Letizia Laera

The third line of treatment for metastatic prostate cancer patients: Option or strategy?

New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include cabaziataxel (Cbz), abiraterone acetate (AA) and enzalutamide (E). In this review, the results of clinical studies in which one of these drugs is included as the third line of treatment are discussed. Our review suggests that AA and E have limited activity, while Cbz seems to retain its efficacy. Prospective studies that further examine sequential treatments are warranted.

Abiraterone in heavily pretreated patients with metastatic castrate-resistant prostate cancer

The aim of this study was to evaluate the activity and tolerability of abiraterone acetate in patients with metastatic castrate-resistant prostate cancer treated previously with more than three lines of chemotherapy. Patients received 1 g of abiraterone acetate (administered as four 250 mg tablets) orally once daily with prednisone at a dose of 5 mg orally twice daily. The primary endpoint was prostate-specific antigen (PSA) response. From August 2011 to January 2013, 36 patients were enrolled. PSA response was observed in 22 patients (61.1%, 95% confidence interval: 0.41–0.81). The median time to PSA progression was 7.3 months and after a median follow-up of 10.1 months, all patients were alive. The treatment was generally well tolerated; side effects secondary to mineralocorticoid excess resulting from blockade of CYP17 were largely controlled with prednisone. Abiraterone acetate seems to be an effective and well-tolerated treatment option for patients with metastatic castrate-resistant prostate cancer irrespective of the number of chemotherapy lines administered previously.

Low-Dose Estramustine Phosphate and Concomitant Low-Dose Acetylsalicylic Acid in Heavily Pretreated Patients With Advanced Castration-Resistant Prostate Cancer.

BACKGROUND The aim of this phase 2 study was to evaluate the activity and tolerability of low-dose estramustine phosphate (EMP) with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent in heavily pretreated patients with advanced castration-resistant prostate cancer. METHODS Patients received 420 mg of oral EMP twice daily and oral ASA 100 mg once daily. The primary endpoint was prostate-specific antigen response. All of the patients had been previously treated with docetaxel and abiraterone acetate, and 12 had also received cabazitaxel. RESULTS Thirty-one patients were enrolled. Prostate-specific antigen response was observed in 9 patients (29.0%; 95% confidence interval [CI], 14-48). Median progression-free survival was 3.6 months (95% CI, 2.2-5.6), and median overall survival was 7.6 months (95% CI, 6.9-9.7). Treatment was generally well tolerated, and no grade 3/4 toxicity was observed. Ten patients (32.2%) had grade 2 nausea and vomiting. No cardiovascular event and no major bleeding occurred. No venous thromboembolism event was observed. CONCLUSION Low-dose EMP with concomitant low-dose ASA seems to be a safe treatment option with some activity for patients with advanced castration-resistant prostate cancer who have been heavily pretreated.

Role of chemotherapy in the treatment of metastatic castration-resistant prostate cancer patients who have progressed after abiraterone acetate

Abstract Abiraterone acetate is a novel irreversible inhibitor of CYP17 that was recently approved for men with post-chemotherapy or chemo-naive castration-resistant prostate cancer. Unfortunately, this agent is not curative, and patients often ultimately develop resistance. However, men who progress after treatment with this new hormonal agent may be considered for another line of chemotherapy-based treatment. In 2004, docetaxel (D) and prednisone were found to improve survival compared with older regimens. More recently, cabazitaxel (C), a novel taxane chemotherapy, has been found to prolong survival in patients who exhibit disease progression during or after D chemotherapy. Here, we review the first clinical studies in which castration-resistant prostate cancer patients received chemotherapy with D or C after progression during abiraterone acetate treatment.

Cisplatin, Etoposide, and Bevacizumab Regimen Followed by Oral Etoposide and Bevacizumab Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer: A Single-Institution Experience

