Phase II trial of doxorubicin therapy for advanced islet cell carcinoma

Twenty evaluable patients with advanced islet cell carcinoma were treated with doxorubicin at a dosage of 60 mg/m2 every 3-4 weeks. Toxicity was clinically tolerable and characteristic of doxorubicin therapy. Although all patients had previously been treated with other chemotherapy regiments, four (20%) had objective therapeutic responses persisting for 2-301/2 months. Doxorubicin has definite therapeutic activity in islet cell carcinoma and is currently being evaluated in combination chemotherapy regimens.     

Methylprednisolone pulse therapy in rapidly progressive glomerulonephritis

Twenty-five patients with rapidly progressive glomerulonephritis (RPGN) were treated with methylprednisolone (MP) pulse therapy (1 g intravenously on 3 successive days). In all patients renal biopsy was done before or just after the start of therapy. Pulse therapy was used in all patients in combination with a low oral maintenance dose of prednisone. In 21 patients additional immunosuppressive treatment was given, either cyclophosphamide (n = 19) or azathioprine (n = 2); in 2 patients plasmapheresis was also applied. Sixteen of the 25 patients were dialysis-dependent at presentation; 11 of them improved, an additional 3 had a temporary recovery, but needed maintenance renal replacement therapy after 5-46 months, mean 22 months. Nine of the 25 patients were not dialysis-dependent, 6 of them improved, an additional one had a temporary recovery, but needed chronic dialysis after 35 months. When many irreversible glomerular lesions were present, the effectiveness of MP pulse therapy was limited or only of a temporary character. Serious side effects did not occur. In conclusion MP pulse therapy is a successful treatment with minimal adverse reactions in patients with RPGN and active histological lesions.     

Phase II trial of capecitabine combined with thalidomide in second-line treatment of advanced pancreatic cancer

BackgroundTo evaluate the efficacy and tolerability of capecitabine combined with thalidomide in patients with advanced pancreatic cancer (APC) who have previously received gemcitabine-based therapy.MethodsA total of 31 patients were recruited prospectively in Shandong Tumor Hospital from May 2007 to April 2009. Capecitabine was offered to patients twice a day at a dose of 1250 mg/m² for 14-day then followed by 7-day rest. Thalidomide was administered 100 mg/day without interruption until disease progression or occurrence of unacceptable toxicity.ResultsTwo patients presented partial response (PR), 11 patients showed stable disease (SD) and eighteen patients presented progressive disease (PD). The median progression-free survival (PFS) was 2.7 months (95% confidence interval (CI), 2.4–3.3) and the median overall survival (OS) was 6.1 months (95% CI, 5.3–6.9). In the subgroup analysis, PFS had a significant difference between the serum CA19–9 level decreasing >25% and decreasing <25%, with 3.0 months (95% CI, 2.5–3.6) and 2.5 months (95% CI, 1.8–3.2), (Log Rank = 0.02), respectively. Hematological toxicity included leukocytopenia, anemia and neutropenia. Non-hematological toxicities included diarrhea, skin rash, nausea/vomiting, hand-foot syndrome, fatigue, dizziness, drowsiness and constipation.ConclusionCapecitabine combined with thalidomide is a well-tolerated second-line regimen, in patients with APC refractory to gemcitabine.     

A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma

CONTEXT: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during transfection gene are considered essential in the pathogenesis of MTC. OBJECTIVE: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC. DESIGN: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months. RESULTS: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects [fatigue (n = 2) and nausea (n = 1)]. In four cases the dose of imatinib was decreased because of toxicity [rash and malaise (n = 2) and laryngeal swelling (n = 2)]. Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism. CONCLUSIONS: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.     

Phase II clinical trial with high-dose methotrexate therapy and citrovorum factor rescue.

One hundred and thirty-four patients with advanced malignant disease were treated with 496 infusions of high-dose methotrexate (HD-MTX) followed by citrovorum factor rescue. Most patients had failed to respond to previous combination chemotherapy. The overall response rate was 29% with 33 partial responses and six complete responses observed in patients with a variety of tumors. Plasma MTX levels were monitored in all patients during each course of therapy in order to identify those patients with delayed plasma MTX clearance. Patients with abnormally slow rates of plasma MTX decay received escalated doses of citrovorum factor rescue in order to prevent drug-induced toxicity. In general, during this study HD-MTX was well-tolerated. Because serious toxicity was neither frequent, severe, nor unpredictable, its use was not limited. HD-MTX should now be evaluated in well-designed controlled clinical trials to compare its antitumor activity to that of conventional- or standard-dose MTX regimens in diseases where HD therapy appears to have efficacy.     

