SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer.

PURPOSE: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS: Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION: The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics.

BACKGROUND & AIMS: Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS: A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS: Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS: We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.

[Shaare Zedek Medical Center's model of an integrated division of internal medicine].

BACKGROUND: The specialty and practice of internal medicine have been subject to serious challenges in the last two decades. METHODS: We describe the integrative model of internal medicine as developed in our hospital, providing solutions to some major challenges. RESULTS: Major components include: (1) Senior physicians and residents are employed by the Division rather than individual Departments of Medicine, allowing for balanced distribution of professional capabilities. (2) Two medical departments specialize in geriatric medicine, while the other departments take care of younger, more intellectually challenging patients. Senior and junior staff members rotate through these departments, allowing for exposure to different patient populations and professional expertise. (3) The backbone of senior physicians is rewarded by a set of incentives, including dedicated time for research. (4) Senior staff from the subspecialties contributes annually 1-2 months as senior physicians in the departments and receive academic and other compensation for their efforts. (5) In cases where medical departments elsewhere are flooded with corridor admissions (a source of frustration and burnout), a short admission unit in the emergency department relieves internal medicine pressures and shortens evaluation and therapy for many patients. CONCLUSION: Our integrative model of internal medicine allows for improved patient and staff distribution, greater satisfaction among patients and family members, greater professional satisfaction among physicians, while resident vacancies are filled with competent residents.

Adjuvant chemotherapy and whole abdominal irradiation for gastric carcinoma.

AIMS AND BACKGROUND: To analyze the efficacy and toxicity of adjuvant chemotherapy followed by whole abdominal irradiation in the treatment of resectable gastric cancer with positive lymph nodes. METHODS AND STUDY DESIGN: Between 1996 and 1999, 10 patients with node-positive gastric cancer underwent complete gross resection and were treated by postoperative chemoradiotherapy. The chemotherapy regimen consisted of 5-fluorouracil, 1000 mg/m2/day as a 96-hr continuous infusion on day 1, and cisplatin, 100 mg/m2 on day 2, every 21 days. Six courses were planned. Radiotherapy was administered 3 weeks after completion of the chemotherapy protocol as a single-fraction dose of 600 cGy in a two-field (anterior and posterior) configuration. RESULTS: Treatment was generally well tolerated, with no treatment-related deaths. However, 9 of the 10 patients died of recurrent disease, with a median survival of 20 months (range, 7-84). CONCLUSIONS: Adjuvant chemotherapy with whole abdominal irradiation for gastric cancer is safe and tolerable but has no apparent effect on patient outcome. Studies in larger series are needed to evaluate the role of the approach in this disease.

Weekly infusional high-dose 5-fluorouracil and leucovorin and biweekly cisplatin: a convenient treatment option in advanced gastric cancer.

BACKGROUND: To summarize our experience using a regimen of weekly 5-FU and leucovorin (LV) and biweekly cisplatin (CDDP) in advanced gastric cancer (AGC). MATERIAL/METHODS: Patients had previously untreated histologically confirmed AGC. Treatment consisted of intravenous weekly infusional 5-FU and LV and biweekly CDDP, given for 6 weeks followed by a 2-week rest. Initially, a lower dose level was used (5-FU 2000 mg/m(2), LV 500 mg/m(2), CDDP 40 mg/m(2)), which was later increased (5-FU 2600 mg/m(2), LV 500 mg/m(2), CDDP 50 mg/m(2)). RESULTS: Forty-five patients were treated, 18 at the lower dose level and 27 at the higher dose level. The median age was 67 years and 55% were male. Grade > or =3 toxicity was documented in 37% of patients but toxicity related hospitalizations or treatment discontinuation occurred in only 22% and 13%, respectively. There were no toxic deaths. The most common hematological toxicities were anemia and neutropenia and the most common non-hematological toxicities were nausea, vomiting and fatigue. Of the 39 patients evaluable for response, 13 (33%) had partial response (PR) and 11 (28%) had stable disease (SD). Control of disease (PR+SD) was achieved in 61%. The higher dose level was associated with a higher response rate (p=0.07) and an increased toxicity (p=0.01), mostly hematological and gastrointestinal. Median progression-free survival and overall survival were 3.5 and 9.2 months, respectively. CONCLUSIONS: This regimen appears safe, with a manageable toxicity profile. Efficacy data resemble those reported for more complex and toxic regimens. The higher dose level had enhanced activity, at the expense of increased toxicity.

[Body weight, nutritional factors and physical activity--their influence on prognosis after breast cancer diagnosis].

Numerous studies have examined the association between body weight, nutritional factors, physical activity and the risk for primary breast cancer. Relatively few studies, however, have examined the associations between these issues and the recurrence of the disease and cure of the primary tumor. Today, three areas of focus are actively being researched for breast cancer survivors: body weight, diet composition and physical activity with specific emphasis on the risk for recurrence, survival and quality of life. Increased body weight or BMI (Body Mass Index) at diagnosis was found to be a significant risk factor for recurrent disease, decreased survival, or both. Overall obesity has been shown to adversely affect prognosis. Appropriate weight control may be particularly beneficial for breast cancer survivors. Breast cancer survivors should be encouraged to achieve and maintain a healthy weight. Limiting fat intake can reduce the risk of breast cancer recurrence. Increasing consumption of vegetables and fruits seems to have possible beneficial effects during and after treatments. To date physical activity after breast cancer diagnosis has been found to reduce the risk of death. The greatest benefit occurred in women who performed the equivalent of walking 3-5 hours per week at an average pace. Safe weight loss via increased physical activity and healthful food choices should be encouraged for normal, overweight or obese breast cancer survivors in order to improve survival and life quality.

