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Radiation therapy combined with hormone therapy for prostate cancer.

Standard-dose radiation therapy has limited capacity to cure bulky and locally advanced prostate cancer. Multiple randomized trials have shown a clinical benefit to adding androgen suppression therapy to external-beam radiation therapy in several subsets of prostate cancer. These studies have made combining hormonal therapy with radiation therapy the standard of care for men with locally advanced (T3-4) and unfavorable prostate cancers (Gleason score >or=8 and/or prostate-specific antigen >20 ng/mL). The clinical impact of hormonal therapy has been seen in biochemical control, local control, distant metastases, disease-specific survival, and overall survival. If hormonal therapy is to be combined with radiation, it should be initiated before the start of radiation and continued during the radiation course rather than used only in the adjuvant setting. Typically, shorter-term hormone therapy is defined as regimens of 4 to 6 months, with longer-term hormone therapy describing durations beyond 24 months. Historically, longer-term hormone therapy was thought to have a more profound systemic effect; however, with the emerging use of hormonal therapy for less-advanced disease, the overall impact of shorter-course hormone therapy is being seen. This review will summarize trials using hormonal therapy and radiation with an emphasis on phase III studies and describe the more recent integration of hormone therapy with radiation for prostate cancer.

Androgen Antagonists↗

A randomized pilot study comparing combination therapy plus enfuvirtide versus a treatment interruption followed by combination therapy plus enfuvirtide.

Most individuals with multidrug-resistant HIV who switch to a new therapeutic regimen containing a single fully effective agent experience incomplete viral suppression. We postulated that interruption of antiretroviral therapy prior to the introduction of such a regimen would improve long-term virological outcomes. Thirty, three-class experienced, enfuvirtide-naive individuals with detectable drug-resistant viraemia were randomized to an immediate enfuvirtide/optimized-background treatment regimen or a 16-week treatment interruption followed by enfuvirtide/optimized-background treatment regimen. The median CD4+ T-cell count and viral load at study entry were 39 cells/mm and 4.72 log10 copies RNA/ml, respectively. There was no evidence of any virological or immunological benefit associated with the interruption. In multivariate analysis, only the baseline phenotypic susceptibility score was predictive of treatment response at week 48 (P=0.009). Only 40% of individuals had evidence of a shift in drug-resistance genotype during the interruption. In summary, interrupting therapy prior to initiating salvage therapy in patients with advanced disease did not result in an improved virological response to enfuvirtide. The collective predictive activity of an enfuvirtide-containing regimen was important in predicting treatment response.

Anti-HIV Agents↗

"Cocktail" therapy for acute pancreatitis: combined therapy of protease inhibitor, xanthine oxidase inhibitor and platelet activating factor antagonist in rat caerulein-induced pancreatis.

A supramaximal dose of caerulein (5 micrograms/kg.hr for 3.5 hours) caused an acute pancreatitis with marked hyperamylasemia and intense interstitial edema in rats. In this model of pancreatitis, the redistribution of lysosomal enzyme in acinar cells as well as the increased lysosomal and mitochondrial fragility were also observed. The combined therapy of a low molecular weight protease inhibitor, FOY, a synthetic platelet activating factor (PAF) antagonist, CV 6209, and a xanthine oxidase inhibitor, allopurinol produced more significant improvements in all the parameters examined than the therapy of any only one of these three agents, each only one therapy exerting a partial significant protective effect. These results indicate that several factors, such as unknown proteases activities, PAF and oxygen-derived free radicals may be involved in the pathogenesis of pancreatic injuries in this caerulein-induced pancreatitis. These results also suggest that such a combined therapy of different kinds of agents, whose therapeutic mechanisms are also different, is useful in the clinical treatment of acute pancreatitis.

Acute Disease↗

Sequential therapy compared with combination therapy in multiple myeloma.

A timed sequential chemotherapeutic regimen for multiple myeloma was desinged, based on plasma cell kinetics. A randomized study comparing this regimen with the combination of intermittent melphalan and prednisone was started after an adequate pilot study. Studies with tritiated thymidine labeling and mitotic indexes were performed on patients treated with sequential therapy. Of 13 patients treated with the combination therapy, the responses were as follows: two, objective improvement; nine, subjective improvement; and two, no responses. Of nine patients treated with sequential therapy, the responses in six patients who could have evaluations were as follows: one, objective improvement; two, subjective improvement; one, no response; one, with progressive disease; and one, cardiac death. The two studies showed differences in pertubation of cell kinetics of myeloma that may be related to exponential growth and immunoblobulin types.

Autoradiography↗

[Combination therapies on osteoporosis].

