John McCaffrey

Long-Term Survival in Metastatic Transitional-Cell Carcinoma and Prognostic Factors Predicting Outcome of Therapy

PURPOSE The variation in reported survival of patients with metastatic transitional-cell carcinoma (TCC) treated with systemic chemotherapy may be a consequence of pretreatment patient characteristics. We hypothesized that a prognostic factor-based model of survival among patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy could account for such differences and help guide clinical trial design and interpretation. PATIENTS AND METHODS A database of 203 patients with unresectable or metastatic TCC was retrospectively subjected to a multivariate regression analysis to determine which patient characteristics had independent prognostic significance for survival. Patients were assigned to three risk categories depending on the number of unfavorable characteristics. Patient selection in phase II studies was addressed by developing a table of expected median survival for patient cohorts that had varying proportions of patients from the three risk categories. RESULTS Two factors had independent prognosis: Karnofsky performance status (KPS) less than 80% and visceral (lung, liver, or bone) metastasis. Median survival times for patients who had zero, one, or two risk factors were 33, 13.4, and 9.3 months, respectively (P =.0001). The median survival time of patient cohorts could vary from 9 to 26 months simply by altering the proportion of patients from different risk categories. CONCLUSION The presence of baseline KPS less than 80% or visceral metastasis has an impact on survival. Reporting the proportion of patients with zero, one, and two risk factors will facilitate understanding of the relevance of the median survival in phase II trials. Phase III trials should stratify patients according to the number of risk factors to avoid imbalance in treatment arms.

Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival.

PURPOSE To evaluate the efficacy and toxicity of ifosfamide- and cisplatin-containing chemotherapy as first-line salvage treatment for patients with germ cell tumors (GCT). PATIENTS AND METHODS Fifty-six patients with advanced GCT resistant to one prior cisplatin-containing regimen were treated with a salvage chemotherapy regimen of ifosfamide, cisplatin, and either vinblastine or etoposide (VeIP/VIP). RESULTS Twenty of 56 (36%) assessable patients achieved a complete response (CR). Thirteen (23%) are alive and continuously free of disease at a median follow-up time of 52 months; the median survival duration was 18 months. Among patients with a testis primary tumor site and a prior CR to first-line therapy, 65% are alive and 41% continuously disease-free, and the median survival time has not been reached. In contrast, for patients with an extragonadal primary tumor or with a testis primary tumor site and an incomplete response (IR) to first-line therapy, 31% are alive and 15% continuously free of disease, with a median survival time of 12 months (P < .03). CONCLUSION Ifosfamide- and cisplatin-containing therapy achieves a durable CR in a minority of patients with resistant GCT as first-line therapy. Patients with a primary testis site who relapsed from a CR to first-line cisplatin therapy have a better prognosis than patients with an extragonadal primary tumor site or an IR to first-line therapy. Risk-directed clinical trials to improve response and survival in both subsets are warranted.

Outcome of Postchemotherapy Surgery After Treatment With Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients With Unresectable or Metastatic Transitional Cell Carcinoma

PURPOSE The role of postchemotherapy surgery for patients with metastatic transitional cell carcinoma (TCC) is controversial. We retrospectively analyzed our experience with patients who underwent postchemotherapy surgery after methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy to assess an impact on long-term survival. PATIENTS AND METHODS This report is based on the retrospective analysis of 203 patients with unresectable primary tumors or metastatic TCC, previously reported in five trials of M-VAC chemotherapy. Fifty patients underwent postchemotherapy surgery for suspected or known residual disease. Characteristics of patients selected for surgery, results of surgery, and the impact of surgery on survival were assessed. RESULTS In 17 patients, no viable tumor was found at postchemotherapy surgery, pathologically confirming a complete response to chemotherapy. Three patients had unresectable residual TCC. In 30 patients, residual, viable TCC was completely resected, which resulted in a complete response to chemotherapy plus surgery. Ten (33%) of these 30 patients remained alive at 5 years, similar to results observed for patients who attained a complete response to chemotherapy alone (41%). Analysis by baseline extent of disease suggested that patients with unresectable primary tumors or with metastases restricted to lymph node sites were most likely to survive for 5 years. CONCLUSION Postchemotherapy surgical resection of residual cancer may result in 5-year disease-free survival in some patients who would otherwise succumb to disease. Optimal candidates include patients whose prechemotherapy sites of disease are restricted to the primary or lymph node sites and who have a major response to chemotherapy.

Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial

BACKGROUND Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. METHODS In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. FINDINGS Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]). INTERPRETATION The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. FUNDING Bristol-Myers Squibb.

2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial

BACKGROUND Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING Sanofi.

Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial.

