EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer.

BACKGROUND AND AIMS: Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy. METHODS: In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death. RESULTS: Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection. CONCLUSIONS: Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.

Impact of diabetes mellitus on clinical outcomes in patients undergoing surgical resection for pancreatic cancer: a retrospective, cohort study.

OBJECTIVES: Diabetes mellitus (DM) has a bidirectional association with pancreatic cancer (PaC); however, its effect on clinical outcomes has not been thoroughly evaluated. We analyzed these data in a large sample of PaC subjects who had undergone surgical resection. METHODS: Subjects enrolled in the Mayo Clinic Pancreatic Cancer SPORE registry from 2000 to 2010 who had resection with curative intent were identified (n=488). Tumor size, cancer stage, and postoperative median survival were evaluated. Median survivals were compared with Kaplan-Meier curves and Cox proportional hazards regression modeling. RESULTS: A total of 275 (56%) subjects had DM before surgery. DM subjects had larger tumors compared with those without DM (3.6 cm vs. 3.3, P=0.002), even after controlling for covariates including age, body mass index, and tumor grade. Cancer stage at the time of surgery was not affected by DM status (P=0.575). Preoperative DM was not associated with an increased risk of death using a multivariable survival analysis (hazard ratio 1.06, 95% confidence interval 0.81-1.38, P=0.676). The median survival following cancer resection was similar between subjects with and without DM (24 vs. 26 months, P=0.610). In addition, postoperative survival was similar on the basis of the duration of DM (new-onset vs. long-standing) and prior use of antidiabetic treatments in diabetic subjects. CONCLUSIONS: PaC subjects with DM have larger tumors than nondiabetic subjects. Despite this observation, preoperative DM does not negatively impact the cancer stage at the time of surgery or postoperative survival. Thus, the effect of DM on tumor size is either overshadowed by early metastatic spread of the cancer or is mitigated by the tumor resection.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Metformin Use and Survival of Patients With Pancreatic Cancer: A Cautionary Lesson.

PURPOSE: The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. RESULTS: Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. CONCLUSION: Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.

A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors.

BACKGROUND: We have previously demonstrated that pemetrexed is clinically active when administered 90 min after gemcitabine in a phase I study. The present study was undertaken to evaluate the efficacy, toxicity, and pharmacokinetics of gemcitabine and pemetrexed when pemetrexed is administered immediately after gemcitabine. PATIENTS AND METHODS: A total of 14 patients received 84 cycles of treatment. Gemcitabine 1250 mg/m(2) was administered on days 1 and 8 of each 21-day cycle, and pemetrexed 500 mg/m(2) on day 8 immediately following gemcitabine administration. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for all treatment cycles. Pharmacokinetic analyses of plasma gemcitabine and pemetrexed concentrations were performed. RESULTS: Neutropenia was the most common severe toxicity. Non-hematologic toxicities, which included nausea, vomiting, fatigue, diarrhea, rash, and elevated transaminases were of mild-to-moderate severity. No increased toxicity was observed with this schedule in comparison to the previous phase I schedule. There was no pharmacokinetic interaction between the two drugs. One partial response was documented in a patient with non-small-cell lung cancer. Eight patients had disease stabilization for five or more cycles. CONCLUSION: Gemcitabine immediately followed by pemetrexed is well tolerated and clinically active, and deserves further evaluation in phase II trials.

Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study.

OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors. METHODS: Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared with controls seen for a general medical evaluation. Patients and controls completed the same questionnaires. After excluding insulinoma and high-grade PNETs, 355 cases were evaluated, and 309 were matched to 602 controls (2:1) on age, sex, and region of residence. RESULTS: Personal smoking history was not associated with PNETs. Alcohol use was less common among cases (54% vs 67%, P < 0.001). Cases were more likely to report a family member with sarcoma (P = 0.02), PNET (P = 0.02), gallbladder cancer (P = 0.02), ovarian cancer (P = 0.04), and gastric cancer (P = 0.01). There was no association with other cancers in family members. Diabetes was more commonly reported by cases than controls (19% vs 11%, P < 0.001). CONCLUSIONS: With the exception of diabetes, risk factors that are associated with pancreatic adenocarcinoma are not risk factors for PNETs.

Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma.

The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 µg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992-1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and ≥18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.

The prognostic value of clinical and pathologic factors in esophageal adenocarcinoma: a mayo cohort of 796 patients with extended follow-up after surgical resection.

