Absence Of Visceral Metastases Research Articles

Quality of Life in Relation to Pain Response to Radiation Therapy for Painful Bone Metastases

To study quality of life (QoL) in responders and nonresponders after radiation therapy for painful bone metastases; and to identify factors predictive for a pain response. The prospectively collected data of 956 patients with breast, prostate, and lung cancer within the Dutch Bone Metastasis Study were used. These patients, irradiated for painful bone metastases, rated pain, QoL, and overall health at baseline and weekly afterward for 12 weeks. Using generalized estimating equations analysis, the course of QoL was studied, adjusted for primary tumor. To identify predictive variables, proportional hazard analyses were performed, taking into account death as a competing risk, and C-statistics were calculated for discriminative value. In total, 722 patients (76%) responded to radiation therapy. During follow-up, responders had a better QoL in all domains compared with nonresponders. Patients with breast or prostate cancer had a better QoL than patients with lung cancer. In multivariate analysis, baseline predictors for a pain response were breast or prostate cancer as primary tumor, younger age, good performance status, absence of visceral metastases, and using opioids. The discriminative ability of the model was low (C-statistic: 0.56). Responding patients show a better QoL after radiation therapy for painful bone metastases than nonresponders. Our model did not have enough discriminative power to predict which patients are likely to respond to radiation therapy. Therefore, radiation therapy should be offered to all patients with painful bone metastases, aiming to decrease pain and improve QoL.

Radium-223 for the treatment of castration-resistant prostate cancer.

The vast majority of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases. Bone metastases are a source of significant morbidity and affect quality of life in these patients. Several bone-targeting agents are approved for the treatment of bone metastases in prostate cancer, including bisphosphonates, denosumab, and radiopharmaceuticals. Radium-223 is a novel first-in-class alpha-emitting radiopharmaceutical that has been approved for treatment of patients with mCRPC with bone metastases. Radium-223 delivers cytotoxic radiation to the sites of bone metastases and offers the advantage of minimal myelosuppression. The landmark Phase III ALSYMPCA trial demonstrated that, in addition to providing bone-related palliation, radium-223 can also prolong overall survival in patients with mCRPC with bone metastases in the absence of visceral metastases and in the absence of lymphadenopathy greater than 3 cm. Ongoing trials will further elucidate its use in sequence or combination with other available therapies for mCRPC.

Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer

BackgroundPrevious studies have reported on prognostic factors for castration-resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC. ObjectiveTo evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset. Design, setting, and participantsThe analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009. Outcome measures and statistical analysisWe developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time. Results and limitationsThe median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase ≤143 U/l (p<0.0001); bone-specific alkaline phosphatase (BSAP) <146 U/l (p<0.0001); corrected urinary N-telopeptide (uNTx) ≤50 nmol/mmol (p=0.0008); mild or no pain (Brief Pain Inventory—Short Form [BPI-SF] score ≤4) (p<0.0001); no previous skeletal-related event (SRE; p=0.0002); longer time from initial diagnosis to first bone metastasis (p<0.0001); and longer time from first bone metastasis to randomization (p<0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level <10 ng/ml (p<0.0001), hemoglobin >128g/l (p<0.0001), absence of visceral metastases (p<0.0001), Eastern Co-operative Oncology Group (ECOG) score ≤1 (p=0.017), and younger age (p=0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study. ConclusionsBone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC. Patient summarySurvival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live.