Combination therapies of bisphosphonates with conjugated equine estrogen (CEE) , vitamin D or parathyroid hormone (PTH) on osteoporotics have been discussed. Combined therapy of bisphosphonate with CEE increased lumbar bone mineral density (LBMD) and femoral neck bone mineral density (FBMD) in elderly patients. Furthermore combination therapy of bisphosphonate with CEE reduced new vertebral fractures in elderly osteoporotics. Similarly combination therapy of bisphosphonate with vitamin D is also advantageous to the increase of LBMD and FBMD. It is likely that the merit of combination therapy is to increase not only the lumbar BMD, but also the femoral BMD, although monotherapy is only to increase lumbar BMD. In contrast to CEE vitamin D seems to assist the effect of bisphosphonate in non-respondent patients to bisphosphonate. However, combination therapy of bisphosphonate with PTH might be complex in reducing the effect of alendronate.

English Abstract↗

A clinical study on SSP (silver spike point) electro-therapy combined with splint therapy for temporo-mandibular joint dysfunction.

When the functional limits of the muscles related to the temporo-mandibular joint and adjacent tissue exceed their anatomical capability, pain, crepitation, and functional abnormality appear as the main complaints. Although the precise nature of the condition is unknown, pain at the temporo-mandibular joint sometimes in combination with muscular tension is assumed to be due to compression of the myoneural mechanism. It is reported that occlusal lifting using a splint enables the alleviation of this muscular tension. On the other hand, there are only a few reports on the usefulness of SSP therapy for Temporo-Mandibular Joint Dysfunction. We studied the efficacy of SSP therapy combined with splint therapy in 33 patients diagnosed as having Temporo-Mandibular Joint Dysfunction who consulted our department primarily due to pain, and report our findings below. Evaluation of the results was conducted 2 weeks later. Very beneficial results were seen in 6 cases. Beneficial results were seen in 7 cases. Slightly beneficial results were seen in 18 cases, while there were no changes found in 2 cases. When combined SSP and splint therapies were conducted for Temporo-Mandibular Joint Dysfunction, favorable results were seen in about 90% of the cases.

Acupuncture Analgesia↗

Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study.

The morphologic changes induced by neoadjuvant combination endocrine therapy were evaluated in prostatectomy specimens from patients diagnosed with localized prostate cancer. These patients participated in a prospective, randomized clinical trial investigating the effect of 3 months of combination therapy with flutamide and an LHRH agonist prior to radical prostatectomy versus radical prostatectomy alone. Ninety-six radical prostatectomy specimens processed according to the same protocol were evaluated without knowledge of prior treatment. Forty-seven patients were randomly assigned to the neoadjuvant combination therapy group and 49 to the control arm. Compared with the control group, several changes were strongly and significantly associated with exposure to neoadjuvant combination therapy. The nonmalignant prostatic tissue showed strong prominence and hyperplasia of the basal cell layer, accompanied by epithelial cell vacuolization and markedly reduced occurrence of prostatic intraepithelial neoplasia (p < 0.001) after combination therapy. Prostate cancer tissue, on the other hand, showed smaller nucleoli (p < 0.001), cell vacuolization (p < 0.001), rare intraluminal crystalloids (p < 0.001), higher Gleason grade (p < 0.001), lower prevalence of capsular penetration (p < 0.001), and less frequent invasion of the perineural spaces (p < 0.001) and surgical margins (p = 0.002). Tumor volume, was also reduced by more than 40% in the treated group (p = 0.007). The present findings show that preoperative endocrine combination therapy induces highly characteristic changes in both nonmalignant and cancerous prostatic tissue. Furthermore, following endocrine treatment, the surgical margins are less likely to be involved by cancer and capsular penetration is reduced.

Adult↗

[The repetitive immune cell transfer therapy combining non-myelosuppressive chemotherapy for patients with advanced and refractory cancer].

Autologous tumor cells stimulated with T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell lines and may have a potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on the conventional conditioning regimen in order to take advantage by both the anticancer effects and reconstruction of antitumor immunity. Nineteen patients were enrolled in a pilot clinical trial. The two administrations of AuTL were given prior to chemotherapy (ChT) for one treatment cycle. The treatment was repeated at least for three cycles over a one-week interval. The conventional ChT regimen was based on the standard dosage. The pts consisted of 3 of gastric cancer, colon cancer, lung adenocarcinoma, respectively, 6 of esophageal cancer, and 2 of breast and pancreas carcinoma, respectively. AuTLs were administered 1x/2 weeks using direct injection or intraarterial infusion. The median duration of the treatment was over 11.5 months, and the median survival time was 14.8 months. Adverse events related to both the ChT and AuTL transfers at all dosages were minimal. Four of the 13 pts achieved major tumor responses (2 CR: complete regression and 2 PR: partial regression) in this study. Three pts showed progressive disease, and 6 pts had stable disease for over 90 days. PBMC were evaluated for cytokine production prior to the treatment and after 3 treatments. Two and one of 4 CR/PR pts had increased IFN-gamma and TNF-alpha production with no TGF-beta1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after the treatment had high IFN-gamma and TNF-alpha responses and no TGF-beta1 or IL-4 response. TGF-beta1 and IL-4 secretion increased in parallel in 3 out of 3 pts that experienced progressive disease after the treatment. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without serious adverse events and without reducing Th1 cytokine responses in peripheral blood for most of the pts that responded to the treatment. According to each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with non-myeloablative ChT for various kinds of cancers should be performed to manage the immunodeficiency in the pts with advanced cancer and to improve the effect of antitumor AuTLs.

