Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial.

BACKGROUND: An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS: Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 µg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS: From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION: The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING: New York University School of Medicine's Department of Radiation Oncology and Cancer Institute.

An update on targeted therapy in metastatic renal cell carcinoma.

An improved understanding of the biological pathways deregulated in renal cell carcinoma has led to the development of various targeted agents, changing dramatically the therapeutic options for this disease. However, despite numerous opinions and guidelines, the optimal treatment still remains uncertain. In this review, we analyze the most recent published reports regarding the agents sunitinib, bevacizumab, sorafenib, temsirolimus, and everolimus. Moreover, we assess the novel targeted drugs pazopanib and axitinib. In addition, given the likely lack of cross-resistance between these targeting agents, we discuss sequential and combination targeted therapy in metastatic renal cell carcinoma, analyzing the most recent data.

Intrapleural paclitaxel for malignant pleural effusion from ovarian and breast cancer: a phase II study with pharmacokinetic analysis.

INTRODUCTION: Malignant pleural effusion (MPE) is a frequent complication in many types of tumors diminishing the patient's ability to perform activities. Despite various studies on talc treatment, some doubts about its safety and effectiveness remain, so the search for a more ideal intrapleural agent continues. We analyzed the effectiveness and safety of intrapleural paclitaxel in ovarian and breast cancer patients. PATIENTS AND METHODS: The primary endpoint was overall response rate (ORR); secondary objectives included time to progression (TTP), overall survival (OS) and safety of intrapleural paclitaxel. Pharmacokinetics of the drug was also analyzed. After drainage of pleural effusion and lung re-expansion, paclitaxel 120 mg/m(2) diluted in normal saline was infused through a preinserted catheter which was immediately closed and reopened 24 h later. Blood and pleural fluid samples were collected 1, 4 and 24 h after the end of paclitaxel instillation. When MPE was less than 200 ml/24 h the catheter was removed. Chest radiographs were performed at the beginning of intrapleural paclitaxel, at 1 and 2 months later or with clinical deterioration. RESULTS: We enrolled 18 patients with recurrent MPE: 11 with ovarian cancer and 7 with breast cancer. ORR was 77.8% at 1 month and 88.8%. at 2 months. Median TTP was 5.5 months (CI 95% 0.9-10.1) and median OS was 8.9 months (CI 95% 0.1-17.6). Patients achieving a complete response obtained a statistically significant longer survival than did patients with partial response or progressive disease. Chest pain, fever, and dyspnea were the most frequent side effects. Intrapleural paclitaxel concentrations were very high (mean ± SD = 478 ± 187 mg/l) and declined slowly (mean 24 h reduction ~30%). Detectable but low taxol plasma levels were found in most patients (mean ± SD = 0.045 ± 0.073 mg/l). CONCLUSION: Intrapleural paclitaxel is a safe and effective palliative treatment for MPE from breast and ovarian cancers and may be integrated with systemic chemotherapy.

BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin.

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.

The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico.

In Mexico, breast cancer is the leading cancer-related death among women and most cases are diagnosed at advanced stages (50-60%). We hypothesized health system factors could be partly responsible for this delay and performed a prospective review of 166 new breast cases at a major public hospital in Mexico City. Our analysis confirmed the prevalence of locally advanced and metastatic disease (47% of patients). A subset analysis of 32 women with confirmed stage I-IIIC breast cancer found an average time interval of 1.8 months from symptom onset to first primary care consultation (PCC), with an additional 6.6 months from first PCC to confirmed diagnosis, and 0.6 months from diagnosis to treatment initiation. Patients underwent an average of 7.9 clinic visits before confirmed diagnosis. Findings suggest that protracted referral time from primary to specialty care accounts for the bulk of delay, with earlier stage patients experiencing longer delays. These findings reveal a critical need for further study and exploration of interventions.

Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma: results of a phase 2 study.