403P - Phase Ii Study Evaluating Oral Vinorelbine As a Single-Agent As First-Line Chemotherapy for Metastatic Breast Cancer Patients with Bone Metastases (Norbreast-228 Trial): First Efficacy Results

ABSTRACT Background: Oral chemotherapy (CT) is a widely recognized treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by hormone therapy (HT). In this phase II study, we evaluated the efficacy and safety of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. Methods: Main eligibility criteria included: age ≥18 years, documented bone disease previously untreated by CT, hormone receptor positive disease previously treated by at least one HT, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. All pts received a bisphosphonate during the study. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment Results: Between April 2010 and April 2012, 70 patients have been included. Main pts characteristics: median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior HT 100% (80% in adjuvant setting, 53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.8 months (range 0.9-18.4), median number of cycles: 6 (range: 1-18); median relative dose intensity: 83.0%. Efficacy: with a median follow up of 26.1 months, median progression-free survival (primary endpoint) was 8.2 months (95% CI [5.5-10.3]). Clinical benefit was observed in 55.7% of pts. Median duration of clinical benefit was 11.1 months (95% CI [8.6-14.7]). Overall survival results are not mature yet, at cut off date 63% of pts being alive. Safety: grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, neutropenic infection 3%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusion: For this particular population of metastatic pts, with hormone receptor positive disease progressing to HT and bone involvement, OV is an active and safe first-line CT option. Disclosure: G.G. Steger: Honoraria and Travel Grants from Pierre Fabre Medicament; G.R. Villanova: Employee of Pierre Fabre Medicament. All other authors have declared no conflicts of interest.

First safety results of an international phase II study evaluating oral vinorelbine as a single agent as first-line chemotherapy for metastatic breast cancer patients with bone metastases (NorBreast-228 trial).

1048 Background: Oral chemotherapy (CT) is an attractive treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by a hormone therapy. In our phase II study, we evaluated the role of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. In this abstract, first safety results of this trial are presented. Methods: Main eligibility criteria included: age ≥18 years, documented bone involvement previously untreated by CT, hormone receptor positive disease previously treated by at least one hormone therapy, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment. Results: Main pts characteristics in the full population were (n=70): median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior hormone therapy 100% (53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.5 months (range 0.9-18.3), median number of cycles: 6 (range: 1-18);61% of pts received at least 6 cycles, 37% of ptsreceived more than 6 cycles and 29% received at least 9 cycles; median relative dose intensity: 83.5%; dose escalation was performed in 79% ofpts.Grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, neutropenic infection 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusions: In this particular population of metastatic pts, with hormone receptor positive disease and bone involvement, OV showed an optimal safety profile. These data shows that OV is a well tolerated first-line CT option in this setting, allowing prolonged active treatment in non-progressing pts.

Electrochemotherapy for the management of melanoma skin metastasis: a review of the literature and possible combinations with immunotherapy

Despite surgical treatment of primary tumor, about 5-10 % of melanoma patients will eventually suffer from cutaneous or subcutaneous metastasis. The presence of skin metastases decreases patients' quality of life. Their management is a challenge and depends on several variables such as size and number of the lesions, their location, the presence or absence of visceral metastasis. When possible, radical surgical resection is the best approach; if surgery is not expected to provide a reasonable functional outcome, alternative treatments must be considered. Several local and loco-regional treatments, such as electrochemotherapy and regional chemotherapy, are available for the management of melanoma skin metastasis. Even if high response rates have been observed in several clinical trials, their impact on survival is not clear. Efforts are being made to improve their efficacy and minimize toxicity. The combination of such treatments with immunotherapy could be a strategy to induce durable responses and improve survival. In fact, regionally treated patients do not have the immune suppression associated with most systemic treatments, which could compromise the efficacy of immunotherapy, and recent findings suggest that the inflammatory reactions following loco-regional cytotoxic treatments, such as electrochemotherapy, may enhance the activity of immunotherapeutic agents. In this manuscript, we review recent studies on electrochemotherapy and melanoma skin metastasis, and we comment about the role that combinations with immunotherapy may have based on the data provided by clinical trials and translational research.

Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer

ObjectiveWe investigated the efficacy of maintenance hormone therapy (MHT), which was given to hormone positive metastatic breast cancer (MBC) patients in non-progression status to the previous chemotherapy. MethodsThis study retrospectively analyzed 76 MBC patients who had been treated with MHT from 2006 to 2010 at a single institute. ResultsFor the 76 patients reviewed, the median progression free survival (PFS) to MHT was 14.4 months (95% CI, 11.6–17.3). Prolonged PFS was associated with less previous palliative chemotherapy, fewer metastatic sites, and the absence of visceral metastasis in univariate analysis. Multivariate analysis showed that only the number of previous palliative chemotherapy (HR 1.73, 95% CI, 1.00–2.98; P = 0.04) remained as a significant variable. MHT was generally well tolerated. ConclusionsMHT showed considerable efficacy and tolerability in this study. Further randomized prospective study is warranted.

Prognostic factors for survivals from first relapse in breast cancer patients: analysis of deceased patients

PurposeThis study was performed to evaluate prognostic factors for survival from first relapse (SFFR) in stage I-III breast cancer patients.Materials and MethodsFrom June 1994 to June 2008, 3,835 patients were treated with surgery plus postoperative radiotherapy and adjuvant chemotherapy for stage I-III breast cancer at Samsung Medical Center. Among them, a total of 224 patients died by June 2009, and 175 deaths were of breast cancer. Retrospective review was performed on medical records of 165 patients who met the inclusion criteria of this study. Univariate and multivariate analysis were done on survivals according to variables, such as age, stage, hormone status of tumor, disease-free interval (DFI), sites of first failure, number of organs involved by recurrent disease (NOR), application of salvage treatments, and existence of brain or liver metastasis (visceral metastasis).ResultsPatients' median overall survival time was 38 months (range, 8 to 123 months). Median SFFR was 17 months (range, 5 to 87 months). Ninety percent of deaths occurred within 40 months after first recurrence. The patients with SFFR ≤1 year had tendency of triple-negativity, shorter DFI (≤2 years), larger NOR (>3), visceral metastasis for first relapse than the patients with SFFR >1 year. In multivariate analysis, longer DFI (>2 vs. ≤2 years), absence of visceral metastasis, and application of salvage treatments were statistically significant prognosticators for longer SFFR.ConclusionThe DFI, application of salvage treatments, and visceral metastasis were significant prognostic factors for SFFR in breast cancer patients.

Prognostic factors and a survival score for patients with metastatic spinal cord compression from colorectal cancer

This study aimed to identify independent prognostic factors and to create a survival score for patients with metastatic spinal cord compression (MSCC) from colorectal cancer (CRC). Data from 121 patients irradiated for MSCC from CRC were retrospectively analyzed. Eleven potential prognostic factors were investigated including tumor type, age, gender, Eastern Cooperative Oncology Group performance status score (ECOG-PS), number of involved vertebrae, ambulatory status prior to radiotherapy (RT), other bone metastases, visceral metastases, interval from cancer diagnosis to RT of MSCC, time of developing motor deficits prior to RT, and the RT schedule. On multivariate analysis, improved motor function was significantly associated with an ECOG-PS of 1-2 (p = 0.011) and a slower development of motor deficits (p < 0.001). Improved local control was significantly associated with absence of visceral metastases (p = 0.043) and longer-course RT (p = 0.008). Improved survival was significantly associated with an ECOG-PS of 1-2 (p < 0.001), ambulatory status (p < 0.001), absence of visceral metastases (p < 0.001), and a slower development of motor deficits (p = 0.047). These four prognostic factors were included in a survival score. The score for each factor was determined by dividing the 6-month survival rate by 10. The prognostic score represented the sum of the factor scores. Four prognostic groups were designed; the 6-month survival rates were 0% for 8-12 points, 26% for 13-18 points, 62% for 20-23 points, and 100% for 24-27 points (p < 0.001). This study identified several independent prognostic factors for treatment outcomes in patients irradiated for MSCC from CRC. The survival prognosis of these patients can be estimated with a new score.

