scholarly journals 418 Phase 1b/2 KEYNOTE-365 cohort I: platinum-containing chemotherapy alone or in combination with pembrolizumab for treatment-emergent neuroendocrine prostate carcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A448-A448
Author(s):  
Johann De Bono ◽  
Neal Shore ◽  
Gero Kramer ◽  
Anthony Joshua ◽  
Xin Tong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Carcinoma ◽  
Response Rate ◽  
Performance Status ◽  
Ecog Performance Status ◽  
End Points ◽  
Status Score ◽  
Modified Recist ◽  
Phase 1B ◽  
Performance Status Score

BackgroundTreatment-emergent neuroendocrine prostate carcinoma (t-NE) can occur de novo or after diagnosis of prostate adenocarcinoma. Treatment often includes platinum-containing chemotherapy because of t-NE’s histologic similarity to small cell lung cancer. The PD-1 inhibitor pembrolizumab has shown promising efficacy and acceptable safety when combined with olaparib, docetaxel, or enzalutamide for treatment of metastatic castration-resistant prostate cancer (mCRPC) in the multicohort phase 1b/2 KEYNOTE-365 study (NCT02861573). Cohort I will be used to compare platinum-containing chemotherapy alone with chemotherapy + pembrolizumab as treatment for t-NE.MethodsPatients who have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review); experienced progression within 6 months of starting a next-generation hormonal agent (NHA) for mCRPC or hormone-sensitive prostate cancer and experienced progression within 6 cycles of docetaxel treatment for mCRPC; and have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 are eligible. Prior therapy with ≤2 NHAs and 1 other chemotherapy for mCRPC is permitted. Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2); in each arm 40–100 patients will be enrolled. Pembrolizumab treatment will continue up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG performance status score (0 or 1). Computed tomography or magnetic resonance imaging will be performed every 9 weeks through week 54 and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression; ORR and radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 by BICR and PCWG3-modified RECIST v1.1 by BICR; and overall survival. End points will be summarized for each arm without formal hypothesis testing.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 425 Pembrolizumab + vibostolimab in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC: phase 1b/2 KEYNOTE-365 cohorts G/H

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A455-A455
Author(s):  
Neal Shore ◽  
Johann De Bono ◽  
Gero Kramer ◽  
Anthony Joshua ◽  
Xin Tong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Disease Progression ◽  
Response Rate ◽  
Group Performance ◽  
Neuroendocrine Cells ◽  
End Points ◽  
Link Type ◽  
Modified Recist ◽  
Phase 1B

BackgroundFrontline treatment for patients with adenocarcinoma mCRPC includes docetaxel, radium 223, or the next-generation hormonal agents (NHAs) abiraterone or enzalutamide. For patients with disease progression on these therapies, approximately 20% will develop treatment-emergent neuroendocrine mCRPC (t-NE) after diagnosis of prostate adenocarcinoma. The PD-1 inhibitor pembrolizumab showed antitumor activity when combined with olaparib in cohort A of the phase 1b/2 KEYNOTE-365 trial, and the TIGIT inhibitor vibostolimab showed antitumor activity in preclinical models. Combining PD-1 and TIGIT inhibition may have enhanced benefit in adenocarcinoma mCRPC or t-NE.MethodsKEYNOTE-365 is a nonrandomized, open-label, multicohort study (NCT02861573) to assess several pembrolizumab combination therapies in patient populations with adenocarcinoma mCRPC or t-NE. In each of cohorts G and H, 40–100 adults with Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1 who received docetaxel for mCRPC will be enrolled. Prior therapy with ≤2 NHAs and 1 other chemotherapy for adenocarcinoma mCRPC is permitted. Patients in cohort G must have adenocarcinoma of the prostate without small cell histology at study entry. Patients in cohort H must have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) that progressed within 6 months of starting an NHA for mCRPC or hormone-sensitive prostate cancer and progressed within 6 cycles of docetaxel for mCRPC. All patients will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg intravenously every 3 weeks until disease progression, consent withdrawal, or other discontinuation event. Adverse events will be monitored through 30 days after discontinuation (90 days if serious) and graded per CTCAE v4.0. Computed tomography or magnetic resonance imaging will be performed at screening, every 9 weeks through week 54, and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression, ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5595-TPS5595
Author(s):  
Christian Gratzke ◽  
Joseph E Burgents ◽  
Cuizhen Niu ◽  
Christian Heinrich Poehlein ◽  
Charles G. Drake
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Response Rate ◽  
Phase Iii ◽  
Antitumor Effects ◽  
End Points ◽  
Once Daily ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

TPS5595 Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .

Prognosis of advanced hepatocellular carcinoma (HCC) in patients undergoing surgery combined with peri- or postoperative treatment with sorafenib.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 377-377
Author(s):  
Liqun Wu ◽  
Xufeng Pang ◽  
Jingyu Cao ◽  
Zusen Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Resection ◽  
Tumor Volume ◽  
Performance Status ◽  
Primary Hepatocellular Carcinoma ◽  
Postoperative Treatment ◽  
Ecog Performance Status ◽  
Status Score ◽  
Performance Status Score

377 Background: Liver resection/transplantation are effective therapies for primary hepatocellular carcinoma (HCC), but high relapse rates can significantly impact long term survival, especially for patients with advanced disease. The objective of this study was to investigate the effects of surgery plus sorafenib on the prognosis of patients with advanced HCC. Methods: 36 male and 2 female patients of mean age 52.6 (range 36-65) years and an ECOG performance status score 0-1 (n=26) or 2 (n=12), received surgical therapy (28 liver resection and 10 liver transplantation) plus sorafenib for treatment of HCC with a high risk of relapse (n=3) or had relapsed. Sorafenib was administered orally 400 mg once or twice daily, and the dose was reduced or the treatment temporarily discontinued if a grade 3 or worse adverse event occurred. Treatment duration was >3 months and patients were evaluated every 4 weeks. The main endpoints were overall survival (OS) and time to progression (TTP). Results: Median follow-up time was 12.9 (range 4-59) months. Kaplan-Meier analysis demonstrated that median OS was 17 months (95%CI: 11.6-22.4), median TTP was 15 months (95%CI: 11.6-18.4). During follow-up, 20 patients died (18 from disease progression, 1 from a lung infection, and 1 accidently). Univariate analysis demonstrated that serum ALT >60 U/L at the beginning of treatment, Child-Pugh grade B, ECOG performance status score 2, tumor cell embolism in blood vessels, tumor volume ≥3 liver segments, and a tumor involving 2 vital organs were important factors affecting OS. The median OS of patients with a tumor volume ≥3 liver segments vs. patients with tumor volume <3 liver segments was 8 vs. 28 months (log-rank test, p<0.001), and median TTP was 5 vs. 24 months (p<0.001). Conclusions: Surgical resection in combination with sorafenib helped prolong OS and TTP in patients with advanced or relapsed HCC. OS for patients treated with sorafenib peri-operatively was longer than that for patients who received therapy after a relapse had occurred. Decreasing tumor burden and administering sorafenib as early as possible are helpful strategies to improve prognosis in patients with HCC.

Real world treatment patterns of first-line combination therapies among BRAF+ metastatic melanoma patients.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 197-197
Author(s):  
Sameer Ghate ◽  
Jackson Tang ◽  
Zhiyi Li ◽  
Antonio Reis Nakasato
Keyword(s):  
Metastatic Melanoma ◽  
Real World ◽  
Performance Status ◽  
Treatment Patterns ◽  
Toxic Effects ◽  
First Line ◽  
Ecog Performance Status ◽  
Status Score ◽  
Study Results ◽  
Performance Status Score