Involvement of the immune response in the cure of metastatic murine CT-26 colon carcinoma by low electric field-enhanced chemotherapy.

Low electric field cancer treatment-enhanced chemotherapy (LEFCT-EC) is a new treatment modality that combines chemotherapeutic agents and low electric field stimulation. LEFCT-EC was found to destroy malignant mouse tumors and cause massive death of tumor cells. This may enable the immune system cells to efficiently recognize and eliminate tumor cells at the primary tumor site and at metastatic foci. Mice with 15 mm diameter intracutaneous colon carcinomas (CT-26) were injected with BCNU (35 mg/kg), and 2 min later the tumors were exposed to low electric fields (intensity 40 V/cm, pulse duration 180 micros, frequency 500 Hz) for 12 min (LEFCT-EC). We found that treatment with LEFCT-EC achieved complete cure of 93% of the animals. In comparison, electric fields alone (13% cure), chemotherapy alone (0%), surgery (15%) or a combination of surgery and bis-chloroethyl-nitrosurea, carmustine (BCNU; 84%) treatments resulted in lower cure rates. After treatment and cure with LEFCT-EC, 50% of the cured mice developed resistance to a tumor challenge (surgery + BCNU only 15%). Furthermore, splenocytes from cured animals protected naive animals from a tumorigenic dose of tumor cells. Separation of spleen cells into lymphocyte subpopulations indicated a major role for CD4 and CD8 T cells in this protection. FACS analysis revealed restoration of normal splenocyte subpopulation proportions impaired by cytotoxic chemotherapy. Our results suggest that LEFCT-EC can directly destroy primary tumors and facilitate the destruction of metastatic disease by enforcement of antitumor immune responses.

High-b-value diffusion-weighted MR imaging for pretreatment prediction and early monitoring of tumor response to therapy in mice.

PURPOSE: To evaluate the use of diffusion-weighted magnetic resonance (MR) imaging with standard and high b values for pretreatment prediction and early detection of tumor response to various antineoplastic therapies in an animal model. MATERIALS AND METHODS: Mice bearing C26 colon carcinoma tumors were treated with doxorubicin (n = 25) and with aminolevulinic acid-based photodynamic therapy (n = 23). Fourteen mice served as controls. Conventional T2-weighted fast spin-echo and diffusion-weighted MR images were acquired once before therapy and at 6, 24, and 48 hours after treatment. Pretreatment and early (1-2 days) posttreatment water diffusion parameters were calculated and compared with later changes in tumor volumes measured on conventional MR images by using the Pearson correlation test. RESULTS: In chemotherapy-treated tumors, a significant correlation (P <.002, r = 0.6) was observed between diffusion parameters that reflected tumor viability, measured prior to treatment, and changes in tumor volumes after therapy. This correlation implies that tumors with high pretreatment viability will respond better to chemotherapy than more necrotic tumors. In tumors treated with photodynamic therapy, no such correlation was found. Changes observed in water diffusion 1-2 days after treatment significantly correlated with later tumor growth rate for both therapies (P <.002, r = 0.54 for photodynamic therapy; P <.0003, r = 0.61 for chemotherapy). CONCLUSION: High-b-value diffusion-weighted MR imaging has potential use for the early detection of response to therapy and for predicting treatment outcome prior to initiation of chemotherapy.

Pretreatment prediction of brain tumors' response to radiation therapy using high b-value diffusion-weighted MRI.

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm(2) to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced T1-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, R(D), reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and R(D) were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P <.002 and r = 0.77, P <.001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.

Early detection of response to radiation therapy in patients with brain malignancies using conventional and high b-value diffusion-weighted magnetic resonance imaging.

PURPOSE: To study the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI), which is sensitive to the diffusion of water molecules in tissues, for detection of early tumor response to radiation therapy; and to evaluate the additional information obtained from high DWMRI, which is more sensitive to low-mobility water molecules (such as intracellular or bound water), in increasing the sensitivity to response. PATIENTS AND METHODS: Standard MRI and DWMRI were acquired before and at regular intervals after initiating radiation therapy for 10 malignant brain lesions in eight patients. RESULTS: One week posttherapy, three of six responding lesions showed an increase in the conventional DWMRI parameters. Another three responding lesions showed no change. Four nonresponding lesions showed a decrease or no change. The early change in the diffusion parameters was enhanced by using high DWMRI. When high DWMRI was used, all responding lesions showed increase in the diffusion parameter and all nonresponding lesions showed no change or decrease. Response was determined by standard MRI 7 weeks posttherapy. The changes in the diffusion parameters measured 1 week after initiating treatment were correlated with later tumor response or no response (P <.006). This correlation was increased to P <.0006 when high DWMRI was used. CONCLUSION: The significant correlation between changes in diffusion parameters 1 week after initiating treatment and later tumor response or no response suggests the feasibility of using DWMRI for early, noninvasive prediction of tumor response. The ability to predict response may enable early termination of treatment in nonresponding patients, prevent additional toxicity, and allow for early changes in treatment.

Analysis of polymorphic patterns in candidate genes in Israeli patients with prostate cancer.

BACKGROUND: The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known. OBJECTIVES: To evaluate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters. METHODS: Jewish Israeli prostate cancer patients (n = 224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters. RESULTS: The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner. CONCLUSIONS: In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.