Prognostic factors for different outcomes in patients with metastatic spinal cord compression from cancer of unknown primary

BackgroundPatients with cancer of unknown primary account for 10% of patients with metastatic spinal cord compression (MSCC). This retrospective study was performed to identify prognostic factors for functional outcome, local control of MSCC, and survival in 175 of such patients treated with radiotherapy alone.MethodsInvestigated were nine potential prognostic factors including age, gender, Eastern Cooperative Oncology Group performance score (ECOG-PS), number of involved vertebrae, pre-radiotherapy ambulatory status, other bone metastases, visceral metastases, time developing motor deficits before radiotherapy, and the radiation schedule.ResultsOn multivariate analysis, better functional outcome was associated with absence of visceral metastases (estimate: 0.72; 95%-confidence interval [CI]: 0.07-1.36; p = 0.030) and a slower (>7 days) development of motor deficits (estimate: 1.93; 95%-CI: 1.18-2.68; p < 0.001). Improved local control of MSCC was associated with absence of visceral metastases (risk ratio [RR]: 10.26; 95%-CI: 2.11-74.73; p = 0.004). Improved survival was associated with favorable ECOG-PS (RR: 2.12; 95%-CI: 1.40-3.29; p < 0.001), being ambulatory prior to radiotherapy (RR: 1.98; 95%-CI: 1.40-2.81; p < 0.001), absence of visceral metastases (RR: 2.74; 95%-CI: 1.93-3.91; p < 0.001), and slower development of motor deficits (RR: 1.27; 95%-CI: 1.07-1.51; p = 0.007). Absence of other bone metastases showed a trend (RR: 1.38; 95%-CI: 0.98-1.95; p = 0.07).ConclusionsThis study identified additional independent prognostic factors for functional outcome, local control of MSCC, and survival after radiotherapy of MSCC from cancer of unknown primary. These prognostic factors can help select the best treatment regimen for each individual patient.

Assessment of prognostic factors in patients with metastatic epidural spinal cord compression (MESCC) from solid tumor after surgery plus radiotherapy: a single institution experience

To identify potential prognostic factors predicting functional outcome and survival after surgery followed by radiotherapy for metastatic spinal cord compression due to solid tumors. 531 consecutive patients with metastatic epidural spinal cord compression (MESCC) were treated at our institution. Surgery followed by radiation therapy was performed in 151 patients (30%) with various histological diagnoses. Three different surgical procedures were performed: minimal resection with or without instrumented fixation, curettage, and total tumorectomy. Within 1 month after surgery, RT was performed, delivering a total dose of 30-36 Gy (3 Gy per fraction). Ten potential prognostic factors were investigated for relationship with functional outcome and survival. Clinical remission of pain was obtained in 91% of patients and 94 (62.5%) had recovery of neurological deficit. Recurrence in the same site of treatment occurred in nine (6%) patients. Median survival was 14 months (range 0-52 months); OS at 1, 2, and 3 years was 43.6, 37, and 21.5%, respectively. Survival was significantly associated with the histology of primary tumor (P < 0.001) and visceral metastases (P < 0.001) in the whole group; for histology, the prognostic factors statistically significant were other bone metastases in breast cancer, control of primary tumor, and the absence of visceral metastases in NSCLC and kind of surgery in the other. The key element for successful treatment of MESCC is multidisciplinary care of the patient, which includes all of those prognostic factors that have been, until now, analyzed and compared. In our set of patients treated for vertebral metastases, PS, time to development of symptoms, and the presence of visceral metastases affected functional outcome and survival.

Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin In Advanced and or Metastatic Bilharzial Urothelial Carcinoma of the Bladder in Egypt.