Adoptive Transfer↗

[Combined therapy of ventriculo-cisternal irrigation with external decompression in acute ruptured aneurysm].

Vasospasm after clipping of an acute ruptured aneurysm plays an important role in its prognosis. An effective therapy for vasospasm has not been established. We had attempted to remove the subarachnoid clot, which probably caused vasospasm, by ventriculo-cisternal irrigation and had not so good results (A: a group without decompression). Therefore, we have performed a therapy combined ventriculo-cisternal irrigation with external decompression (B: a group with decompression). We wish to report the efficacy of external decompression for an acute ruptured aneurysm. Evaluation of the outcome is due to Table 2. 55% of A group and 80% of B group have a better grade than "fair". Furthermore, a significant difference lies between A and B group associated with symptomatic vasospasm (brain ischemia caused by vasospasm). Namely, A group has all poor or dead cases but B group has 80% of the cases better than "fair". We concluded that relieving ICP by external decompression could suppress the aggravation of the post operative symptomatic vasospasm.

Acute Disease↗

The contribution of metformin to glycaemic control in patients with Type 2 diabetes mellitus receiving combination therapy with insulin.

Combination therapy of oral hypoglycaemic agents and insulin is a therapeutic option for those who have deterioration in glycaemic control. We examined the contribution of metformin by withdrawing it from Type 2 diabetic patients who had been stabilised on combination therapy. Fifty-one subjects with Type 2 diabetes and secondary oral hypoglycaemic agent failure were studied in a randomised, open and parallel study. In the first phase of 36 weeks, subjects were stabilised on combined therapy of sulphonylureas and nocturnal insulin, with or without metformin. During the second phase, metformin was withdrawn. The primary variables for efficacy were HbA(1c), fasting plasma glucose and 3-point capillary blood glucose profiles. After stabilisation with combination therapy, those subjects on metformin used less insulin to maintain glycaemic control (13.7+/-6.8 vs. 23.0+/-9.4 U/day, P=0.001) and had lower HbA(1c) values (8.13+/-0.89 vs. 9.05+/-1.30%, P=0.003) compared with those not given metformin. Withdrawal of metformin therapy caused deterioration in HbA(1c) (P=0.001). This study confirms that metformin plays an important role in the success of the combination therapy. The rational use of metformin and sulphonylurea together with insulin will help to improve metabolic control in Type 2 diabetes patients who have secondary drug failure.

Blood Glucose↗

[Clinical investigation of combined therapy (cefotiam, sulbenicillin and cefsulodin) against infections complicated by acute leukemia].

Prophylaxis effect and clinical therapy of combination use of cefotiam (CTM), sulbenicillin (SBPC) and cefsulodin (CFS) have been investigated, and the results were as follows. 1. Prophylaxis effect of CTM-SBPC combination therapy was very useful. CTM-SBPC combination therapy was performed to patients who are at high risk for infectious complications. Prophylaxis effect of CTM-SBPC was judged by fever over 38 degrees C, and was better than usual antibiotic treatment. 2. CTM-SPBC-CFS combination therapy was performed against severe infections during early remission, and the overall effectiveness rate was 83.3% (5/6). 3. No remarkable side effect was observed in this investigation.

Acute Disease↗

Efficacy of chloroquine + sulfadoxine--pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh.

Bangladesh faces growing levels of Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). Alternative antimalarial therapies, particularly combination regimens, need to be considered. Therefore, the efficacy of three antimalarial combination therapies was assessed in Chittagong Hill Tracts. A total of 364 P. falciparum patients were recruited and randomly assigned to either CQ + SP, mefloquine + artesunate (MQ + AS) or lumefantrine + artemether (Coartem). Results showed that CQ + SP therapy was less effective than the two artemisinin-based combination therapies. The day 42 PCR-corrected efficacy rate was 62.4% for CQ + SP, 100% for MQ + AS and 97.1% for Coartem. Failures occurred at a shorter interval after CQ + SP treatment than after Coartem. The artemisinin-based therapies effectively prevented development of gametocytes, whereas CQ + SP did not. All three therapies were well tolerated, although reports of mild complaints during treatment appeared higher with MQ + AS. We conclude that CQ + SP is not a viable option for replacing CQ monotherapy as first-line P. falciparum treatment in this area of Bangladesh. A change to artemisinin-based combination therapy is recommended. Both Coartem and MQ + AS appear to be good options, effective in curing P. falciparum malaria and in preventing recrudescences following treatment.

