Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BACKGROUND: In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS: Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS: The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS: Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER: NCT00863655.

Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.

BACKGROUND: Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. PATIENTS AND METHODS: HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. RESULTS: The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). CONCLUSIONS: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

We conducted a phase II trial to investigate the efficacy of concurrent chemoradiation in patients with stage III non-small-cell lung cancer (NSCLC). Thirty patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Patients received six weekly cycles of paclitaxel 45 mg/m(2) over 1 h; carboplatin at (area under the curve) AUC 2; and radiation therapy of 60 Gy. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy over 4 weeks) followed by a boost to the primary tumor (20 Gy in 2 weeks). After the initial phase of concurrent chemoradiation, patients received an additional four cycles of paclitaxel 175 mg/m(2) over 3 h and carboplatin at AUC 6 every 3 weeks. The overall objective response rate of 30 assessable patients was 76.7%. At the median follow-up time of 13.1 months, the median survival time was 14.5 months (95% CI, 10.59-18.48). The median progression-free survival was 10.5 months (95% CI, 7.72-13.28). The major toxicity was hematologic. The incidence of grade 3 esophagitis was 10%. In conclusion, this chemoradiation regimen is well tolerated and shows significant clinical results for locally advanced NSCLC. Locoregional failure rate remains an important issue with this newer chemotherapeutic regimen. A novel chemotherapy and radiation therapy is clearly needed.

Case report of metastatic familial pheochromocytoma treated with cisplatin and 5-fluorouracil.

We report on a rare case of malignant pheochromocytoma in a patient with a family history of this disease. After three cycles of treatment with cisplatin and 5-fluorouracil, a decrease in the need for antihypertensive treatment occurred, which lasted almost 2 years despite the discontinuation of chemotherapy. The patient showed an objective response, which was technically a minor response, although in this slow-growing tumor it was of major clinical significance. This chemotherapy regimen may play a role in the management of malignant pheochromocytoma.

Replantation of the avulsion of the scalp: a case report.

We reported a case of successful replantation of the avulsion scalp after 11 hours of ischemic time. The surgical management and postoperative management were presented. The fourteenth month follow-up result was satisfactory.

Ketoconazole and Flutamide in the treatment of disseminated intravascular clotting from prostate cancer: a case report and review.

Disseminated intravascular clotting (DIC) is a well-recognized complication of malignancy. Prostatic cancer can produce chronic DIC as well as acute severe DIC. Treatment of DIC are general supportive measures including heparin, transfusion of blood, platelets and clotting factors, but the most important aspect is correction of underlying malignant diseases i.e. cancer of the prostate gland. For metastatic prostatic cancer presenting with an emergency oncologic condition, the treatment of choice is surgical orchiectomy, but surgery may not be possible in the presence of severe DIC. Ketoconazole and Flutamide are drugs with different mechanisms for hormonal manipulation of this cancer. Due to severe DIC, we combined both drugs trying to put maximum therapeutic effect on this life threatening profound DIC patient.

Phase II study of concurrent chemoradiotherapy for inoperable (bulky) stage III (A/B) non-small cell lung cancer (NSCLC): a preliminary report.

We designed a phase II study to determine the feasibility and toxicity of concomitant radiotherapy and Paclitaxel/Carboplatin followed by adjuvant chemotherapy of the same regimen in patients with newly diagnosed inoperable stage III A/B non-small cell lung cancer. Patients were irradiated with a total dose of 66 Gy. Weekly courses of Paclitaxel 45 mg/m2 and Carboplatin AUC 2 were administered intravenously during the irradiation period. After completion of concurrent chemoradiotherapy, adjuvant chemotherapy with Paclitaxel 175 mg/m2 and Carboplatin AUC 6 intravenously every 3 weeks for 4 cycles were given. Since March 1998, 15 patients have been enrolled. All patients were assessable for efficacy and toxicity after concurrent chemoradiotherapy. Eleven patients were assessable for efficacy and toxicity after adjuvant chemotherapy. After concomitant chemoradiotherapy, complete response (CR) was documented in 2 of 15 (13%). Partial response (PR) was documented in 9 of 15 (60%). After completion of adjuvant chemotherapy in 11 patients, the overall response rate was 91 per cent. (18% CR, 73% PR). There were 8 per cent gr. 3-4 neutropenia which occurred during adjuvant chemotherapy. Concomitant Paclitaxel/Carboplatin and radiotherapy are promising modalities in the treatment of inoperable stage III A/B non-small cell lung cancer.

Uracil with ftorafur and low dose oral folinic acid in advanced colorectal cancer.

BACKGROUND: Low dose oral Folinic acid was used together with uracil with ftorafur (UFT) producing some response with low toxicity in advanced colorectal cancer. However, the 28 day regimen produced 20 per cent severe (grade III, IV) diarrhea. This study required 21 days' treatment to evaluate the response rate and toxicity in advanced colorectal cancer. METHOD: UFT 300 mg/m2/day together with oral Folinic acid 7.5 mg/dose for 21 days with 7 days rest were required to treat 28 cases of recurrent or metastatic colorectal cancer. RESULTS: Partial response was seen in 13.6 per cent of 22 evaluable cases and minimal response seen in 18.2 per cent. The majority (77%) of these patients had previously been treated with 5-fluorouracil (5-FU). These results are comparable to other studies. Toxicity was low with 3.3 per cent grade III, IV diarrhea. CONCLUSION: This regimen produced some activity in metastatic colorectal cancer with low toxicity.