Purpose: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)were compared in patients with locally advanced or metastatic bilharzial urothelial carcinoma.Patients and Methods: Patients with with locally advanced or metastatic bilharzial urothelial carcinoma (no prior systemic chemotherapy) were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, 15, cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles (Methotrexate = 30 mg/m2 on days 1, 15 and 22, Vinblastine = 3 mg/m2 on days 2, 15 and 22,Doxorubicin = 30 mg/m2 on day 2 and Cisplatin = 70 mg/m2 on day 2 (1-2 h infusion).Results: forty-one patients were randomized, twenty-one to the GC arm and twenty to the MVAC arm. Overall survival was similar(13 months) on both arms. Time to progressive disease was 7 months with GC group and 6 months with MVAC group and response rate (GC, 47.6% vs MVAC 45%). Significant prognostic factors correlating with better overall survival were Karnofsky performance status ≥ 70, TNM staging (Mo vs.M1) and the absence of visceral metastasis. Hematologic toxicities were significantly higher with GC therapy. More GC patients, compared with MVAC patients had grade 3/4 anemia (28.5% vs 15%) and thrombocytopenia(47.6% vs 25%). More MVAC patients, compared with GC patients had grade 3/4 neutropenia (80% vs 67.6%P = 0.001), grade 3/4 mucositis (20% v 9.5%) and alopecia (25% v 14.3%) Conclusion: GC provides a similar survival advantage to MVAC with a better tolerability. These results strengthen the role of GC as a standard of care in patients with locally advanced or metastatic bilharzial-related urothelial carcinoma.

Radiotherapy for Patients With Metastases to the Spinal Column: A Review of 603 Patients at Shizuoka Cancer Center Hospital

Long- and short-course radiotherapy have similar outcomes in the treatment of spinal metastases. Long-course radiotherapy is recommended for patients with good predicted survival to reduce the risk of in-field recurrence, whereas short-course radiotherapy is used for those with poor predicted survival. Therefore, prediction of prognosis and local control is required for selecting the optimal course of radiotherapy. The subjects were 603 patients with spinal metastases who received radiotherapy at the Shizuoka Cancer Center Hospital between September 2002 and February 2007. Factors associated with survival and local control were retrospectively investigated by multivariate analyses. Local recurrence was defined as regrowth within the irradiated field or exacerbation of symptoms such as pain and motor deficits. Of the 603 patients, 555 (92%) were followed for 12 months or until death. The survival rates after 6, 12, and 24 months were 50%, 32%, and 19%, respectively, with a median survival of 6.2 months. The median survival periods after long- and short-course radiotherapy were 7.9 and 1.8 months, respectively. In multivariate analysis, primary tumor site, good performance status, absence of previous chemotherapy, absence of visceral metastasis, single bone metastasis, younger age, and nonhypercalcemia were associated with good survival. The local control rates after 6, 12, and 24 months were 91%, 79%, and 69%, respectively, and non-mass-type tumor, breast cancer, and absence of previous chemotherapy were predictors of good local control. Identification of factors associated with good local control and survival may allow selection of an optimal radiotherapy schedule for patients with spinal metastases.

Predictive factors for response and prognostic factors for long-term survival in consecutive, single institution patients with locally advanced and/or metastatic transitional cell carcinoma following cisplatin-based chemotherapy

Purpose. The study was undertaken to identify pre-treatment clinical and histopathological factors of importance for response and survival after cisplatin-based combination chemotherapy, in patients with locally advanced or metastatic transitional cell carcinoma of the urothelium. Patients and methods. Clinical, laboratory and histopathological data from 178 consecutive patients, representing all patients treated between 1991 and 2001 in a single institution, were collected. Correlations between these data and response and survival after chemotherapy were analysed using univariate and multivariate analyses. Results. Absence of visceral metastasis was the only parameter with independent correlation to the response to chemotherapy. Two of the analysed parameters were independently associated with increased survival: good performance status (PS≤1) and absence of visceral metastases. Stratification of the patient material according to number of these risk-factors present showed strong association with survival. Conclusion. It was possible to predict survival from pre-treatment clinical parameters and consequently it is possible to select groups with a high and low probability of obtaining long term survival following cisplatin-containing chemotherapy.

