Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.

BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive

Differential responses to chemoimmunotherapy in patients with metastatic malignant melanoma.

An open, multicentre non-randomised study was performed to evaluate the activity and toxicity of combination chemoimmunotherapy, consisting of cisplatin, interleukin-2 and interferon-alpha, in metastatic malignant melanoma. Between March 1992 and September 1993, 28 patients with pathologically proven metastatic malignant melanoma, bidimensionally measurable disease and an Eastern Co-operative Oncology Group score < or = 1 were treated with the combination chemoimmunotherapy. The regimen consisted of cisplatin (100 mg/m2 on day 0), interleukin-2 (Proleukin, Chiron, Middlesex, U.K.) 18 x 10(6)IU/m2/d continuous intravenous infusion on days 3-7 and 17-22, with interferon-alpha (Roferon-A, Roche, Hertfordshire, U.K.) 9 x 10(6) U/d subcutaneously on days 3, 5, 7, 17, 19, 21 during the interleukin-2 infusions. The treatment cycle lasted 28 days. Among 27 assessable patients, 5 patients achieved partial responses, for an overall response rate of 18% (95% CI 6-37%). Median progression-free survival was 44 days (range 8-279) and median overall survival was 264 days (range 41-1432). Differential responses were noted in 41% of patients and responses were more frequent in non-visceral disease (skin, lymph node and soft tissue disease) (P = 0.04). These results indicate that differential responses to chemoimmunotherapy are common in patients with metastatic melanoma. This may account for the broad range of response rates reported in the literature.

Comparison of in situ methods to assess DNA cleavage in apoptotic cells in patients with breast cancer.

BACKGROUND: Apoptosis has a role in many cellular processes including development, normal tissue homeostasis, and malignancy. This aspect of research is relatively new with distinct methods of analysing disparate biochemical and genetic events to measure apoptotic cells. The use of biotinylated nucleotides to identify DNA strand breaks is a commonly reported method of estimating cells numbers undergoing apoptosis; however, investigators report inconsistent results for a variety of reasons. AIMS AND METHOD: To compare two in situ techniques of measuring apoptosis: in situ nick translation (ISNT) and TdT mediated dUTP-biotin nick end labelling (TUNEL); and to assess DNA cleavage in 20 paired paraffin wax embedded breast cancer tissues from patients; one group who had received no prior treatment and one group who had received chemohormonal treatment. RESULTS AND CONCLUSIONS: Apoptotic scores obtained from paraffin wax embedded human breast cancer after using ISNT and TUNEL methods were not significantly different (p = 0.11). A strong correlation between scores obtained from the two techniques was found (r = 0.758, p < 0.0001). Optimisation of both techniques is crucial to ensure maximal assay performance in breast cancer tissue.

Oral idarubicin as a single agent therapy in patients with relapsed or resistant multiple myeloma.

The established treatment for multiple myeloma (MM) comprises induction with infusional chemotherapy, high dose chemotherapy (HDC) and autologous transplantation followed by maintenance interferon. On relapse, patients (pts) are reconsidered for this however some are unsuitable and in this situation the therapeutic options are limited. Between June 1995 and May 1997, 14 pts with previously treated relapsed or refractory MM were recruited. Using a prospective database, the tolerability and efficacy of chronic low dose oral idarubicin was evaluated. The median age of pts was 63 years. All had received previous anthracycline in the form of infusional cVAMP chemotherapy. 11/14 had received previous HDC. Median time from diagnosis to commencing idarubicin was 77 months. 10 mg idarubicin was administered 3 times/week for 3 weeks of a 5 week cycle. The maximum number of courses was 6. Three pts completed 6 courses, 5 pts 3 courses, 2 pts 2 courses and 4 pts 1 course. The reasons for stopping treatment were death due to progressive disease (PD) in 7 pts, persistent thrombocytopenia in 2 pts, PD in 1 pt and 1 pt suffered a cerebral infarction not considered to be related to the idarubicin therapy. Two pts showed evidence of response, neither amounting to a partial response. One had stabilisation of paraprotein with a reduction in bone marrow infiltration (47% to 7% plasma cells), the other had a reduction in bone marrow infiltration after 3 course but an increase after 6 courses. In total forty-one courses of treatment were administered. Grade 3/4 haematological toxicities were noted in a minor fraction of cases and were as follows: anaemia 6/41, neutropenia 10/41 and thrombocytopenia 11/41. Our data therefore shows a minor response in 2/14 (14%) of heavily pretreated patients with MM, without evidence of severe toxicity. It provides the rationale for using oral idarubicin as either single agent or in combination therapy for patients earlier on in their disease course especially if they are unsuitable for standard therapy.

The importance of dose and schedule in cancer chemotherapy: epithelial ovarian cancer.

Selection of specific appropriate drugs has been facilitated by a series of randomised clinical trials confirmed by overview analysis. Hitherto these issues have dominated the debate over optimal chemotherapy management of advanced ovarian cancer. The impact of true dose escalation therapy is yet to be evaluated but appears to be worthy of examination in demonstrably chemosensitive disease.

The immune response to breast cancer, and the case for DC immunotherapy.