BACKGROUND: Over the years, doxorubicin and gemcitabine have been among the most widely used drugs for hepatocellular carcinoma (HCC), with relative efficacy. The authors report the results of a phase 2 study of the combination of gemcitabine plus pegylated liposomal doxorubicin. METHODS: Patients with advanced HCC received combination chemotherapy with gemcitabine 1000 mg/m² on Days 1 and 8, followed by pegylated liposomal doxorubicin 30 mg/m² on Day 1. Treatment was repeated every 4 weeks to a maximum of 8 cycles. Primary endpoint was overall response rate, and secondary endpoints were time to disease progression (TTP), overall survival (OS), and toxicity. RESULTS: Forty-one patients were enrolled and were evaluable for response, toxicity, and survival. A total of 194 cycles of treatment were administered. Three (7%) patients had a complete response, and 1 of these patients underwent liver transplantation. Seven (17%) patients had a partial response and, among these patients, 1 patient underwent surgical resection. Among the 31 patients who had initial alpha-fetoprotein levels >400 ng/mL, 20 (64.5%) had a >20% decrease after 2 cycles of treatment. The median TTP and OS were 5.8 and 22.5 months, respectively. Hematologic toxicity was the most common side effect, including neutropenia (17%) and anemia (7%). CONCLUSIONS: The combination of gemcitabine plus pegylated liposomal doxorubicin was active and safe in advanced HCC. Moreover, this treatment induced some complete responses and converted some untreatable HCCs into lesions eligible for resection or transplantation.

Tolerability of PLD/oxaliplatin regimen in recurrent ovarian cancer patients with previous fragility to carboplatin/paclitaxel treatment.

OBJECTIVES: This retrospective analysis aims at describing the safety profile of treatment with pegylated liposomal doxorubicin (PLD) and oxaliplatin in recurrent ovarian cancer patients who experienced myelotoxicity (principally neutropenia) during first line chemotherapy with carboplatin and paclitaxel. METHODS: We reviewed the medical records of patients with relapsed ovarian cancer treated with PLD/Oxaliplatin at the Istituto Oncologico Veneto (IOV)/IRCCS, Padua University between 2002 and 2008. RESULTS: A cohort of 16 patients who developed myelodepression and other toxicities of grade 3 to grade 4 during first line chemotherapy with carboplatin/paclitaxel, were selected for this retrospective study. Patients had developed predominantly grade 3 to grade 4 neutropenia and grade 1 to grade 3 thrombocytopenia as major toxicities during primary chemotherapy with carboplatin and paclitaxel. Following relapse or disease progression, PLD/oxaliplatin chemotherapy was administered at 30 to 35 and 70 mg/m(2), respectively, over 2 day, every 4 weeks. CONCLUSIONS: Complete regression and stabilization of bone marrow suppression and no allergic reactions were seen with PLD/oxaliplatin treatment. The estimated median overall survival was 51.2 months. PLD/oxaliplatin chemotherapy did not show hematological toxicity and was feasible and active in this group of pretreated frail patients.

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival.

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m² intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response.

Combined use of biomarkers for detection of ovarian cancer in high-risk women.

The aim of this study was to examine the negative predictive value for a panel of serum markers in women at high risk for developing ovarian cancer. A total of 201 serum samples were collected and analyzed from 102 women at "high risk" for ovarian cancer: 26 with primary ovarian cancer, 31 with recurrent ovarian cancer, 28 with benign gynecologic diseases, and 14 with other cancers. Samples were tested for cancer antigen (CA) 125 II, CA19-9, CA72-4, CA15-3, and macrophage colony-stimulating factor, OVX1, and the marker values were further used as input to be evaluated by a previously trained artificial neural network (ANN). CA125 alone identified 72% of the primary ovarian cancers at a specificity of 95%. If either CA125 or CA72-4 were elevated, sensitivity rose to 80%. Adding macrophage colony-stimulating factor-improved sensitivity to 84% and when CA15-3 was included, a sensitivity of 88% was achieved. Specificity of the four marker panel was, however, reduced to 82.5%. By contrast, at the same sensitivity of 88%, the ANN exhibited a much higher specificity at 92.5% (p = 0.0105). Our data suggest that the combined use of multiple biomarkers improve sensitivity in women at high risk for ovarian cancer. In contrast to the simple "or" combination rule, the ANN was able to achieve a higher sensitivity without significant loss in specificity.

