Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).

BACKGROUND: RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting. METHODS: Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis. RESULTS: Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug). CONCLUSIONS: These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience. CLINICAL TRIAL NAME AND IDENTIFIER: Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

Short versus conventional preoperative radiotherapy of rectal cancer: indications.

PURPOSE: Preoperative radiotherapy (RT) at high-dose short-course or at conventional fractions for rectal cancer has proven effect in increasing the tumor control. The aim of this study was to test the impact of 2 different preoperative RT schemes on local recurrence, distant metastasis and survival rates and to defi ne the indications for each of them. PATIENTS AND METHODS: The study included 84 patients with biopsy-proven rectal adenocarcinoma of the middle and lower third, clinically staged T2-T4, N0-2, M0. Group I patients (n=51) received a total dose of 25 Gy in 5 fractions of 5 Gy each for 5 consecutive days; operation was performed 3-5 days later. Group II patients (n=33) received a total dose of 50 Gy in 25 fractions of 2 Gy each in 5 weeks, followed by surgery after 4-5 weeks. Surgery included abdomino-perineal resection (APR) for tumors of the lower half of distal rectum, abdomino-transanal resection (ATR) for tumors of the upper half of distal rectum and anterior resection (AR) for tumors of the middle rectum. RESULTS: After a median follow-up of 53 months (range 22-84) overall survival (OS) of all patients at 4 years was 84% and the distant metastasis-free survival (DMFS) 82%. For stage II patients only, OS and DMFS was 100% in both preoperative RT groups. For stage III patients, OS in group I and II was 72% and 70%, respectively (p >0.05) and DMFS 66% and 68%, respectively (p >0.05). Local recurrence - free survival (LRFS) for all stages was 94% with 5 x 5 Gy and 25 x 2 Gy; for stage ?? only it was 100% and for stage III only 90%. However, the use of short preoperative 5 x 5 Gy scheme for tumors of the lower third of the rectum and sphincter-saving surgery was accompanied with higher rates of local recurrence: 11% after 5 x 5 Gy vs. 0% after 25 x 2 Gy. Partial tumor regression with 50 Gy of conventional RT was achieved in 79% of the cases. Such regression was not possible to assess for the 5 x 5 Gy group since surgery was performed 3-5 days after RT. No late adverse effects on normal tissues were observed with any scheme of preoperative RT. CONCLUSION: The conventional preoperative RT with 50 Gy proved more effective for advanced rectal cancer (T4 or N2) and for sphincter-saving resections for lower-lying tumors. The short scheme 5 x 5 Gy is appropriate for less advanced tumors (T2-3, N0-1), therefore requiring accurate clinical staging.

In vivo transfection and/or cross-priming of dendritic cells following DNA and adenoviral immunizations for immunotherapy of cancer--changes in peripheral mononuclear subsets and intracellular IL-4 and IFN-gamma lymphokine profile.

In order to provoke an immune response, a tumor vaccine should not only maximize antigen-specific signals, but should also provide the necessary "co-stimulatory" environment. One approach is to genetically manipulate tumor cells to either secrete lymphokines (GM-CSF, IL-12, IL-15) or express membrane bound molecules (CD80, CD86). Furthermore, patient dendritic cells can be loaded with tumor-associated antigens or peptides derived from them and used for immunotherapy. Genetic modification of dendritic cells can also lead to presentation of tumor-associated antigens. Transfection of dendritic cells with DNA encoding for such antigens can be done in vitro, but transfection efficiency has been uniformly low. Alternatively, dendritic cells can also be modulated directly in vivo either by "naked" DNA immunization or by injecting replication-deficient viral vectors that carry the tumor specific DNA. Naked DNA immunization offers several potential advantages over viral mediated transduction. Among these are the inexpensive production and the inherent safety of plasmid vectors, as well as the lack of immune responses against the carrier. The use of viral vectors enhances the immunogenicity of the vaccine due to the adjuvant properties of some of the viral products. Recent studies have suggested that the best strategy for achieving an intense immune response may be priming with naked DNA followed by boosting with a viral vector. We have successfully completed a phase I and phase II clinical trials on immunotherapy of prostate cancer using naked DNA and adenoviral immunizations against the prostate-specific membrane antigen (PSMA) and phase I clinical trial on colorectal cancer using naked DNA immunization against the carcinoembryonic antigen (CEA). The vaccination was tolerated well and no side effects have been observed so far. The therapy has proven to be effective in a number of patients treated solely by immunizations. The success of the treatment clearly depends on the stage of the disease proving to be most efficient in patients with minimal disease or no metastases. A panel of changes in the phenotype of peripheral blood lymphocytes and the expression of intra-T-cell lymphokines seems to correlate with clinical improvement.

Is there an alternative approach to abdominoperineal resection for the treatment of very low lying rectal cancer? Five-year results.

