[Combination therapy with radiation and antineoplastic drugs. 2. Combination therapy with radiation and combination chemotherapy].
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Breast Neoplasms↗
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[Problems of prolonged and combination therapy of tuberculosis; value of combination therapy with thiosemicarbazones].
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Combined Modality Therapy↗
Drug unresponsiveness & combination therapy for kala-azar.
Pentavalent antimonials (SbV) have been successfully used for treatment of kala-azar since last six decades. Since 1970s its conventional dosages have failed to achieve with 60 per cent unresponsiveness reported with WHO regimen in Bihar (India). Pentamidine initially used as a second line of drug, acquired resistance (25%) even with prolonged dosage. Newer oral drug miltefosine is a potent antileishmanial drug with longer half-life, a property likely to acquire resistance. Paromomycin has undergone extensive clinical trials in Indian kala-azar patients. Being an aminoglycoside, acquired resistance is likely to occur when used as a monotherapy. To encounter the problem of treatment failure in kala-azar and to reduce length of therapy, combination of at least two effective antileishmanial agents is a desirable option. In India sodium stibogluconate (SSG) in standard dose has been combined with other antileishmanial agents including paromomycin without encouraging result. Infection with Leishmania donovani depresses cell-mediated immunity. Immunological balance is tilted in favour of Th2 suppressive cytokines over Th1 producing protective cytokines. Interferon gamma (IFN-gamma) has been used in combination with SbV in Indian kala-azar patients with unexpectedly discouraging results. Combination of two most potent leishmanicidal drugs amphotericin B and miltefosine which are not dependent on host immune system, may shorten the course of therapy besides encountering unresponsiveness. A combination therapy should be preferred when treating kala-azar associated with HIV/AIDS. Immunotherapy with exogenous Th1 stimulating cytokines or use of antileishmanial vaccine in combination with a potent chemotherapeutic agent is a future option.
Amphotericin B↗
Design and analysis of trials of combination therapies.
OBJECTIVE: Combination therapies can have significant advantages over monotherapies. Combinations of therapies can provide additive (or even synergistic) effects on efficacy. They may permit use of lower doses of each component to achieve a given level of efficacy, improving tolerability and reducing adverse effects. A multicomponent treatment may facilitate tailoring of therapy to the needs of individual patients (e.g., treatment augmentation in nonresponders). These characteristics seem highly attractive in developing treatment strategies for alcohol abuse and dependence, because existing monotherapies have shown modest efficacy, at best. METHOD: However, trials of combination therapies present challenges in design, execution and interpretation, including: (1) choice of the treatment combinations to be compared; (2) definition of primary and secondary hypotheses; (3) differences between interventions in the duration of treatment, the time lag from the start of treatment to an observable effect on outcomes and interval for assessment of efficacy; (4) study power/sample size; (5) logistics of treatment delivery, masking and outcome assessment; and (6) attribution of adverse events. RESULTS: Most of these issues arose in the COMBINE project, a sequence of trials intended to explore the use of combinations of behavioral and pharmacological approaches in the treatment of alcohol dependence. The resolution and impact of the challenges above for the COMBINE trial will be described. CONCLUSIONS: Trials of combination therapies address many important clinical questions; however, their level of complexity requires considerable forethought, pilot investigations and organization.
Alcoholism↗
The first hypertension trial comparing the effects of two fixed-dose combination therapy regimens on cardiovascular events: Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH).
Current recommendations for the treatment of hypertension clarify the need to achieve lower blood pressure levels in the general population (<140/90 mm Hg) and in specific high-risk patient groups such as patients with diabetes or chronic renal disease (<130/80 mm Hg). Further, it is evident that to reach appropriate blood pressure control, most patients with high blood pressure will require two or more antihypertensive agents. There is scarce clinical trial outcome evidence to guide clinicians in the selection of optimal combinations of antihypertensive classes for high-risk hypertensive patients. A new clinical trial, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is the first large clinical trial to directly compare cardiovascular mortality and morbidity rates for two fixed-dose combination therapies. Results from ACCOMPLISH should provide much-needed guidance for selecting optimal combination therapy for high-risk hypertensive patients.
