Insights into the Use of Peripherally Acting µ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

OPINION STATEMENT: Management of chronic pain is crucial to improve the quality of life of cancer and palliative care patients. Opioid-based treatments used to control pain can be prolonged over time. Unfortunately, constipation is one of the most disturbing adverse effects of long-term use of opioids. Opioid-induced constipation (OIC) occurs when opioids bind to the specific receptors present in the gastrointestinal (GI) tract, and can affect any patients receiving chronic opioid therapy, including cancer patients. The limited efficacy of laxatives to treat OIC symptoms prompted the search for new therapeutic strategies. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric µ-receptors. Little information is available on the use of PAMORAs in real-life practice for OIC treatment in cancer patients. In this paper, a panel of experts specializing in cancer and palliative care pools their clinical experience with PAMORAs in cancer patients presenting OIC and highlights the importance of timing and choice of therapy in achieving prompt OIC management and benefitting patients.

Second-line treatment in advanced non-small-cell lung cancer in the epidermal growth factor receptor wild-type population: review of patient profile.

After progression during first-line treatment in advanced non-small-cell lung cancer (NSCLC), a large percentage of patients are candidates for second-line treatment. The majority do not have epidermal growth factor receptor-activating mutations (EGFRwt). This article reviews the treatment options available for this subpopulation of patients, which includes essentially docetaxel, pemetrexed and erlotinib. These drugs all have similar efficacy, both in terms of objective response rates and overall survival, although with different toxicity profiles. In view of the similar efficacy of the three agents (docetaxel, pemetrexed and erlotinib) in the second-line treatment of NSCLC in the EGFRwt population, and although there are no prospective studies on predictive variables or new molecular markers available, selection of the treatment will depend on the histological type (pemetrexed); patient preference (oral as opposed to intravenous formulation); the presence of comorbid conditions; quality of life; previous or residual toxicities; the risk of neutropenia; response to and the duration of the first-line chemotherapy; and history of smoking.

New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer.

Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).

Patterns of Progression and Feasibility of Re-biopsy After First-line Erlotinib for Advanced EGFR Mutation-positive Non-small-cell Lung Cancer.

AIM: To assess the patterns of disease progression in advanced/metastatic epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) on first-line treatment with erlotinib and identify potential prognostic factors for progression-free survival (PFS). PATIENTS AND METHODS: Patients with stage IIIB/IV EGFR-mutation-positive NSCLC receiving first-line erlotinib were followed-up until 24 months after the last patient was enrolled or until premature withdrawal for any cause. RESULTS: A total of 127 evaluable patients were enrolled. The median PFS and overall survival were 8.8 and 19.1 months, respectively. Disease progression was asymptomatic in 57.6% of patients and 53.3% developed new sites of metastasis. The presence of liver metastasis was identified as an independent prognostic factor for poor PFS. CONCLUSION: Metastatic progression with asymptomatic disease seems to be the predominant pattern of disease progression on first-line erlotinib in real-life practice in patients with advanced/metastatic EGFR-mutant NSCLC. Additionally, the presence of liver metastases may negatively affect PFS in these patients.

Dramatic Response of Leptomeningeal Carcinomatosis to Nivolumab in PD-L1 Highly Expressive Non-small Cell Lung Cancer: A Case Report.

In a patient who had been diagnosed of located squamous cell lung carcinoma, pneumonectomy, and adjuvant chemotherapy were performed. Brain recurrence and subsequent lung metastatic disease were uncontrolled by neurosurgery, holocranial radiotherapy, and first-line chemotherapy. In August 2015, appearance of leptomeningeal carcinomatosis triggered severe clinical deterioration and threatened the patient's life. Anti-PD1 immune checkpoint inhibitor Nivolumab was initiated in an attempt to stop tumor growth, achieving a spectacular brain and pulmonary complete response and clinical improvement, without serious adverse effects. High expression PD-L1 level (100%) was found in the pathological tissue sample. Nivolumab was maintained for more than 2 years and stopped in December 2017 after 28 months of treatment, with no disease evidence. More than 3 years after its onset, the patient maintains an outstanding PS with complete tumor response and no evidence of disease in last surveillance CT scan and brain MRI.