PURPOSE: To investigate whether sphincter-saving surgery combined with preoperative radiotherapy and postoperative adjuvant chemotherapy can compare successfully with abdominoperineal resection in the treatment of very low lying rectal cancer. PATIENTS AND METHODS: Two groups of patients were studied. Group I included 65 patients (T2-3 N0-2 M0) with very low lying rectal cancer treated since 1995 by a sphincter- saving surgical procedure. All of them received preoperatively external radiotherapy and postoperatively adjuvant chemotherapy with 5-fluorouracil (5-FU) and folinic acid. This group was prospectively evaluated. Group II included 122 patients with the same tumor stage and location as Group I, who were treated by abdominoperineal resection and were retrospectively evaluated. The rate of local recurrence was compared between the two groups. RESULTS: In Group I patients the local recurrence rate was 13.84% (9 patients) for a period ranging from 6 months to the end of the second year after the operation. This group of patients were followed up to 60 months after the initial treatment. The local recurrence rate in Group II patients was 17.21% (21 patients; p >0.05). CONCLUSION: We consider that sphincter-preserving surgery combined with preoperative radiotherapy and postoperative adjuvant chemotherapy represents a successful alternative to abdominoperineal resection of very low lying rectal adenocarcinoma.

Different chemotherapy schedules in metastatic colorectal cancer: a response and survival analysis.

PURPOSE: To evaluate the response rate and overall survival (OS) of chemotherapy-naïve patients with metastatic colorectal adenocarcinoma treated with 4 different chemotherapy regimens. PATIENTS AND METHODS: One hundred fifty-eight patients with metastatic colorectal cancer (CRC) were included in this prospective study. The treatment regimens were as follows: a) Intraarterial (i.a.) chemotherapy: 5-fluorouracil (5-FU) 600 mg/m(2)/day by 120 hour-infusion, mitomycin C 8 mg/m(2) day 1, and epirubicin 80 mg/m(2) day 5, every 3 weeks, b) Intravenous (i.v.) chronochemotherapy: 5-FU 800 mg/m(2) i.v. infusion during 18.00 h-06.00h, leucovorin (LV) 100 mg/m(2) i.v. infusion during 18.00h-06.00h; and cisplatin 20mg/m(2) i.v. infusion, during 10.00h-18.00 h, all given on days 1-5, every 3 weeks, c) Scheme: 5-FU 500 mg/m(2) i.v. bolus, days 1-5, vincristine 1.2 mg/m(2) i.v. bolus, day 1, CCNU 120 mg/m(2) per so (p.o.), day 5, every 3 weeks. Scheme I was used as control group, d) Scheme II: 5-FU 425 mg/m(2) i.v. bolus, days 1-5, and LV 50 mg/m(2) i.v. bolus, days 1-5, every 3 weeks. The patients received 3-26 cycles of chemotherapy. The results taken were compared using the Kaplan-Meier life-table method, logrank test, Cox proportional hazard model, and Cox model with time-dependent covariates. RESULTS: Nine (26%) out of 34 patients with i.a. chemotherapy achieved complete response (CR), 8 (24%) partial response (PR), and 11 (32%) stable disease (SD). In the group of 42 patients with chronochemotherapy 4 (10%) achieved CR, 15 (36%) PR and 12 (28%) SD. In the group of 61 patients with conventional treatment with 5-FU and LV (scheme II) no CR was achieved with 11 (18%) patients responding partially. In the control group of treatment (scheme I) with 21 patients PR was observed in 2 (10%) patients. Patients with i.a. chemotherapy and chronochemotherapy achieved a similar OS, which was better than OS of scheme II. The survival was worst with scheme I. CONCLUSION: I.a. chemotherapy and chronochemotherapy showed an almost equivalent efficacy in terms of response rates, which were clearly superior to those achieved by schemes I and II. Also, OS was significantly better in the patients treated with i.a. chemotherapy and chronochemotherapy compared to patients treated with scheme II. The worst survival was seen in scheme I patients.

[A combined method for treating metastases of colorectal carcinoma to the liver]. / Kombiniran metod za lechenie na metastazi ot kolorektalen kartsinom v cherniia drob.

The method is a combination of operative treatment of metastases in the liver and regional intra-arterial chemotherapy. The indications for operative treatment of the underlying tumor, the metastases in the liver and the regional chemotherapy are pointed out. Two groups of patients with colorectal cancer and remote metastases in the liver are presented: one received surgical treatment alone, the other combined therapy. It is assumed that the combined treatment of the basic tumor, the metastases in the liver plus regional intra-arterial chemotherapy is a new trend in the treatment of advanced colorectal cancer metastasized in the liver.

A multicenter study of recombinant human erythropoietin (epoetin alpha) in the management of anemia in cancer patients receiving chemotherapy.

Current evidence suggests that epoetin alpha administration is well tolerated and effective in the management of anemia of cancer and cancer chemotherapy. An open-label, multinational, non-comparative study was conducted in 215 cancer patients with anemia secondary to chemotherapy with platinum- or non-platinum-based combinations. Epoetin alpha was administered s.c. (150 IU/kg three times/week) for a planned period of 16 weeks. The response rate of epoetin alpha, defined as an increase in hemoglobin level of 2 g/dl or more from baseline, was 67%. The rate of response was not related to the chemotherapy regimen administered (platinum or non-platinum based). The percentage of patients transfused and the transfusion rate during epoetin alpha treatment were reduced. Transfusional need was eliminated in 64 (75%) of the 85 patients transfused before the study start, after 1 month of therapy. Quality of life, assessed using a visual analog scale, improved markedly in patients who experienced a hematological response. These patients also experienced a statistically significant (p < 0.0001) improvement in mean WHO performance score. These findings indicate that epoetin alpha is a well tolerated and effective agent which increases hemoglobin concentration and reduces transfusion requirements in anemic cancer patients receiving chemotherapy.