The long-held belief that breast cancer is a weakly immunogenic tumor and a poor candidate for immunotherapy should be reappraised. There is ample evidence for the existence of an immune response, which is, however, attenuated by multiple inhibitory factors. Many tumor-associated antigens (TAA) have been identified in breast cancer, some of which appear to play a critical role in tumorigenesis and may be attractive targets for immunotherapy. There is evidence for DC recruitment and activation within breast cancers, and the presence of intratumoral activated DCs impacts favorably upon survival. Furthermore, there is a striking paucity of activated DCs within the primary draining or sentinel lymph nodes of breast cancers. Tumor infiltrating lymphocytes (TIL) are often documented, however, their function is impaired by inhibitory cytokines, increased regulatory T lymphocyte activity, tumor cell MHC molecule alterations, and aberrant Fas ligand expression, amongst others. DCs are recognized as one of the critical interfaces between a cancer and the immune system, and have emerged as a promising platform for cancer vaccination via ex vivo immunomodulation. Clinical evaluation of DC vaccination in breast cancer is still relatively limited, although evolving. This article details evidence for the immune response in breast cancer and its many failings, and reviews the clinical trials and significant preclinical data which, taken together, validate the concept of DC vaccination in breast cancer.

Continuous infusional topotecan in advanced breast and non-small-cell lung cancer: no evidence of increased efficacy.

Two open, phase II studies were performed to evaluate the activity and toxicity of infusional topotecan in patients with advanced non-small-cell lung carcinoma (NSCLC) and advanced breast cancer who had not received previous chemotherapy for metastatic disease. Twenty-five patients with an ECOG performance score < 2 were treated with infusional topotecan administered as a daily, continuous intravenous infusion starting at 0.6 mg m(-2) day(-1) (NSCLC) and 0.5 mg m(-2) day(-1) (breast cancer) for 21 days every 4 weeks. Three patients achieved a partial response as defined by WHO criteria: one with NSCLC (8%; 95% CI 0-39%) and two with advanced breast cancer (15%; 95% CI 2-45%). The major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic sepsis. These data suggest that topotecan delivered as a continuous intravenous infusion over 21 days as single-agent therapy does not appear to offer a clinical advantage over conventional 5-day schedules against advanced NSCLC and advanced breast cancer.

Analysis and sorting of apoptotic cells from fine-needle aspirates of excised human primary breast carcinomas.

Numerous recent studies have indicated the central role of apoptosis as a determinant of the growth abnormalities occurring with malignancy and of the effectiveness of a wide range of therapeutic manoeuvres in cancer treatment. However, there has been a relative paucity of studies measuring apoptosis in human solid tumours, because of the low incidence of apoptotic cells, the difficulty of identifying cells undergoing apoptosis, and the ethical and practical restrictions on obtaining repeat biopsies from patients during therapy. Fine-needle aspirates (FNAs) may be obtained from breast carcinomas as a minimally invasive technique allowing repeat sampling. We describe an approach in which the in situ end labelling (TUNEL) assay is applied to cells in FNAs prior to their analysis by flow cytometry, which allows many thousands of cells to be analysed automatically by objective criteria. Cells that were discriminated as apoptotic on flow cytometric analysis were sorted onto microscope slides and found to show nuclear morphology typical of apoptotic cells. A statistically significant relationship was found between the flow cytometric analysis and the conventional application of TUNEL on histological sections (P = 0.03). Repeat analyses of FNAs from 12 carcinomas showed a median 2.05% apoptotic cells and an overall coefficient of variation of 34.9%. Of the total variability in 12 tumours, 80% was attributed to variation between tumours, 12% between batches, and 8% was random. Thus, this technique should be able to detect the major differences in the percentage of apoptotic cells that occur between different tumours (range 0.3-11.3% by flow cytometry) and between different phases of treatment, and should provide a useful tool for further research on this process in solid tumours.

Mitoxantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high-grade lymphoma: results of a BNLI randomized trial of PAdriaCEBO versus PMitCEBO.

A prospective, multicenter, randomized trial was undertaken to compare the efficacy and toxicity of adriamycin with mitoxantrone within a 6-drug combination chemotherapy regimen for elderly patients (older than 60 years) with high-grade non-Hodgkin lymphoma (HGL) given for a minimum of 8 weeks. A total of 516 previously untreated patients aged older than 60 years were randomized to receive 1 of 2 anthracycline-containing regimens: adriamycin, 35 mg/m(2) intravenously (IV) on day 1 (n = 259), or mitoxantrone, 7 mg/m(2) IV on day 1 (n = 257); with prednisolone, 50 mg orally on days 1 to 14; cyclophosphamide, 300 mg/m(2) IV on day 1; etoposide, 150 mg/m(2) IV on day 1; vincristine, 1.4 mg/m(2) IV on day 8; and bleomycin, 10 mg/m(2) IV on day 8. Each 2-week cycle was administered for a minimum of 8 weeks in the absence of progression. Forty-three patients were ineligible for analysis. The overall and complete remission rates were 78% and 60% for patients receiving PMitCEBO and 69% and 52% for patients receiving PAdriaCEBO (P =.05, P =.12, respectively). Overall survival was significantly better with PMitCEBO than PAdriaCEBO (P =.0067). However, relapse-free survival was not significantly different (P =.16). At 4 years, 28% of PAdriaCEBO patients and 50% of PMitCEBO patients were alive (P =.0001). Ann Arbor stage III/IV, World Health Organization performance status 2-4, and elevated lactate dehydrogenase negatively influenced overall survival from diagnosis. In conclusion, the PMitCEBO 8-week combination chemotherapy regimen offers high response rates, durable remissions, and acceptable toxicity in elderly patients with HGL.