Amlodipine↗
[AUFRAP therapy: combined modality treatment of malignant gliomas with intraarterial infusion of ACNU].
A method of combination therapy was proposed for the treatment of malignant gliomas, and the clinical results were reported. This combination consisted of ACNU (nimustine), UFT (tegafur + uracil), Radiation, vitamin A and PSK (krestin), and was named AUFRAP therapy. Intracarotid infusion of ACNU (100 or 150 mg/body) was done after the administration of vitamin A (100,000 units), in the first and last week of radiation therapy with a total dose of 60-70 Gy. UFT (400-600 mg/day) and PSK (3g/day) were also given orally. After the induction of remission, patients were treated in the outpatient clinic under a similar maintaining protocol. Two patients who received 150 mg of ACNU and daily 600 mg of UFT in combination with radiation therapy showed severe myelosuppression in the early stage of treatment, and the combination therapy was aborted. Two of four patients who received 100mg of ACNU and daily 400mg of UFT did not show such severe side effects and two showed transient, moderate myelosuppression and vomiting. The serum phenitoin concentration doubled and was thought to be a side effect of tegafur. All four patients completed the induction protocol and follow-up CT scans disclosed shrinkage of the remained tumors, decreased contrast enhancement or no evidence of recurrence. Interactions of these drugs and radiation were discussed and the literature was reviewed.
Adult↗
Bridging the gap with new strategies in acute ST elevation myocardial infarction: bolus thrombolysis, glycoprotein IIb/IIIa inhibitors, combination therapy, percutaneous coronary intervention, and "facilitated" PCI.
Achieving early reperfusion with thrombolytic agents or primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) is the cornerstone of current therapy. Two advances in pharmacologic therapy are: (1) bolus thrombolysis, which simplifies therapy, reduces door-to-needle time, and reduces the potential for medication errors, and (2) Low-dose fibrinolytic therapy combined with a glycoprotein (GP) IIb/IIIa inhibitor which can achieve higher rates of reperfusion than fibrinolytic therapy alone. In addition, the IIb/IIIa inhibitor as part of the reperfusion regimen will support any acute-phase interventions that are performed. The combination of fibrinolytic therapy and GP IIb/IIIa inhibition to "facilitate" PCI is being examined in TIMI-14, SPEED, and GUSTO IV. Early findings in the SPEED trial have shown promising results with "facilitated" PCI when patency is achieved before PCI is attempted. Results of these trials will further define the role of combination therapy in facilitating mechanical interventions.
Angioplasty, Balloon, Coronary↗
L-dopa therapy combined with peripheral decarboxylase inhibitor (MK-486) in Parkinsonism.
Eighteen patients with parkinsonism were treated with a combination of L-dopa and peripheral decarboxylase inhibitor, L-alphahydrazinomethyldopa (MK-486). Modification of L-dopa effect by MK-486 was also studied in parkinsonian patients as well as in cats. (1) Concentrations of dopa and dopamine in plasma and brain were measured in cats following intraperitoneal injection of L-dopa alone (100 mg/kg) or combined with MK-486 (10 mg/kg). Dopa levels in plasma and brain in the combination with MK-486 were three times as high as in L-dopa alone. Dopamine levels in caudate nucleus and putamen were increased nearly fourfold with the combination. (2) Plasma dopa and dopamine levels were measured in parkinsonian patients. Clinical pharmacological studies disclosed that a 1 : 10 ratio of MK-486 to L-dopa in dosage was preferable. (3) Maximum plasma dopa levels with the combination were four times those following L-dopa alone. Plasma dopa sustained a high level over a period of five hours. MK-486 markedly reduced plasma levels of dopamine. (4) There was no significant difference in dopa and dopamine levels in cerebrospinal fluid between L-dopa alone and a combination of MK-486, but dopamine levels in the CSF were still high at four hours after the combination of MK-486. (5) In clinical studies of eighteen patients with parkinsonism, the effectiveness of the combination therapy (mean dosage of L-dopa: 750 mg/day) was observed in all cases. Marked improvement was noted in 10 cases out of 15 (67%) with akinesia, in 12 cases out of 17 (71%) with rigidity and in six cases out of 14 (43%) with tremor. Maximum plasma dopa levels were higher in those cases with marked improvement, and were highest in patients with diskinesias as a side effect. (6) An addition of vitamin B6 did not show adverse effects. (7) Transient nausea and vomiting as a side effect, less severe than those experienced with L-dopa alone, were noted in five cases (28%). Dyskinesias in extremities, face, mouth and tongue were observed in six cases (33%). These dyskinesias were seen in a high percentage of cases with marked improvement and were never observed in the extremities contralateral to the side of thalamotomy.