OBJECTIVE: To identify and describe clinicopathologic prognostic factors in patients with esophageal adenocarcinoma who underwent surgical resection with curative intent. PATIENTS AND METHODS: The study cohort consisted of 796 patients with adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia who underwent complete tumor resection at Mayo Clinic from January 1, 1980, to December 31, 1997. We reviewed individual patient medical records and abstracted demographic, pathologic, perioperative, and cancer outcome data. Median follow-up for vital status and disease recurrence was 12.8 and 5.8 years, respectively. RESULTS: Univariate analysis revealed the following factors to be statistically associated with worse 5-year disease-specific survival: higher N and T status, higher tumor grade, age older than 76 years, and the presence of extracapsular lymph node extension and signet ring cells. The following factors remained significantly linked with worse 5-year disease-specific survival on multivariate analysis: higher N and T status, grade, and age and the absence of preoperative chemotherapy or radiotherapy. Anatomic location of tumor was not associated with differential prognosis. Lymph node metastases were found in 25 (27%) of 93 T1b tumors, 397 (85%) of 468 T3 tumors, and 22 (67%) of 33 T4a tumors. Disease-specific survival was better in T3-4N0 than in T1bN1-3 carcinomas (hazard ratio, 0.50; 95% confidence interval, 0.28-0.89, adjusted for grade and age; P=.02). CONCLUSION: Our results confirm the importance of T and N status and tumor grade and suggest that age may affect prognosis. In addition, we show that a significant proportion of superficial esophageal adenocarcinomas exhibit regional metastases and have worse prognosis than more invasive nonmetastatic tumors.

Obesity adversely affects survival in pancreatic cancer patients.

BACKGROUND: Higher body-mass index (BMI) has been implicated as a risk factor for developing pancreatic cancer, but its effect on survival has not been thoroughly investigated. The authors assessed the association of BMI with survival in a sample of pancreatic cancer patients and used epidemiologic and clinical information to understand the contribution of diabetes and hyperglycemia. METHODS: A survival analysis using Cox proportional hazards by usual adult BMI was performed on 1861 unselected patients with pancreatic adenocarcinoma; analyses were adjusted for covariates that included clinical stage, age, and sex. Secondary analyses incorporated self-reported diabetes and fasting blood glucose in the survival model. RESULTS: BMI as a continuous variable was inversely associated with survival from pancreatic adenocarcinoma (hazard ratio [HR], 1.019 for each increased unit of BMI [kg/m2], P<.001) after adjustment for age, stage, and sex. In analysis by National Institutes of Health BMI category, BMIs of 30 to 34.99 kg/m2 (HR, 1.14; 95% confidence interval [CI], 0.98-1.33), 35 to 39.99 kg/m2 (HR 1.32, 95% CI 1.08-1.62), and ≥40 (HR 1.60, 95% CI 1.26-2.04) were associated with decreased survival compared with normal BMI of 18.5 to 24.99 kg/m2 (overall trend test P<.001). Fasting blood glucose and diabetes did not affect the results. CONCLUSIONS: Higher BMI is associated with decreased survival in pancreatic cancer. Although the mechanism of this association remains undetermined, diabetes and hyperglycemia do not appear to account for the observed association.

Older versus younger patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and stomach: a pooled analysis of eight consecutive North Central Cancer Treatment Group (NCCTG) trials.

Whether elderly patients with metastatic esophageal, gastroesophageal, and gastric cancer do as well with chemotherapy as their younger counterparts was investigated in this pooled analysis. In total, 367 patients from 8 consecutive, first-line trials were included: i) etoposide + cisplatin; ii) 5-fluorourucil + leucovorin; iii) 5-fluorouracil + levamisole; iv) irinotecan; v) docetaxel + irinotecan; vi) oxaliplatin + capecitabine; vii) docetaxel + capecitabine; and viii) bortezomib + paclitaxel + carboplatin. One hundred and fifty-four (42%) patients were > or =65 years old (range: 65-86), and 213 younger (range: 20-64). Elderly patients had worse performance scores (2-3): 19 vs. 8% (p<0.0001). Rates of grade 3+ adverse events across all chemotherapy cycles in univariate and multivariate analyses (adjusted for gender, performance score, and stratified by individual study) were higher among elderly patients. Rates of neutropenia, fatigue, infection, and stomatitis in elderly vs. younger patients were 31 vs. 29% (p=0.02 by multivariate analyses); 15 vs. 5% (p=0.01); 9 vs. 4% (p=0.03); 6 vs. 1% (p=0.04). In contrast, duration of chemotherapy, overall survival, and progression-free survival were comparable. Although age should not preclude trial entry, these adverse event rates suggest a need to develop more tolerable regimens for older patients with these malignancies.

Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer.