Prognostic Factors That Determine the Long-Term Survival of Patients with Unresectable Metastatic Melanoma

This retrospective analysis aimed to identify the prognostic factors that influenced long-term survival of patients with metastatic melanoma. The medical records for 616 chemo-naïve patients who were treated with systemic therapy on eight phase II/III clinical trials were reviewed. Clinical characteristics, disease stage, metastatic sites, baseline serum albumin, LDH, and response to treatment were compared between the treatment groups and significant prognostic factors were identified. Cox proportional-hazards regression analysis identified treatment with biochemotherapy, younger age, normal baseline serum albumin and LDH levels, ECOG P.S. < 2 and absence of visceral metastasis as favorable prognostic factors for long-term survival.

Cyberknife radiosurgery for breast cancer spine metastases

There are few options for breast cancer patients with spinal metastases recurrent within a previous radiation treatment field. CyberKnife radiosurgery has been used in our institution to treat such patients. To evaluate their outcomes, as there are no comparable radiation treatment options, the outcomes were compared between 18 patients with spinal metastases from breast cancer treated with CyberKnife stereotactic radiosurgery, 17 of which had prior radiotherapy to the involved spinal region and were progressing, and 18 matched patients who received conventional external beam radiotherapy (CRT) up-front for spinal metastases. Radiosurgery was delivered in 3 to 5 fractions to doses ranging from 2100 to 2800 cGy. Women were matched to patients in a CRT group with respect to time from original diagnosis to diagnosis of metastases, estrogen receptor / progesterone receptor (ER/PR) status, presence or absence of visceral metastases, prior radiotherapy, and prior chemotherapy. Survival and complications were compared between treatment groups. Surviving patients were followed out to 24 months. The CyberKnife and CRT groups were comparable along all matching dimensions and in performance status before treatment. Outcomes of treatment were similar for patients in both groups; ambulation, performance status, and pain worsened similarly across groups posttreatment. Survival and the number of complications appeared to favor the CyberKnife group, but the differences did not reach statistical significance. The statistical comparability of the CyberKnife and CRT groups reflects the small sample size and stringent requirements for significance of the matched-pair analysis. Nevertheless, comparability in these difficult cases shows that salvage CyberKnife treatment is as efficacious as initial CRT without added toxicity.

Renal safety of intravenous ibandronate 6mg infused over 15 or 60 minutes in patients with breast cancer and bone metastases: A randomized, open-label study

1114 Background: Clinical data show that a single 15-minute intravenous infusion of ibandronate (IA) 6mg is associated with no significant changes in renal functioning. The aim of this study was evaluation of renal safety of repeated 15-minute intravenous infusions of IA 6mg in women with breast cancer and bone metastases. Methods: Patients (n=127) were randomized to receive treatment with intravenous ibandronate as a 15-minute infusion (n=101) or as a 60-minute infusion (n=26) every 3–4 weeks. Patients were stratified according to previous treatment and the presence or absence of visceral metastases. All patients had serum creatinine within normal limits and calculated creatinine clearance =50mL/min as assessed prior to each infusion throughout the trial. The primary endpoint was the percentage of patients with an increase in serum creatinine from baseline of =44.2μmol/L (0.5mg/dL) at any point in the study. Results: Three percent of patients in the 15 minute infusion (3/101) met the primary endpoint with either hydronephrosis due to tumor, severe diarrhea or pre-existing diabetes with urinary tract infection. No patients in the 60-minute infusion arm (0/26) had an increase in serum creatinine that met the primary endpoint. No clinically relevant changes were seen in serum creatinine, calculated or measured creatinine clearance, or levels of N-acetyl-β-D- glucosaminidase, a1-microglobulin or microalbumin in either arm. There were no marked changes in mean bone pain or analgesic requirement scores. A slight increase in mean WHO performance status score was seen in both arms. Most adverse events were mild or moderate. No clinically-relevant mean changes were observed in vital signs, hematology, blood chemistry including renal function or urinalysis parameters. Renal impairment was related to IA in the 3 patients with increased serum creatinine. Conclusions: IA 6mg administered as a 15- minute intravenous infusion every 3–4 weeks had a renal safety profile consistent with that of the 60-minute infusion, suggesting that a 15-minute infusion of ibandronate 6mg is well-tolerated in patients with breast cancer and bone metastases. No significant financial relationships to disclose.

Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression

In many centers worldwide, radiotherapy for metastatic spinal cord compression (MSCC) is performed with 30 Gy in 10 fractions. This study investigated the potential benefit of dose escalation. Data from 922 patients with carcinomas causing MSCC were retrospectively evaluated. The outcome of 345 patients treated with 10 fractions of 3 Gy in 2 weeks was compared with the outcomes of 577 patients treated with 37.5 Gy in 15 fractions within 3 weeks or 40 Gy in 20 fractions within 4 weeks. Additionally, 10 potential prognostic factors were investigated: age, gender, performance status, tumor type, interval between cancer diagnosis and MSCC, number of involved vertebrae, other bone and visceral metastases, ambulatory status, and the interval to the development of motor deficits before radiotherapy. Motor function improved in 19% of patients after 30 Gy in 10 fractions and in 22% after greater doses (p = 0.31). The local control (p = 0.28) and survival (p = 0.85) rates were not significantly different with doses >30 Gy. Better functional outcome was associated with the absence of visceral metastases, an interval between tumor diagnosis and MSCC of >12 months, ambulatory status, and an interval to the development of motor deficits of >7 days. Improved local control was significantly associated with no visceral metastases, improved survival with favorable histologic features (breast or prostate cancer), no visceral metastases, ambulatory status, an interval between cancer diagnosis and MSCC of >12 months, and an interval to the development of motor deficits of >7days. Escalation of the radiation dose to >30 Gy in 10 fractions did not improve the outcomes in terms of motor function, local control, or survival but did increase the treatment time for these frequently debilitated patients. Therefore, doses >30 Gy in 10 fractions are not recommended.

Functional outcome and survival after radiotherapy of metastatic spinal cord compression in patients with cancer of unknown primary

Patients with cancer of unknown primary (CUP) account for about 10% of patients with metastatic spinal cord compression (MSCC). This study aims to define the appropriate radiation regimen for these patients. Data of 143 CUP patients irradiated for MSCC were retrospectively evaluated. Short-course radiotherapy (RT) (1x8 Gy, 5x4 Gy, n = 68) and long-course RT (10x3 Gy, 15x2.5 Gy, 20x2 Gy, n = 75) plus 8 further potential prognostic factors (age, gender, performance status, visceral metastases, other bone metastases, number of involved vertebrae, ambulatory status, time of developing motor deficits before RT) were compared for functional outcome and survival. Improvement of motor function occurred in 10% of patients, no further progression of motor deficits in 57%, and deterioration in 33%. On multivariate analysis, functional outcome was positively associated with slower development of motor deficits (p < 0.001), absence of visceral metastases (p = 0.008) and other bone metastases (p = 0.027), and ambulatory status (p = 0.054), not with the radiation regimen (p = 0.74). Recurrence of MSCC in the irradiated region occurred in 7 patients after median 6 months. Median survival was 4 months. On multivariate analysis, better survival was significantly associated with absence of visceral metastases (p < 0.001), absence of other bone metastases (p = 0.005), ambulatory status (p = 0.001), and slower development of motor deficits (p = 0.030). For MSCC treatment in patients with CUP, no significant difference was observed between short-course and long-course RT regarding functional outcome and survival. Short-course RT appears preferable, at least for patients with a poor predicted survival, as it is more patient convenient and more cost-effective.

299 POSTER Randomized phase II trial of irofulven/prednisone, irofulven/capecitabine/prednisone, or mitoxantrone/prednisone in hormone refractory prostate cancer (HRPC) patients failing first-line docetaxel: preliminary results

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.Janssen Research & Development.