UNLABELLED Cisplatin and etoposide (PE) is the most used chemotherapy regimen in extensive-stage disease small-cell lung cancer (ED-SCLC), and usually achieves a high initial response rate. An intriguing maintenance strategy could be the combination of the angiogenic agent bevacizumab (Bev) with a convenient and well tolerated chemotherapy agent such as oral etoposide. Results of the current single-institutional phase II study suggest that a regimen that includes conventional PE chemotherapy combined with Bev followed by oral etoposide and Bev as maintenance treatment is feasible and effective in terms of 9-month disease control rate in patients with ED-SCLC. BACKGROUND In the present study we evaluated the efficacy and safety of a cisplatin (P), etoposide (E), and bevacizumab (Bev) regimen followed by maintenance oral E and Bev in patients with extensive-stage disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS Patients were administered 3-day fractionated P 25 mg/m(2) and E 100 mg/m(2) on days 1 to 3, every 3 weeks. After 3 PE cycles, all patients whose disease did not progress continued treatment with PE combined with Bev 15 mg/kg on day 3 every 3 weeks. After completion of 3 PE/Bev cycles, patients who did not experience tumor progression continued maintenance treatment with oral E 50 mg on days 1 to 14 every 21 days combined with Bev 3 times per week until occurrence of disease progression or unacceptable toxicity. RESULTS At our institution, 22 patients were enrolled and their median age was 66 years (range, 38-79 years). After completion of induction chemotherapy (3 PE cycles with 3 PE/Bev cycles) the objective response rate was in 17 patients (77.2%) (95% confidence interval [CI], 54.6-92.1). Twenty-one patients received maintenance treatment with oral E and Bev. The 9-month disease control rate was 8 patients (36.3%). Median progression-free survival was 7.8 months (95% CI, 7.0-11.3 months) and median overall survival was 13.2 months (95% CI, 11.8-18.7 months). Grade 3 to 4 neutropenia occurred in 12 patients (54.4%) and 14 patients (63.6%) of patients during cycles 1 to 3 and cycles 4 to 6 of induction chemotherapy, respectively. Severe adverse events during maintenance treatment were rarely observed. CONCLUSION A PE and Bev regimen followed by oral E and Bev maintenance treatment appears feasible and effective in terms of 9-month disease control rate in patients with ED-SCLC.

Abiraterone in heavily pretreated patients with metastatic castrate-resistant prostate cancer: final analysis of overall survival.

In the April 2014 issue [1], we reported the activity and tolerability of abiraterone acetate (AA) in patients with metastatic castrate-resistant prostate cancer previously treated with more than three lines of chemotherapy; we now report the results of the final analysis of overall survival (OS). In addition, we compared these results with those of patients who had been treated in our institution with AA as a second line after a docetaxel-based chemotherapy progression. This group of consecutive 28 patients, observed between 2011 and 2013, presented characteristics similar to those of the population exposed to AA in our previous study. Their median age was 75 years (range 44–93 years). A total of 24 (85.7%) patients had bone metastases; the median baseline serum prostate-specific antigen (PSA) was 81.25 ng/ml (range 1.2–603.4 ng/ml). The characteristics of two groups of patients are summarized in Table 1.

Tolerability of cabazitaxel in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and abiraterone acetate: a single-institution experience.

Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m2 plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade≥3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients.

Safety of sorafenib therapy in elderly adults with advanced hepatocellular carcinoma.

To the Editor: The incidence of hepatocellular carcinoma (HCC) is increasing worldwide and even more significantly with advancing age, reaching a peak at approximately age 75. Therefore, the proportion of elderly adults with HCC is expected to rise steadily in the coming years. Sorafenib represents the standard of care for individuals with advanced HCC, but data on the safety of this drug in elderly adults is lacking in the literature. Because a cancer treatment in older adults should be evaluated first in terms of tolerability and quality of life and only secondarily in terms of efficacy, it was decided to assess the safety of sorafenib-based therapy in elderly adults with advanced HCC. Therefore, a consecutive cohort of 51 individuals with advanced HCC aged 70 to 83, Child-Pugh A or B, and Eastern Cooperative Oncology Group performance status 0 to 2 who were not suitable candidates for or had progressed after locoregional therapies were retrospectively analyzed. Treatment with single-agent sorafenib at a standard dose of 400 mg was administered twice daily orally after informed consent was obtained. Therapy was continued until disease progression or unacceptable toxicity. Effect of treatment on quality of life and self-sufficiency were evaluated according to the instrumental activity of daily living (IADL) scale at baseline and every clinic visit. Adverse events were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Because the study population was composed of elderly individuals, comorbidities were frequent, with cardiovascular diseases being the most common (72.6%), with hypertension the most represented. The median duration of sorafenib treatment was 217.5 days (~7 months; range 1–48 months). Nonhematological toxicity was reported in all participants, mostly during the first month and of Grade 1 or 2 according to NCI CTCAE version 3.0 grading scale. The most common were hypertransaminasemia (74.5%), fatigue (64.7%), hand–foot syndrome (49.0%), hyperbilirubinemia (49.0%), diarrhea (47.1%), abdominal pain (41.2%), anorexia (29.4%), high blood pressure (11.7%), and nausea (9.8%). The most frequent Grade 3 adverse reactions were fatigue (15.7%), hand–foot syndrome (15.7%), abdominal pain (11.7%), and hyperbilirubinemia (11.7%). Of the six individuals with high blood pressure, who were receiving proper antihypertensive treatment before starting sorafenib, only one interrupted sorafenib therapy because of progressive disease and hypertensive crises; the antihypertensive therapy was modified according to the increases in blood pressure during sorafenib treatment in the remaining five. Hematological toxicity, commonly of Grade 1, was observed as thrombocytopenia in 60.7% of cases, of which 11.7% were Grade 3. No Grade 4 was reported (Table 1). Dose reduction (from 800 to 400 mg/d) due to toxicity was required in 28 individuals (54.9%), mainly because of thrombocytopenia (15.7%). Twenty-four individuals (47.1%) interrupted treatment, mostly because of fatigue (13.7%), thrombocytopenia (11.7%), and diarrhea (11.7%). Data obtained in other studies of sorafenib in elderly adults with cancer confirm these data. As reported in studies of older adults with renal cell carcinoma, those adverse events could be attributable to greater sensitivity of elderly adults than of younger individuals to the drug, although lower efficacy was not described in older adults. In the current study, the disease control rate, which was higher in the first 12 weeks than during the rest of the follow-up, was 45.1%, and partial response was achieved in five individuals over the first 12 weeks and in one individual over the first 24 weeks; furthermore, over the first 48 weeks, partial response was seen in one individual and complete response was obtained and maintained in two individuals for 5 and 4 years, respectively. Finally, stable disease was achieved during treatment in most individuals, as frequently reported in the literature. All participants showed good self-sufficiency (IADL score >5 in 68.6%, median at baseline 5.8 1.7). During treatment, IADL score decreased in 13 patients (25.5%). Mean IADL score was 5.5 2.2 at Day 30, 5.8 2.0 at Day 60, 5.9 1.8 at Day 90, 6.1 1.4 at day 120, and 6.1 1.3 at Day 150, indicating that the observed toxicity only modestly affected the quality of life and selfsufficiency of most participants.