PURPOSE A phase II trial of ifosfamide, paclitaxel, and cisplatin (ITP) was conducted in previously untreated patients with advanced transitional-cell carcinoma (TCC) to assess its efficacy and toxicity. PATIENTS AND METHODS Thirty patients with metastatic or unresectable TCC were treated with ifosfamide 1.5 g/m2/d for 3 days with paclitaxel 200 mg/m2 over 3 hours and cisplatin 70 mg/m2 on day 1 of each 28-day treatment cycle. Therapy was continued for a maximum of six cycles. Prophylactic hematopoietic growth factor (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was given on days 6 to 17 of each cycle. RESULTS Twenty-three of 29 assessable patients (79%; 95% confidence interval [CI], 60% to 92%) demonstrated a major response (six complete [CR] and 17 partial [PR]) with response durations that ranged from 5 to 24+ months. Five patients with T4 bladder primary tumors had a major response, two with pathologic CR. At a median follow-up duration of 17.9 months, nine (31%) patients remain disease-free (range, 10+ to 24+). Hematologic toxicity included anemia, thrombocytopenia, and neutropenia; febrile neutropenia was observed in 17% of patients and 4% of cycles. No grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, allergy (3%), renal insufficiency (13%), and neuropathy (10%). Dose reductions or drug omissions were necessary for adverse events in seven (23%) patients. CONCLUSION ITP is an active, well-tolerated regimen in previously untreated patients with TCC of the urothelial tract. Further study of this regimen in patients with both TCC and non-transitional-cell urothelial tumors is ongoing.

Low-Volume Nodal Metastases Detected at Retroperitoneal Lymphadenectomy for Testicular Cancer: Pattern and Prognostic Factors for Relapse

PURPOSE To determine the incidence, pattern, and predictive factors for relapse in patients with low-volume nodal metastases (stage pN1) at retroperitoneal lymphadenectomy (RPLND) and identify who may benefit from chemotherapy in the adjuvant or primary setting. PATIENTS AND METHODS Fifty-four patients with testicular nonseminomatous germ cell tumor had low-volume retroperitoneal metastases (pathologic stage pN1, 1997 tumor-node-metastasis classification) resected at RPLND, 50 of whom were managed expectantly without adjuvant chemotherapy. The dissection was bilateral in 12 and was a modified template in 38 patients. Retroperitoneal metastases were limited to microscopic nodal involvement in 14 patients. Follow-up ranged from 1 to 106 months (median, 31.4 months). RESULTS Eleven patients (22%) suffered a relapse at a median follow-up of 1.8 months (range, 0.6 to 28 months). The most frequent form of recurrence was marker elevation in nine (18%) patients. Persistent marker elevation after orchiectomy and before retroperitoneal lymphadenectomy was a significant independent predictor of relapse (relative risk, 8.0; 95% confidence interval, 2.3 to 27.8; P =.001). Four of five (80%) patients with elevated markers (alpha-fetoprotein alone in three, alpha-fetoprotein and beta human chorionic gonadotropin in one) suffered a relapse, compared with seven of 45 (15.6%) patients with normal markers. CONCLUSION Clinical stage I and IIA patients with normal markers who have low-volume nodal metastases have a low incidence of relapse and can be managed by observation only if compliance can be assured. In contrast, patients with elevated markers before retroperitoneal lymphadenectomy have a high rate of relapse and should be considered for primary chemotherapy.

The fate of chemoresistance in triple negative breast cancer (TNBC)

Background Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. Scope of Review How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. Major conclusions Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. General Significance Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy.

Phase I evaluation of sequential doxorubicin + gemcitabine then ifosfamide + paclitaxel + cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract

PURPOSE This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.

Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial.

LBA8 Background: SRC kinases may contribute to androgen independence of mCRPC.Dasatinib (DAS) inhibits tyrosine kinases including SRC kinases with preclinical evidence for antimetastatic activity, inhibition of osteoclast function in tumor microenvironment, and synergistic activity with docetaxel (D). In phase I/II trials of mCRPC patients (pts), DAS in combination with D had an acceptable safety profile with objective response rates (ORR) improved over historical data and decreased levels of bone turnover markers. METHODS READY was a multinational, randomized, double-blinded, placebo-controlled, phase III study. Pts with mCRPC (n = 1,522) were randomized (1:1) to receive either D 75 mg/m2q3wk + prednisone with double-blinded DAS 100 mg qd (DAS/D, n = 762) or placebo (PBO/D, n = 760). Primary endpoint was overall survival (OS). Secondary endpoints were ORR, time to first skeletal-related event (TFSRE), time to prostate-specific antigen progression (TPSAP), urinary N-telopeptide (uNTX) reduction, pain reduction, progression-free survival (PFS), and safety. RESULTS No OS difference between DAS/D and PBO/D (median, 21.5 vs. 21.2 mos; hazard ratio [HR], 0.99; log-rank P = 0.90) was observed. Results of secondary endpoints for DAS/D vs. PBO/D were: ORR (30.5 vs. 31.9%); TFSRE (median, not reached vs. 31.1 mos; HR, 0.81 [95% CI, 0.64-1.02]); uNTX reduction (66.0 vs. 60.6%); PFS (median, 11.8 vs. 11.1 mos; HR, 0.92); TPSAP (median, 8.0 vs. 7.6 mos; HR, 0.91), and pain reduction (66.6 vs. 71.5%). Twenty-three percent of DAS/D and 14% of PBO/D pts received therapy for <3 mos. Most common AEs in DAS/D arm included diarrhea, fatigue, alopecia, and nausea. Grade 3-4 AEs of interest for DAS/D vs. PBO/D included anemia (8.0 vs.5.9%), neutropenia (6.2 vs. 5.5%), hypocalcemia (3.5 vs.3.1%), GI bleeding (2.6 vs.1.3%), and pleural effusion (1.3 vs. 0.4%). CONCLUSIONS The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS. There was a modest reduction in the risk of TFSRE with DAS/D vs. PBO/D. With a median follow-up of 19 mos of 761 DAS/D-treated pts, no unexpected toxicities for DAS were observed. CLINICAL TRIAL INFORMATION NCT00744497.