Intravenous pulse methylprednisolone therapy of acute crescentic rapidly progressive glomerulonephritis.

Idiopathic acute crescentic rapidly progressive glomerulonephritis (RPGN) with oliguria, proteinuria and rapid decline of renal function is usually associated with death or the need for support by dialysis. Spontaneous recovery is rare, and various modes of therapy have been generally unsuccessful.We describe nine patients with rapidly progressive glomerulonephritis of less than six weeks' duration whose creatinine clearance decreased over 50 per cent. All had normal-sized kidneys and were proteinuric, six of nine were oliguric, and five of nine required dialysis. Renal biopsy specimens were examined by light, electron and immunofluorescence microscopy. Rapidly progressive glomerulonephritis without immune deposits was present in six, immune complex disease in two and antiglomerular basement membrane disease in one. All were treated with intravenous pulse methylprednisolone followed by oral steroids. Serum creatinines decreased in seven of nine patients from one to four weeks after pulse therapy and remained stable or improved in six of these. Three of five patients undergoing dialysis were able to discontinue that support. The mean creatinines of 10.6 ± 2.2 mg/dl before therapy decreased to 2.2 ± 0.5 mg/dl after four to 24 months in the six responding patients. Two other patients died of causes unrelated to therapy. Tissue obtained from four patients four to 12 months after pulse therapy showed resolution of inflammatory changes and regression of crescents.The marked and sustained improvement of renal function in six of our nine (67 per cent) patients with rapidly progressive glomerulonephritis who were treated with pulse methylprednisolone is in sharp contrast to experience previously reported and suggests the need for further evaluation in a prospective controlled study.     

Phase II trial of methylprednisolone pulse therapy in childhood chronic thrombocytopenia

Nineteen children with chronic idiopathic thrombocytopenia (ITP) were treated with a single intravenous injection of methylprednisolone (MP), 15 mg/kg/day, for 3 consecutive days. The 3-day pulses gave rise to a positive and fast therapeutic response with increase of the platelet count in about three quarters of the patients. The platelet count remained above 50 X 10(9)/1 for more than 1 month in 10 children. Eight out of them still presented a safe platelet count (greater than 50 X 10(9)/1) 4 months after the onset of the therapy. The MP therapy improved the platelet count more in the older children and possibly in the females. No severe side effects were observed. Our results suggest that this therapeutic approach could be useful in the management of acute bleeding episodes in children with chronic ITP.     

Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas.

BACKGROUND/AIMS: Patients with advanced unresectable hepatobiliary carcinomas have a dismal prognosis. The efficacy of systemic chemotherapy in these patients is negligible and often, in particular in patients with hepatocellular carcinomas, the toxicity of chemotherapy outweighs the potential palliative effect of antineoplastic agents. Gemcitabine is a new anticancer agent with a mild toxicity profile, which has demonstrated antineoplastic activity in many solid tumors. Therefore we investigated the effect of gemcitabine in patients with advanced nonresectable hepatocellular and cholangiocellular carcinomas in a phase II study. METHODOLOGY: Twenty-three patients with cholangiocellular carcinoma and 20 patients with hepatocellular carcinoma were enrolled into the study. Eighteen of the 20 patients with hepatocellular carcinomas had liver cirrhosis. Gemcitabine was administered once weekly over 30 min for 3 consecutive weeks out of every 4 weeks. Patients with cholangiocellular carcinomas received gemcitabine also in the forth week of the first cycle with no rest to the following cycle. Disease status was assessed every 4 weeks. RESULTS: Overall the regimen was well tolerated. The median number of gemcitabine administration was 15 (range, 3-37) in the group of patients with cholangiocellular carcinomas and 7.6 (range, 3-21) in the group of patients with hepatocellular carcinomas. In the group of patients with hepatocellular carcinomas thrombocytopenia was the most frequent side effect (30% grade 3/4). Among the patients with cholangiocellular carcinomas nausea and neutropenia were the most commonly observed side effects. The overall response rate of hepatocellular carcinomas was only 5% and chemotherapy generally did not improve the tumor symptoms of the patients in this group. In contrast, in the group of cholangiocellular carcinomas, seven patients achieved a partial response (overall response rate 30%). Eleven patients with cholangiocellular carcinomas revealed tumor symptoms before the onset of gemcitabine treatment. Seven of these patients developed a treatment related clinical benefit as defined as a relief of tumor symptoms or gain of weight. CONCLUSIONS: Our results indicate that the treatment of cholangiocarcinomas with gemcitabine is effective and should be further evaluated in phase III studies. In contrast, palliative chemotherapy with gemcitabine cannot be recommended in patients with hepatocellular carcinoma and liver cirrhosis.     