Positive experience of intraperitoneal chemotherapy followed by intravenous chemotherapy in heavily pretreated patients with suboptimal residual ovarian cancer and primary peritoneal cancer.

AIMS AND BACKGROUND: To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. METHODS: Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. RESULTS: Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). CONCLUSIONS: Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.

Good response to second-line bevacizumab and interferon-alpha in a sunitinib-refractory patient with metastatic renal cell carcinoma.

In recent years with the development of targeted agents such as bevacizumab, sunitinib, sorafenib, temsirolimus, and everolimus, the treatment of metastatic renal cell carcinoma has changed dramatically. In clinical practice, sunitinib and bevacizumab are reserved for first-line treatment, but despite various guidelines, optimal treatment is still uncertain. We present, for the first time, a case of a good response to second-line bevacizumab and interferon-alpha in a patient who failed classical sunitinib treatment.

Diagnosis and treatment of malignant pleural effusion: a systematic literature review and new approaches.

Malignant pleural effusion is a frequent complication in many types of tumors, and its presence indicates short expected survival. This review updates the current knowledge about diagnosis and management of malignant pleural effusion. In recent years, progress has been made in diagnosis through the use of new pathologic and radiologic approaches, such as the introduction of positron emission tomography-computed tomography, immunohistochemical marker combinations, and genetic studies to identify malignant cells. Treatment is always palliative. New promising drugs have been tested, but, awaiting randomized studies, talc pleurodesis is still the treatment of choice, although doubts remain about its safety. A long-term indwelling pleural catheter could be a valid alternative to talc pleurodesis in selected patients with trapped lung syndrome (a lung that fails to reexpand after drainage of pleural effusion) and short life expectancy. However, the correct treatment depends on several factors such as performance status, expected survival, presence of lung reexpansion following pleural drainage and comorbidities.

Family history of cancer rather than p53 status predicts efficacy of pegylated liposomal doxorubicin and oxaliplatin in relapsed ovarian cancer.

BACKGROUND: The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations. METHODS: Seventy-two women received a median of 7.5 courses of PLD at 30 to 35 mg/m2 plus oxaliplatin at 70 mg/m2, and associations between BRCA1/2 and TP53 status and overall survival (OS) were determined. Thirty-eight had a short platinum-free interval (PFI; <12 months), and 34 had a long PFI (> or =12 months). RESULTS: Nine patients had BRCA1 mutations, and 1 had a BRCA2 mutation. Platinum sensitivity was associated with OS (P = 0.0001). At a median follow-up of 9.3 months, objective response rate, median time to progression, and OS were 47.3%, 5.8 months, and 12.9 months, respectively, in short PFI compared with the 76.5%, 11.5 months, and 47.7 months in long PFI. p53 status did not correlate to these parameters. The median time to progression was 11.5 months for high-risk patients versus 6.5 months for patients with sporadic cancer (P = 0.0188), and the median OS from the start of treatment was 48.7 and 16.2 months (P = 0.0032), respectively. Toxicity was mostly grade 1 or 2. CONCLUSIONS: High response rates in the long-PFI patients indicate that this treatment is beneficial and well tolerated. Platinum sensitivity and positive family history and/or a BRCA1/BRCA2 mutation are a useful predictor of response.

Correlation between magnetic resonance imaging and histopathological tumor response after neoadjuvant chemotherapy in breast cancer.