Adult↗
Mechanisms of action of topical therapies and the rationale for combination therapy.
The advent of new topical agents such as topical calcineurin inhibitors, as well as the reformulations of older agents in new vehicles, has broadened the treatment approaches to psoriasis and atopic dermatitis. The clinician must now consider additional novel physiologic pathways and mechanisms of action as well as expanding options for combination therapy. Combination therapy is especially beneficial when the selected agents possess differing mechanisms of action that provide additive or synergistic efficacy, reducing the required doses of the individual agents compared with monotherapy and potentially limiting side effects. Therapeutic approaches also can be rotated or used in various sequences for maintenance therapy. In psoriasis, a number of trials have demonstrated the effectiveness of combination therapy. Although combination therapy has not been extensively studied in atopic dermatitis, many practitioners combine topical corticosteroids and topical calcineurin inhibitors in their clinical practice because the two drug classes have different and possibly complementary mechanisms of action. For both diseases, the decision as to what agents are combined must also be tempered by patient type, disease presentation or severity, and patient preferences.
Administration, Topical↗
A pilot study of radiation therapy combined with daily low-dose cisplatin for esophageal cancer.
From March 1992 to October 1997, a total of 38 patients with histologically proven esophageal cancer received combination therapy of daily low-dose cisplatin (CDDP) and radiation therapy. The clinical stages (UICC 1997) were I in 3, IIA,B in 13, III in 13, and IVA in 9 patients. CDDP (5 mg/m2) was administered intravenously with 100 ml saline 30 min before each irradiation from Monday to Friday. All patients received at least 60 Gy of radiation therapy. The average number of CDDP administrations was 23, and the mean total CDDP dose was 115 mg/m2. Of the 38 patients, 14 patients completed full course of chemoradiation therapy. The overall survival rates at 1, 2, and 5 years were 51%, 19%, and 8%, respectively. The median survival period was 12 months. The objective response rate was 82% with 11 (29%) CR. Survival of the stage II-IVA patients who received daily low-dose CDDP and radiation therapy was a little better than that of historical control patients who were treated by radiation therapy alone. Most of the patients experienced nausea. Grade 3 esophagitis was observed in two (5%) patients. Grade 4 leukocytopenia and thorobocytopenia were observed in one (3%) and two (5%) of the patients, respectively. Except for leukocytopenia (18%), frequencies of toxicity of grade 3 or more were less than 10%. Although the results indicate that daily low-dose CDDP combined with radiation therapy may slightly improve the survival of esophageal cancer patients with acceptable toxicity, further efforts should be made to optimize clinical trial protocols. Escalation of daily CDDP dose should be considered to obtain a more effective radiosensitizing effect.
Aged↗
Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.
BACKGROUND: Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. OBJECTIVES: We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. SEARCH STRATEGY: Cochrane Library (Issue 4,2001), the Cochrane Cancer Network Register of trials (July 2000), EMBASE (January 1980-2000), MEDLINE (1966-8/2001), and ICAAC conference proceedings (1995 onwards). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. DATA COLLECTION AND ANALYSIS: Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. MAIN RESULTS: Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. REVIEWER'S CONCLUSIONS: We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.