Treatment of advanced oesophagogastric cancer with FOLFOX-4 regimen followed by leucovorin/bolus and continuous infusion 5-FU as maintenance chemotherapy in patients aged ≥75 years with impaired performance status

OBJECTIVES To evaluate the efficacy and safety of FOLFOX-4 combination chemotherapy, followed by leucovorin (LV)/bolus and continuous infusion 5-fluorouracil (5-FU) as maintenance chemotherapy in elderly (≥ 75 years) patients with advanced oesophagogastric cancer with impaired performance status (PS). MATERIALS AND METHODS Patients with a PS score >1 were included in this study. PS evaluations were performed by a geriatrician and two medical oncologists. FOLFOX-4 consisted of oxaliplatin concurrently with LV/bolus and continuous infusion 5-FU every 2 weeks. After a maximum of six FOLFOX-4 cycles, patients with no evidence of disease progression received maintenance treatment with LV/bolus and continuous infusion 5-FU every 2 weeks until disease progression or unacceptable toxicity. RESULTS Thirty-eight patients were enrolled in this study. Of these, 32 (84.2%) patients had a PS score of 2 and six (15.7%) patients had a PS score of 3. After completion of FOLFOX-4, 18 (47.3%) patients achieved a partial response and 14 (36.8%) patients had stable disease. Thirty-two patients (84.2%) received maintenance chemotherapy for a median of eight cycles (range one to 26 cycles). The 6-month disease-control rate was 47.3% [95% confidence interval (CI) 30.9-64.1]. The median progression-free survival was 5.9 months (95% CI 4.7-6.8) and the median overall survival was 9.6 months (95% CI 8.1-11.7). Grade 3 neutropenia occurred in six patients (15.7%), and Grade 3 anaemia and thrombocytopenia occurred in two patients (5.2%). CONCLUSION FOLFOX-4 followed by LV/bolus and continuous infusion 5-FU as maintenance chemotherapy seems to be an active and well-tolerated first-line treatment strategy for elderly patients with advanced oesophagogastric cancer and impaired PS.

Maintenance treatment with oral cyclophosphamide and bevacizumab in patients with recurrent epithelial ovarian cancer

AIM To evaluate the efficacy and safety of maintenance treatment with oral cyclophosphamide (Cy) and bevacizumab (Bev) in patients with recurrent ovarian cancer. PATIENTS & METHODS Induction treatment consisted of cisplatin, epirubicin, Cy and Bev every 3 weeks, for a maximum of six cycles. Maintenance treatment consisted of oral Cy 50 mg, days 1-14 and Bev 15 mg/kg, every 3 weeks until disease progression occurred. RESULTS In total, 39 patients were enrolled: after induction chemotherapy, the objective response was 74.3%. The median progression-free survival was 13.3 months, and the median overall survival was 33.2 months. Toxicity during maintenance treatment was mild. CONCLUSION Maintenance with Cy and Bev may achieve encouraging results in terms of progression-free survival and overall survival in recurrent ovarian cancer patients.