy; RT+Ht: 67.85 Gy) and in average maximum node diameter (RT arm: 4.81 cm; RT+Ht: 4.88 cm). Acute local toxicities were similar in irradiated and heated plus irradiated neck regions; only one skin burn was observed. As possible treatment related death, one patient in the RT+Ht arm died 2 months after completion of therapy with a carotid rupture associated with extensive tumor necrosis. These results confirm previous non-randomized reports suggesting that hyperthermia in combination with full dose conventionally fractionated irradiation significantly enhances the chance of early local control of fixed N 3 neck nodes without exhibiting an increase of acute local toxicity.

Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer

Combined treatment modality was applied in 110 consecutive women with primary inoperable (T3b-T4) Breast cancer. Treatment was started with four cycles of adriamycin plus vincristine (AV). This was followed in responders by high-energy radiotherapy (RT). At the end of combined therapy, patients in complete remission (CR) were randomized to either no further treatment or six more cycles of chemotherapy. AV induced objective response in 89% of patients (complete 15.5%, partial 54.5%, improvement 19%). At the end of RT, 81% of 98 (82.7%) patients responding to AV were classified in CR. The median duration of CR was 15 months. The median free interval was statistically prolonged by additional chemotherapy. The three-year survival was 52.8%. Altogether, present findings indicate that combined treatment modality has improved the three-year survival compared to the previous series treated with radiotherapy alone. However, to achieve a satisfactory control of T3b-T4 breast cancer a more aggressive and prolonged treatment is required.