AIM: To evaluate the accuracy of magnetic resonance imaging in assessing tumor response following neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: Twenty-six patients entered a phase II study of neoadjuvant chemotherapy, undergoing bilateral breast magnetic resonance imaging before therapy and before surgery. Tumor response was classified using RECIST criteria, using tumor size at magnetic resonance imaging. The latter was then compared to residue found at histopathological examination. RESULTS: Magnetic resonance imaging showed 6 (23%) complete responses, 17 (65%) partial responses, 3 (11.5%) disease stabilizations and no disease progressions. Twenty-three tumors (88.5%) were considered responsive and 3 (11.5%) unresponsive. Pathological tumor response was: 6 complete responses (23%), 17 partial responses (65%), 2 stable disease (8%), 1 progression (4%). When results of the preoperative magnetic resonance imaging were compared to pathological tumor response, magnetic resonance imaging overestimated tumor size in 12 cases (46%) and underestimated it in 9 (35%). However, preoperative magnetic resonance imaging failed to detect invasive tumor in 2 false-negative cases (8%), 1 of which was multifocal. Mastectomy was performed in 12 cases: 1 case of disease progression even though the neoplasm appeared smaller at magnetic resonance imaging, 3 cases with stable disease, and 4 cases with T3 or T4 disease. The 9th patient was T2N2 with initial retroareolar disease and negative magnetic resonance imaging after chemotherapy. The 10th patient, affected by lobular cancer, was in partial remission but was T3N1. The 11th patient was 57 years old but was not interested in conservative surgery. The 12th patient requested bilateral prophylactic mastectomy due to her positive family history of breast cancer. CONCLUSIONS: Magnetic resonance imaging of the breast allowed conservative surgery in 54% of the patients. This low value is primarily due to overestimation of tumor size, with a negative predictive value of 67% in our population. However, surgeons were able to choose conservative surgery with relative safety in cases of small residual disease.

Neoadjuvant carboplatin and vinorelbine followed by chemoradiotherapy in locally advanced head and neck or oesophageal squamous cell carcinoma: a phase II study in elderly patients or patients with poor performance status.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of neo-adjuvant carboplatin and vinorelbine followed by concomitant chemoradiotherapy in patients > or =70 years of age or with Karnofsky performance status (PS) 70-80, diagnosed with locally advanced head and neck (H&N) or oesophageal carcinoma. PATIENTS AND METHODS: The treatment plan consisted of three courses of carboplatin AUC4 on day 1 and vinorelbine 25 mg/m2 on day 1 and 8, every 21 days, followed by chemoradiotherapy. Carboplatin 100 mg/m2 was delivered weekly for the duration of the radiation therapy (70 Gy, 2 Gy/daily). RESULTS: Thirty-five patients with an average age of 68 years (range 42-85, 16 patients > or =70 years) were treated. Twenty-seven patients (77.1%) responded to neo-adjuvant chemotherapy (2 complete and 25 partial responses). Haematological toxicity was grade 3-4 in 13 patients (37.2%), while gastrointestinal toxicity was grade 3-4 in 20 patients (57.1%). All the patients completed the chemoradiotherapy plan, with grade 4 mucositis plus febrile neutropenia in 3 patients (8.5%). Median time to progression (TTP) was 10.2 months, with 31.5% of patients being alive at two years. CONCLUSION: The regimen of neo-adjuvant carboplatin and vinorelbine followed by chemoradiotherapy is feasible and active in older (> or =70 years) or low PS (Karnofsky 70-80) patients, although toxicity is not negligible and long-term outcome remains poor.

Lack of cardiotoxicity with liposomal doxorubicin in an elderly case of ovarian cancer.

Ovarian cancer is typically a disease of elderly women, usually occurring after menopause with a peak incidence in the eighth decade of life. Elderly patients are more likely to suffer the adverse effects of chemotherapy, which may influence successive lines of treatment. We describe the case of an elderly woman with platinum-sensitive ovarian cancer treated with several lines of chemotherapy who developed acute cardiogenic pulmonary edema with her first line of therapy, which included paclitaxel, and her fourth line containing gemcitabine. However, a complete regimen of pegylated liposomal doxorubicin in association with oxaliplatin was well tolerated. Other authors have reported absence of cardiotoxicity with liposomal doxorubicin in their study populations, but no mention was made of patients with a known prior susceptibility to transient heart failure when treated with other chemotherapeutic agents. Our case provides evidence that even in these more difficult-to-treat cases, where cumulative cardiotoxicity may be relatively unpredictable, liposomal doxorubicin does not affect cardiac function.