197 Background: For patients (pts) with metastatic melanoma (MM) and BRAF V600 mutation (BRAF+), options for first-line (1L) systemic combination therapy include immunotherapy (IO) or targeted therapy (TT). This study describes real world treatment patterns among BRAF+ MM pts treated with 1L ipilimumab+nivolumab (I+N) or dabrafenib+trametinib (D+T). Methods: This retrospective observational analysis used Flatiron Health’s electronic health record-derived database from Oct 2015 - Jul 2016. Oct 2015 was chosen as the start date as both combo use of I+N and D+T had been approved by the FDA. Pts were aged ≥18 years with a MM diagnosis, tested BRAF+ prior to therapy, and treated with either I+N or D+T as 1L therapy. Baseline demographic and clinical characteristics, and treatment patterns were collected from structured data and unstructured data in physician notes, and were descriptively assessed. Kaplan-Meier (KM) analysis measured time to discontinuation. Statistical inferences were not planned in this study. Results: Among 76 BRAF+ pts, 62% (47) were treated with D+T as 1L, and 38% (29) were treated with I+N as 1L. Compared to D+T pts, lower proportion of I+N pts had a history of brain metastases (31% vs. 34%) and elevated ( > 333 IU/L) lactate dehydrogenase (10% vs. 19%), while a higher proportion of I+N pts reported ECOG performance status score of zero (38% vs. 23%). The two cohorts were similar in age, gender and baseline comorbidities. Discontinuation among D+T and I+N was 43% (20) and 48% (14) respectively. The primary reason for discontinuation was progression among D+T pts (10/20) vs. toxic effects of therapy among I+N pts (8/14). KM median time to discontinuation was 213 days for D+T pts vs. 196 days for I+N pts. 55% of I+N pts did not complete full induction of 4 doses of ipilimumab, citing toxic effects of therapy. Conclusions: 1L D+T patients had higher tumor burden, elevated LDH levels, and higher ECOG performance status score, but lower discontinuation rate and longer time to treatment discontinuation relative to BRAF+ 1L I+N pts.

343 Phase 3 study of pembrolizumab + docetaxel and prednisone/prednisolone for metastatic castration-resistant prostate cancer (mCRPC) pretreated with next-generation hormonal agents (NHAs) (KEYNOTE-921)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A368-A368
Author(s):  
Daniel Petrylak ◽  
Neal Shore ◽  
Mostefa Bennamoun ◽  
Raffaele Ratta ◽  
Josep Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Response Rate ◽  
Abiraterone Acetate ◽  
Prior Treatment ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Psa Response ◽  
Modified Recist

BackgroundCohort B of the phase 1b/2 KEYNOTE-365 study (NCT02861573) found that docetaxel + pembrolizumab + prednisone demonstrated activity in patients previously treated with abiraterone acetate or enzalutamide for mCRPC. The prostate-specific antigen (PSA) response rate was 28%; objective response rate (ORR) was 18% (7 partial responses); duration of response (DOR) was 6.7 months; progression-free survival (PFS) was 8.3 months; overall survival (OS) was 20.4 months; and the 12-month PFS and OS rates were 24.0% and 75.8%, respectively. The safety and tolerability profile of this combination was consistent with the profiles of each individual agent. The KEYNOTE-921 (NCT03834506) phase 3 trial will evaluate efficacy and safety of pembrolizumab + docetaxel + prednisone/prednisolone in patients with mCRPC after prior treatment with NHA.MethodsEligible patients are adults with histologically or cytologically confirmed mCRPC who experience disease progression with androgen deprivation therapy (or after bilateral orchiectomy) within 6 months of screening and have Eastern Cooperative Oncology Group performance status 0/1. Other eligibility criteria are disease progression or intolerance to NHA in the metastatic hormone-sensitive prostate cancer setting or CRPC setting, no prior treatment with chemotherapy for mCRPC, and tissue available for biomarker analysis. Treatment stratification factors are prior treatment with abiraterone acetate (yes or no) and metastases location (bone only, liver, other). Approximately 1000 patients will be randomly assigned to receive docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg PO BID + placebo IV Q3W (1:1 ratio). Response and progression will be determined using imaging (CT/MRI/bone) according to PCWG3–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment maximums are 10 cycles for docetaxel + prednisone/prednisolone and 35 cycles for pembrolizumab or placebo. Treatment discontinuation regardless of therapy received is mandated for disease progression, unacceptable toxicity, or consent withdrawal. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS, and the key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include PSA response rate, time to PSA progression, ORR, DOR, time to radiographic soft tissue progression, time to radiographic bone progression, and safety. KEYNOTE-921 is ongoing or planned in 22 countries across, Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/AEthics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Radiosurgery for parasagittal and parafalcine meningiomas

2013 ◽  
Vol 119 (4) ◽  
pp. 871-877 ◽  
Author(s):  
Dale Ding ◽  
Zhiyuan Xu ◽  
Ian T. McNeill ◽  
Chun-Po Yen ◽  
Jason P. Sheehan
Keyword(s):  
Cox Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Tumor Control ◽  
Who Grade ◽  
Tumor Control Rate ◽  
Karnofsky Performance Status Score ◽  
Status Score ◽  
Performance Status Score