BACKGROUND: Sipuleucel-T is an investigational active cellular immunotherapy product designed to stimulate an immune response against prostate cancer. The safety and efficacy of sipuleucel-T was evaluated in 2 identically designed, randomized, double-blind, placebo-controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer. METHODS: A total of 225 patients were randomized in D9901 or D9902A to sipuleucel-T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart. Patients were followed for survival until death or a prespecified cutoff of 36 months after randomization. RESULTS: In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel-T demonstrated a 33% reduction in the risk of death (hazard ratio, 1.50; 95% confidence interval, 1.10-2.05; P = .011; log-rank). The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, poststudy treatment chemotherapy use, and non-prostate cancer-related deaths. Additional support for the activity of sipuleucel-T is provided by the correlation between a measure of the product's potency, CD54 up-regulation, and overall survival. The most common adverse events associated with treatment were chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. These events were primarily grade 1 and 2, with durations of 1 to 2 days. CONCLUSIONS: The integrated results of D9901 and D9902A demonstrate a survival benefit for patients treated with sipuleucel-T compared with those treated with placebo. The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk-benefit ratio for sipuleucel-T in patients with advanced prostate cancer.

Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916.

PURPOSE: Prostate-specific antigen progression (PSA-P) is an indicator of progression in hormone-sensitive (HS) and castration-resistant (CR) prostate cancer (PC). We evaluated different definitions of PSA-P as predictors of overall survival (OS). PATIENTS AND METHODS: A total of 1,078 patients with HSPC who were on hormones (Southwest Oncology Group [SWOG] trial 9346 [S9346]) and 597 patients with CRPC who were treated with chemotherapy (SWOG trial 9916 [S9916]) were eligible for this analysis. PSA-P definitions tested included the following: PSA Working Group, Prostate Cancer Working Group (PCWG 2008), and other definitions. A time-varying approach analyzed associations between PSA-P at any time and OS. A landmark analysis examined the relationship between PSA-P status at 7 months for S9346, or 3 months for S9916, and subsequent OS. RESULTS: In the time-varying analysis, both working groups definitions were strongly associated with OS (P < .001) in both study settings. In patients enrolled onto S9346, both definitions predicted a 2.4-fold increased risk of death (ROD) and a greater than four-fold increased ROD if PSA-P occurred in the first 7 months. In S9916, they predicted a 40% increase in ROD and a two-fold increase in ROD if PSA-P occurred at 3 months. In landmark analyses of patients on S9346 by using the PCWG 2008 definition of PSA-P, median subsequent OS was 10 months versus 44 months in patients who did or did not have PSA-P by 7 months, respectively; in S9916, data were 11 months versus 18 months for patients who did or did not have PSA-P by 3 months, respectively. CONCLUSION: PSA-P, defined as an increase of > or = 25% greater than the nadir and an absolute increase of at least 2 or 5 ng/mL, predicts OS in HSPC and CRPC and may be a suitable end point for phase II studies in these settings.

Predictors of survival from urachal cancer: a Mayo Clinic study of 49 cases.

BACKGROUND: Outcome results of a long-term analysis of urachal cancer using a new staging system are presented. METHODS: The authors analyzed clinical outcomes from 49 patients with the diagnosis of urachal cancer who were seen at the Mayo Clinic, Rochester, Minnesota from 1950 to 2003. The TNM staging system was used to predict outcome after surgical resection. RESULTS: Among 49 study patients, 33 were men, 16 were women, and their median age at presentation was 57.5 years. The vast majority of tumors were adenocarcinomas (89%), 4% were sarcomas and transitional cell carcinomas, and the rest were high-grade mixed neoplasms. Among the adenocarcinomas, 63.6% were mucin-producing tumors. Partial cystectomy with or without pelvic lymph node dissection and removal of the urachus was performed in 41 (83%) cases. Overall survival for all stages was 62 months with 17 (34%) patients still alive more than 5 years after treatment. Applying the TNM staging system, the authors demonstrated a median survival time for stage I/II patients of 10.8 years (95% CI, 6.9 years to 12.0 years) compared with a median survival of 1.3 years (95% CI, 1.1 years to 1.9 years; log-rank P<.0001) for patients with advanced disease (stages III and IV). CONCLUSIONS: Stage at presentation by the TNM staging system proved to be the main predictor of outcome after surgery for urachal cancer. Better systemic modality treatments are needed for advanced stages of this disease.

A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors.

CS-682 (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N4-palmitoylcytosine) is a novel orally administered 2'-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3-4) were seen more frequently with 10 patients experiencing grade 3-4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 +/- 0.9 h after drug administration and the terminal elimination half-life was 1.7 +/- 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 +/- 0.31 h, peak plasma concentrations were achieved 3.1 +/- 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 +/- 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m2/day for 4 weeks repeated after a 2-week rest period.

Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone.

PURPOSE: Palliation of bone pain can be achieved in men with androgen-independent prostate cancer treated with docetaxel and estramustine (DE) or mitoxantrone and prednisone (MP). While Southwest Oncology Group trial 99-16 demonstrated a survival improvement of DE over MP, the study also was designed to compare the palliation of disease-related symptoms. METHODS: Pain palliation and global quality of life (QOL) were the two primary patient-reported outcomes. Pain was measured with the Present Pain Intensity scale of the McGill Pain Questionnaire-Short Form. The European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (QLQ-C30) and its Prostate Cancer Module (PR25) measured QOL and symptom status. Pain and analgesic use were measured at random assignment, every cycle for eight cycles, and 1 year from random assignment; the QLQ-C30 and the PR25 were administered at random assignment, before cycle four (week 10) and cycle eight (month 6) and at 1 year. In addition to the primary intent-to-treat, missing at random analysis, sensitivity analyses were performed to assess robustness of global QOL conclusions under alternative informative missing data assumptions. RESULTS: Six hundred seventy four eligible patients received DE (n = 338) or MP (n = 336). In an intention-to-treat analysis, median overall survival was 17.5 months for the DE arm and 15.6 months for the MP arm (P = .02). There were no statistically significant differences in pain palliation between the treatment arms. The sensitivity analyses showed a consistent lack of statistically significant global QOL differences for the two arms. CONCLUSION: DE had superior clinical efficacy (overall survival, time-to-progression, and prostate-specific antigen declines) with similar global QOL and pain palliation in the MP arm.

Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16.

BACKGROUND: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. METHODS: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. RESULTS: Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. CONCLUSIONS: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

Phase II study of gemcitabine plus cisplatin in patients with metastatic breast cancer: a North Central Cancer Treatment Group Trial.

BACKGROUND: This 2-stage, phase II cooperative group trial examined the efficacy and toxicity of 1000 mg/m2 gemcitabine plus 25 mg/m2 cisplatin weekly for 3 weeks and repeated every 28 days for patients with previously treated metastatic breast cancer. METHODS: Eligible patients had to have measurable metastatic disease. Progression on prior treatment with at least 1 chemotherapy program for metastatic disease and 1 prior anthracycline and/or taxane-containing regimen in either the metastatic or adjuvant setting was required. Patients who had received more than 2 chemotherapy treatments were not eligible for this study. RESULTS: Fifty-eight eligible patients were entered on this 2-stage study. A 38% incidence of grade 4 thrombocytopenia observed in the first stage of accrual required lowering the chemotherapy doses to 800 mg/m2 gemcitabine plus 20 mg/m2 cisplatin weekly for the first 3 weeks of a 4-week cycle during the second stage of the study. The overall response rate was 29% (95% confidence interval [CI], 11-52%) among patients receiving the original study dose and 32% (95% CI, 18-50%) for patients receiving the lower dose. In the original- and lower-dose groups, median time to progression was 30.7 weeks (95% CI, 12.7-43.4 weeks) and 26.0 weeks (95% CI, 19.0-32.1 week), respectively. Median survival of the original- and low-dose groups was 67.9 weeks (95% CI, 42.3-90.6 weeks) and 54.1 weeks (95% CI, 41.6-73.6 weeks), respectively. Hematologic toxicities were more manageable in the lower-dose group, whereas the nonhematologic toxicity profile was similar in the 2 dose groups. CONCLUSIONS: The response rate of this combination of gemcitabine and cisplatin is similar to that reported by other investigators but may not differ substantially from reports with single-agent gemcitabine in this patient population. The original dose level we used had unacceptable toxicity, which required lowering the doses of both gemcitabine and cisplatin by 20% to achieve acceptable toxicity and preserve clinical activity.

Intratumoral administration of a 1,2-dimyristyloxypropyl-3- dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidylethanolamine formulation of the human interleukin-2 gene in the treatment of metastatic renal cell carcinoma.