Adolescent↗

Combination therapy for onychomycosis.

Combination therapy is one way of improving the cure rate of onychomycosis. The LION Study examined the efficacies of terbinafine and itraconazole. The Icelandic cohort of the study reported that after 5 years only 46% of the terbinafine-treated patients and 13% of the itraconazole-treated patients were still disease-free, suggesting that relapses and reinfections were common in the long term treatment of onychomycosis with monotherapy. Combination therapy is a well-established principle in mycology; the current strategy involves the combination of oral and topical antifungal treatments. A number of specific drug combinations have proved to be useful in the treatment of onychomycosis: tioconazole and griseofulvin, amorolfine and griseofulvin, amorolfine and terbinafine, and amorolfine and itraconazole. However, comparison of the combination trials can be difficult because of the short duration of some of the studies and variation in global cure rates. Although it is necessary to consider these factors it is clear that combination therapy offers advantages when compared with monotherapy. Combination therapy can be administered sequentially or in parallel. Parallel therapy is recommended for patients who are likely to fail therapy (e.g. patients with diabetes), whereas sequential therapy is recommended for patients who show a poor response to initial treatment.

Administration, Cutaneous↗

Results of radiation therapy combined with neoadjuvant hormonal therapy for stage III prostate cancer: comparison of two different definitions of PSA failure.

BACKGROUND: We herein report the clinical outcome of radical radiation therapy combined with neoadjuvant hormonal therapy (NHT) for stage III (International Union Against Cancer [UICC] 1997: UICC 97) prostate cancer. Prostate-specific antigen (PSA) failure-free survival was assessed according to two different definitions, and the appropriateness of each definition is discussed. METHODS: Between October 1997 and December 2000, 27 patients with stage III prostate cancer were enrolled in this study. The median pretreatment PSA level was 29 ng/ml (range, 7.4-430 ng/ml). The Gleason score (GS) was 7 or more in 22 patients (81%). All patients received 3 months of NHT with a luteinizing hormone-releasing hormone (LH-RH) analogue, in combination with an antiandrogen (flutamide), given during the first 2 weeks, followed by 70-Gy external-beam radiation therapy (EBRT) in 35 fractions. The initial 46 Gy was given with a four-field technique, while the remainder was given with a dynamic conformal technique. No adjuvant hormonal therapy (AHT) was given. RESULTS: The median follow-up time was 63 months. PSA levels decreased to the normal range (<4 ng/ml) after irradiation in all but one patient. The 5-year PSA failure-free survival was 34.8% according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition and it was 43.0% according to the "nadir plus 2" definition. Discordance of the results between the two definitions was seen in two patients. The 5-year overall and cause-specific survivals were 83.0% and 93.3%, respectively. No severe acute or late adverse effects were observed. CONCLUSION: Seventy Gy of EBRT following 3 months of NHT produced therapeutic results comparable to those reported in other studies which used long-term AHT. The value of long-term AHT for Japanese men should be tested in a clinical trial.

Adenocarcinoma↗

[Study of combination therapy for thymoma: a case of stage IV which presented as total spinal block caused by epidural metastasis and which preoperative combination therapy was effective for minimizing the tumor].

We experienced 24 cases of thymoma in the past 17 years. Associated syndromes as myasthenia gravis and pure red cell anemia (PRCA) were found in 7 patients. Preoperative therapies were done for the cases of stage IV. Total resection of the tumor was performed except 3 cases which ended in exploratory thoracotomy. Postoperative therapies were done except the cases of stage I. Each one case of stage III and IV a whose operation ended in exploratory thoracotomy died of tumors, but latter case had some period of PR after chemotherapy. A case of stage I with PRCA died from pneumonia but other cases of autoimmune disease had been well controlled by medical treatment. A case of stage IVb was first admitted to the hospital for paralysis of bilateral lower limb. After resecting the epidural tumor of thoracic spine, chemotherapy (CAV 1 kur) and radiotherapy (4,200 rad) was performed which was effective for minimizing the antero-mediastinal tumor. Though operation ended in exploratory thoracotomy, majority of the tumor was found to be replaced for fibrous tissue which suggested the effectiveness of the combination therapy. But this case died from pancreatitis during the postoperative therapy. In conclusion, combination therapy of surgical resection and adjuvant radiotherapy & chemotherapy including the care for autoimmune disease is important in the treatment of thymoma.

Adult↗