Aminoglycosides↗
Drug therapy reviews: tricyclic antidepressant and monoamine oxidase inhibitor combination therapy.
Combinations of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) are discussed with regard to general toxicity, drug interactions, animal studies, clinical reports, efficacy of combination therapy and usage conditions. Although MAOI-TCA combinations are usually considered contraindicated, informed opinion has shifted to cautious recommendation for the combination. Only refractory patients in whom less hazardous treatment has failed should be considered for combination therapy. The preferred dosage regimen is administration of the MAOI t.i.d. during the day and the entire TCA dose at bedtime. Patients should be informed of the immediate need for medical advice should side effects occur. It is concluded that the simultaneous administration of these agents is potentially efficacious and safe is carefully monitored and controlled.
Animals↗
Transcatheter arterial chemoembolization therapy combined with percutaneous ethanol injection for unresectable large hepatocellular carcinoma: an evaluation of the local therapeutic effect and survival rate.
BACKGROUND/AIMS: This study was undertaken to evaluate the effectiveness of combination therapy with transcatheter arterial chemoembolization followed by percutaneous ethanol injection in patients with unresectable large hepatocellular carcinoma by comparing the use of this combined regimen with transcatheter arterial chemoembolization alone. METHODOLOGY: Six hundred and thirty-one consecutive patients with hepatocellular carcinoma lesions observed from Jan 1989 to Dec 1999 (11 years) at the Internal Medicine Department, Saga Prefectural Hospital Koseikan were retrospectively enrolled in the study. The series included 120 patients with large unresectable hepatocellular carcinoma lesions, the largest of which were greater than 3 cm in largest dimension. Fifty-two patients underwent a single transcatheter arterial chemoembolization followed by percutaneous ethanol injection, which were compared with 68 patients treated by transcatheter arterial chemoembolization alone. Both groups of patients with hepatocellular carcinoma did not differ regarding the base-line characteristics. The overall survival rates and recurrence ratio of initially treated lesions were compared in both groups. RESULTS: On overall survival rates by the Kaplan-Meier method, three- and five-year survival in the transcatheter arterial chemoembolization and percutaneous ethanol injection group (59.0%, 32.1%) proved to be significantly longer than those in the transcatheter arterial chemoembolization group (27.1%, 17.0%). In addition, during the follow-up local recurrence in the combination group (23.1%) was significantly lower than that in the transcatheter arterial chemoembolization group (50.0%). CONCLUSIONS: The combined treatment with transcatheter arterial chemoembolization and percutaneous ethanol injection proved to be more effective and safer. Furthermore, a lower incidence of local recurrence was observed than transcatheter arterial chemoembolization alone which resulted in an increased survival of the patients associated with unresectable large hepatocellular carcinoma lesions.
Adult↗
Rotational 3D-conformal radiation therapy (conformation therapy) combined with hormone therapy for the treatment of stage B2/C prostate cancer in Japanese men.
BACKGROUND AND PURPOSE: In our institution, rotational 3D-conformal radiation therapy (also called conformation therapy) has been applied since the late 1970s to conform the target volume of high-dose radiation to the cancerous tissue while minimizing radiation to the surrounding normal tissues. This technique has been used most commonly to treat prostate cancers in combination with hormonal therapy. The results of Stage B2/C prostate cancer treated with this method were analyzed. PATIENTS AND METHODS: Between 1987 and 1997, 33 cases of prostate cancer were definitively treated with this method: 9 Stage B2 tumors and 24 Stage C tumors. Of these 33 tumors, 3 were well differentiated, 18 were moderately differentiated, and 12 were poorly differentiated. The average patient age was 75.6 years. The median pretreatment PSA value was 23.8 ng/ml. The total radiation dose ranged from 60 Gy to 70 Gy (average: 63.5 Gy) with conventional fractionation. Hormone therapy was administered permanently; the primary hormonal agent was diethylstilbestrol phosphate. RESULTS: The overall survival rate after 5 years was 58.2% and that after 10 years was 29.6%. The biochemical relapse-free rate after 5 years was 87.0% and that after 10 years was still 87.0%. There were 4 cases of biochemical failure, but no cases of death from prostate cancer. Stage, differentiation, and pretreatment PSA value were not prognostic factors. One of the 2 cases with delayed complications was a case of RTOG Grade 3 gastrointestinal complication. CONCLUSIONS: Rotational 3D-conformal radiation therapy combined with hormone therapy might be promising for the treatment of prostate cancer.