Rapid-detection GBM-ANCA ELISA. An emergency tool for the early diagnosis of type I and II rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritides (RPGN) are forms of necrotizing glomerulonephritis associated with anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) against the antigens proteinase-3 (anti-PR3) and myeloperoxidase (anti-MPO). RPGN have a course of rapid progression to renal failure. We compared the results from the semiquantitative ELISAs for anti-GMB antibodies, PR3-ANCA and MPO-ANCA and the indirect immunofluorescence technique (IIF) against a new rapid assay (30 minutes) for the same antibodies in patients with clinically suspected RPGN. The semiquantitative ELISAs for anti-GBM antibodies and PR3-ANCA and MPO-ANCA have a proven diagnostic significance in patients with RPGN I and III. There were no significant differences between the ANCA-GBM screening test and the results from the semiquantitative ELISAs (p > 0.05). We did not find significant differences between the results for PR3-ANCA and MPO-ANCA from the ANCA-GBM screening test with C-ANCA and P-ANCA IIF values (p > 0.05). We also corroborated that the ANCA-GBM screening test is a diagnostic tool for RPGN I and III as useful as the semiquantitative ELISAs and the IFF technique. The ANCA-GBM ELISA screening test is a tool as useful as the semiquantitative ELISA against anti-GBM antibodies for diagnosis of RPGN I. The comparison of the screening ELISA with the IIF technique and the semiquantitative ELISAs against PR3-ANCA and MPO-ANCA showed similar utility for diagnosis of RPGN III. The advantages of the new screening assay are that three antibodies are tested at the same time, yielding results in only 30 minutes.     

Phase II study of metronidazole therapy for advanced colorectal carcinoma.

Thirty-two patients with advanced carcinoma of the colon or rectum were given metronidazole orally at a dose of 500-1000 mg/m2 three times a day for 7 consecutive days every 6 weeks. The dose-limiting toxic effects consisted of severe nausea, vomiting, and major motor seizures. Mild peripheral neurotoxic effects were also noted. No objective responses were noted in any of the 32 patients treated. High-dose metronidazole would not seem to have any role in the treatment of advanced colorectal carcinoma and may cause serious neurotoxicity.     

Phase II trial of high-dose dexamethasone for previously treated immunoglobulin light-chain amyloidosis.

Immunoglobulin light-chain amyloidosis (AL) is a rare disorder characterized by production of a monoclonal light chain. This insoluble light chain, or a fragment thereof, deposits in tissues as amyloid and results in disruption of organ function and, ultimately, in death. Although melphalan and prednisone are beneficial in approximately 30% of patients with the disease, many patients fail to respond, and the median survival with this disease remains < 2 years. There is a need for new agents for those patients who fail to respond to melphalan-based chemotherapy. A study was undertaken of high-dose dexamethasone in the treatment of 19 patients with AL because of reports of its benefits in previously untreated patients with amyloidosis and its known activity in the management of multiple myeloma, which has many characteristics in common with AL. In this cohort, 3 of 19 patients showed an objective organ response of the disease. The median survival of the entire group was 11.2 months. We conclude that high-dose dexamethasone therapy is of occasional benefit in patients previously treated for amyloidosis. Combining dexamethasone with other therapies may increase the response rate.     

Phase II evaluation of dianhydrogalactitol in advanced head and neck carcinomas

Twenty-eight patients with advanced squamous cell carcinomas and adenocarcinomas of the head and neck were treated with dianhydrogalactitol at a dose of 25 mg/m2 iv on each of 5 consecutive days monthly. All patients except one had received previous surgical and/or radiotherapeutic treatments and 12 had received previous chemotherapy. Disease progression (or symptomatic deterioration) occurred in nine patients after the initial course and in eight others after two courses. In 11 patients, the disease remained stable during at least three courses; however, no instances of objective regression of disease were observed during treatment with dianhydrogalactitol despite significant toxic effects in most patients.