BACKGROUND: Leuvectin (Vical Inc., San Diego, CA) is a gene transfer product in which a plasmid encoding the human interleukin-2 (IL-2) gene is complexed with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). In the current study, the authors investigated the safety and efficacy of in situ vaccination with Leuvectin in patients with metastatic renal cell carcinoma. METHODS: Thirty-one patients with metastatic renal cell carcinoma were treated with intratumorally administered Leuvectin at doses ranging from 0.75 to 4 mg. These patients subsequently were evaluated for response and for treatment-related toxicity. RESULTS: Treatment was well tolerated: no Grade 3 or 4 toxicities were observed in association with the study agent. Documented side effects included Grade 1 pain at the injection site (20%); mild (i.e., Grade 1 or 2) constitutional symptoms, including malaise/myalgia, low-grade fever, and chills (74%); Grade 1 fatigue (19%); Grade 1 or 2 nausea (10%); and Grade 2 allergy (1 occurrence). Two patients experienced partial responses, which endured for 32 months and 6 years, respectively, and 1 patient currently is experiencing a pathologic complete response, which, to date, has persisted for 50 months; thus, the overall response rate was 10%. In addition, 7 patients (23%) experienced disease stabilization for a median of 8 months (range, 4-48 months). The median duration of survival from the start of Leuvectin treatment was 11 months (range, 2-72 months), with a 1-year survival rate of 48% and a 3-year survival rate of 19%. Laboratory analysis of tumor samples revealed the presence of IL-2 plasmid DNA in six of eight patients posttreatment, increased IL-2 expression in tumor cells in four of eight patients posttreatment, and increased tumor infiltration by CD8-positive lymphocytes in five of eight patients posttreatment. CONCLUSIONS: Immunotherapy with intratumorally administered Leuvectin is safe and can lead to durable objective responses in patients with metastatic renal cell carcinoma.

Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial.

BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in American men, yet treatment of its metastatic androgen-independent form remains inadequate. This mandates development of new therapies such as immunotherapy. In this Phase 2 trial, we determined the efficacy of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein containing prostatic acid phosphatase (PAP) and GM-CSF. METHODS: We enrolled 21 patients with histologically documented androgen-independent prostate carcinoma that could be evaluated by radionuclide bone scan or computed tomography scan. APC8015 was prepared from a leukapheresis product; it contained autologous CD54-positive PA2024-loaded APCs with admixtures of monocytes, macrophages, B and T cells. APC8015 was infused intravenously twice, 2 weeks apart. Two weeks after the second infusion, patients received three subcutaneous injections of 1.0 mg of PA2024 1 month apart. We monitored patients' physical condition, immune response, and laboratory parameters. RESULTS: Nineteen patients could be evaluated for response to treatment. The median time to progression was 118 days. Treatment was tolerated reasonably well; most adverse effects were secondary to APC8015 and were NCI Common Toxicity Criteria Grade 1-2. Four of the 21 patients reported Grade 3-4 adverse events. Two patients exhibited a transient 25-50% decrease in prostate-specific antigen (PSA). For a third patient, PSA dropped from 221 ng/ml at baseline to undetectable levels by week 24 and has remained so for more than 4 years. In addition, this patient's metastatic retroperitoneal and pelvic adenopathy has resolved. PBMC collected from patients for at least 16 weeks proliferated upon in vitro stimulation by PA2024. For the patient with responsive disease, PBMC could be stimulated for 96 weeks. CONCLUSIONS: This study demonstrates a definite clinical response of androgen-independent prostate cancer to APC immunotherapy. Currently we are studying this mode of therapy in Phase 3 trials.

A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma.

BACKGROUND: Recent laboratory and epidemiologic studies have suggested that green tea has antitumor effects in patients with prostate carcinoma. This Phase II trial explored green tea's antineoplastic effects in patients with androgen independent prostate carcinoma. METHODS: This study, which was conducted by the North Central Cancer Treatment Group, evaluated 42 patients who were asymptomatic and had manifested, progressive prostate specific antigen (PSA) elevation with hormone therapy. Continued use of luteinizing hormone-releasing hormone agonist was permitted; however, patients were ineligible if they had received other treatments for their disease in the preceding 4 weeks or if they had received a long-acting antiandrogen therapy in the preceding 6 weeks. Patients were instructed to take 6 grams of green tea per day orally in 6 divided doses. Each dose contained 100 calories and 46 mg of caffeine. Patients were monitored monthly for response and toxicity. RESULTS: Tumor response, defined as a decline >/= 50% in the baseline PSA value, occurred in a single patient, or 2% of the cohort (95% confidence interval, 1-14%). This one response was not sustained beyond 2 months. At the end of the first month, the median change in the PSA value from baseline for the cohort increased by 43%. Green tea toxicity, usually Grade 1 or 2, occurred in 69% of patients and included nausea, emesis, insomnia, fatigue, diarrhea, abdominal pain, and confusion. However, six episodes of Grade 3 toxicity and one episode of Grade 4 toxicity also occurred, with the latter manifesting as severe confusion. CONCLUSIONS: Green tea carries limited antineoplastic activity, as defined by a decline in PSA levels, among patients with androgen independent prostate carcinoma.