Adenocarcinoma↗
Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV+3TC) combination therapy in patients previously treated with ZDV+ddC.
OBJECTIVE: To evaluate the immunological and virological efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) and a double (ZDV+3TC) combination therapy in patients previously treated with ZDV plus ddC. DESIGN: A 6-month follow-up open-label randomized study was undertaken in 46 HIV-1-infected patients previously treated for at least 6 months with ZDV plus ddC, who were allocated to receive either ZDV/ddC/3TC (n = 15) or ZDV/3TC (n = 15) or to continue with the ZDV/ddC regimen (control group; n = 16). METHODS: Changes in CD4+ cell counts and plasma viral load (VL) were analysed with analysis of variance. Sequencing of the reverse transcriptase gene was performed in a subset of 3TC-treated patients. RESULTS: Mean CD4+ cell counts increased significantly above baseline in both 3TC regimens whereas counts decreased in the control group. Significant plasma VL reduction was achieved in both 3TC combination therapy groups at weeks 4 and 24 compared with the control group. Coexistence of mutations conferring resistance to ZDV and 3TC were found in patients from both 3TC treatment groups. CONCLUSIONS: Both therapy strategies, switching ddC to 3TC or adding 3TC, significantly improved the virological and immunological efficacy compared with continuing ZDV/ddC. Our results support the use of 3TC in patients previously treated with the ZDV/ddC combination.
Adult↗
[The use of autogenic training in the combined therapy of bronchial asthma patients].
Since 1976 in the Allergologic Clinic autogenous training is applied in asthmatic patients as group therapy combined with respiratory exercises. In 10 asthmatic patients in the conditions of an acute experiment the forced vital capacity, forced expiratory flow for I s and maximum mean expiratory flow were followed up after autogenous training. An improvement of the ventilation indices was found. The autogenous training is a suitable nonmedicamentous method as a part of the total rehabilitation therapy in asthmatic patients.
Adolescent↗
[Successful 5'-DFUR, CDDP and MMC combination therapy and 5'-DFUR and carboplatin combination therapy for a patient with inoperable advanced gastric cancer with peritonitis carcinomatosa].
A 71-year-old man with Borrmann type 3 gastric cancer and peritonitis carcinomatosa was treated with 5'-DFUR 600 mg/body p.o. daily, CDDP 50-80 mg/m2 i.v. on day 1 and MMC 6 mg/m2 i.v. on day 2 after intraperitoneal injection of CDDP and OK-432. The cycle of CDDP and MMC was repeated every 4 or 5 weeks. After 15 cycles of treatment, the primary gastric lesion disappeared and regional lymph node metastasis was reduced. Because of relapsing of the original lesion and concomitant renal dysfunction, a changed regimen of CDDP and Carboplatin was tried. Then the gastric lesion was reduced and lymph node metastasis disappeared. The patient has lived for about 3 years after diagnosis, but his gastric lesion is gradually worsening with duodenal invasion. This case indicates that these combination chemotherapies are quite promising as an effective treatment for advanced gastric cancer and good quality of patient's life.
Aged↗
[Effect of a combination therapy of cisplatin and local irradiation on a mouse fibrosarcoma].
The authors applied the method of regrowth delay in order to investigate the effect of a therapy combination consisting of cis-platinum and irradiation on the fibrosarcoma SSK2 in C3H mice. An independent addition of the effects of both therapy modalities was found. It could be shown especially that no elective radiosensitization of hypoxic tumor cells is caused by cis-platinum.
Animals↗