Object Parasagittal and parafalcine (PSPF) meningiomas represent the second most common location for intracranial meningiomas. Involvement of the superior sagittal sinus or deep draining veins may prevent gross-total resection of these tumors without significant morbidity. The authors review their results for treatment of PSPF meningiomas with radiosurgery. Methods The authors retrospectively reviewed the institutional review board–approved University of Virginia Gamma Knife database and identified 65 patients with 90 WHO Grade I parasagittal (59%) and parafalcine (41%) meningiomas who had a mean MRI follow-up of 56.6 months. The patients' mean age was 57 years, the median preradiosurgery Karnofsky Performance Status score was 80, and the median initial tumor and treatment volumes were 3 and 3.7 cm3, respectively. The median prescription dose was 15 Gy, isodose line was 40%, and the number of isocenters was 5. Kaplan-Meier analysis was used to determine progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to identify factors associated with PFS. Results The median overall PFS was 75.6 months. The actuarial tumor control rate was 85% at 3 years and 70% at 5 years. Parasagittal location, no prior resection, and younger age were found to be independent predictors of tumor PFS. For the 49 patients with clinical follow-up (mean 70.8 months), the median postradiosurgery Karnofsky Performance Status score was 90. Symptomatic postradiosurgery peritumoral edema was observed in 4 patients (8.2%); this group comprised 3 patients (6.1%) with temporary and 1 patient (2%) with permanent clinical sequelae. Two patients (4.1%) died of tumor progression. Conclusions Radiosurgery offers a minimally invasive treatment option for PSPF meningiomas, with a good tumor control rate and an acceptable complication rate comparable to most surgical series.

Comparison of two Different Radiotherapy Schedules for Spinal Cord Compression in Prostate Cancer

1998 ◽  
Vol 84 (4) ◽  
pp. 472-477 ◽  
Author(s):  
Ernesto Maranzano ◽  
Paolo Latini ◽  
Sara Beneventi ◽  
Luigi Marafioti ◽  
Fabrizio Piro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Spinal Cord ◽  
Spinal Cord Compression ◽  
Response Rate ◽  
Recovery Of Function ◽  
Performance Status ◽  
Cord Compression ◽  
Severe Toxicity ◽  
Indwelling Catheter ◽  
Short Course

Aims and background To assess the clinical outcome and toxicity of two different radiotherapy (RT) schedules for the management of metastatic spinal cord compression from prostate cancer, we performed a prospective analysis of 44 patients with the complication. Methods Two different RT schedules were adopted, a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5, and a short-course regimen of 8 Gy, 7 days rest, and then 8 Gy. The split-course RT was adopted for all prostate cancer patients referred to our center between 1986 and 1992. Starting in 1993, the short-course RT was added for patients with a poor prognosis (i.e., paresis or paraplegia, low performance status, and/or short life expectation), whereas others still underwent the split-course regimen. So, 27 (61%) patients were treated with the split-course and the other 17 (39%) with the short-course regimen. Medium follow-up was 48 months (range, 6 to 123). Results Back pain total response rate was 82%. Effectiveness of RT on motor and bladder capacity was conditioned by pretreatment status of patients. All 20 (100%) walking cases maintained the function, whereas 11 of 24 (46%) with motor impairment regained the ability. The difference in response rate was statistically significant (P<0.001). All 36 (100%) patients, able to void at presentation preserved the capacity, whereas 3 of 8 (38%) with sphincter dysfunction no longer needed an indwelling catheter. Posttreatment neurologic status was the only factor found to affect survival. Median survival, 9 months for the whole group, was 10 and 2 months for posttreatment walking and nonwalking patients, respectively (10 vs 2 months, P<0.001). Neither presence of other metastases nor RT regimen used (split vs short-course) conditioned response rate, duration of response or survival. Acute or late, severe toxicity was never recorded. No patient complained of spinal cord morbidity. Conclusions Both split-course and short-course RT schedules were effective and without complications. Early diagnosis was the most important prognostic factor, but there was also recovery of function in about half of the patients unable to walk, and about one-third of patients with bladder dysfunction before treatment. Since length of the course of therapy is a factor with an important impact on the patient's quality of life, the short-course RT regimen adopted in the trial merits further investigation.

A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13029-13029
Author(s):  
E. Gallerani ◽  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
G. Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]

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