EGFR testing and clinical management of advanced NSCLC: a Galician Lung Cancer Group study (GGCP 048-10).

PURPOSE: This study aimed to assess the incidence of mutations in the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients in the Galician region of Spain and the clinical management and outcome of patients carrying EGFR mutations. PATIENTS AND METHODS: All newly diagnosed advanced or metastatic NSCLC patients were screened for EGFR mutations in matched tumor samples (tissue or cytology specimens) and serum samples. RESULTS: Of 198 patients screened for EGFR mutations in tumor samples, 184 had evaluable data and, of these, 25 (13.6%) had EGFR mutations (84% sensitizing mutations). EGFR mutation was found in serum in 14 (8.1%) patients (of 174 evaluable). Compared to matched tumor tissue, serum EGFR mutation testing specificity and sensitivity were 99% and 52%, respectively. All but two patients received gefitinib. Median progression-free survival and overall survival were 10 (95% confidence interval: 4.8-15.3) months and 17.8 (95% confidence interval: 13.9-21.6) months, respectively, in patients carrying sensitizing mutations. CONCLUSION: The incidence of EGFR mutations in Galicia is consistent with previous data in Spain. Our results also support the feasibility of EGFR testing to guide treatment decision making using tumor tissue or cytology samples, or serum samples if tumor specimens are unavailable. These findings also confirm that first-line gefitinib is an active treatment option in Caucasians with EGFR mutation-positive NSCLC.

Full-dose cisplatin and oral vinorelbine concomitant with radiotherapy in unresectable stage III non-small cell lung cancer: a multi-center phase II study.

AIM: To evaluate the efficacy and toxicities of combination of cisplatin and oral vinorelbine given at full doses concomitantly with radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Untreated patients with locally advanced inoperable stage IIIA/IIIB NSCLC were eligible for study inclusion. Treatment consisted of four cycles of oral vinorelbine at 60 mg/m(2) on days 1 and 8, and cisplatin at 80 mg/m(2) on day 1 every three weeks plus radiotherapy 66 Gy starting on day 1 of cycle 2 in fractions of 2 Gy/day over 6.5 weeks. RESULTS: Forty-eight patients were enrolled. Their characteristics included: median age 61 years; female gender 10%; stage IIIA 46% and IIIB 54%; squamous carcinoma 63%, performance status PS0 42%; PS1 58%. Selected grade 3/4 toxicities were as follows: neutropenia 33%, concomitant febrile neutropenia 14.6%, anemia 12.5%, thrombocytopenia 16.6%, and esophagitis 12.5%. Two treatment-related deaths were reported, both during cycle 1. Radiotherapy was administered to 87.5% of patients; 7.1% of them received less than 60 Gy and 23.8% had delays due to adverse events. The objective response rate was 77.3%, with two complete responses and 32 partial responses. With a median follow-up of 19 months, the median progression-free survival was 12 months, and the 1-year overall survival rate was 72.3%. Median overall survival was 27.8 months, although the 95% confidence interval has not yet been achieved. CONCLUSION: Full doses of cisplatin and oral vinorelbine can be administered with concomitant radiotherapy, with good efficacy and an acceptable safety profile for patients with stage IIIA/IIIB NSCLC.

First-line bevacizumab, cisplatin and vinorelbine plus maintenance bevacizumab in advanced non-squamous non-small cell lung cancer chemo-naïve patients.

OBJECTIVE: The aim of this study was to evaluate efficacy and safety of first-line treatment with bevacizumab, cisplatin and vinorelbine and bevacizumab maintenance in non-squamous, non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: Forty-nine patients with stage IIIB plus pleural effusion or stage IV NSCLC were included in a Phase II clinical trial. Treatment consisted of 3-week cycles of bevacizumab (15 mg/kg on day 1), cisplatin (80 mg/m(2) on day 1) and vinorelbine (25 mg/m(2) on days 1 and 8). After 6 cycles, non-progressing patients received bevacizumab maintenance therapy. The primary end point was progression-free survival (PFS), calculated using the Kaplan-Meier method. RESULTS: Thirteen (29%) of 45 evaluable patients presented a partial response. PFS and overall survival were 6.0 months (95% confidence interval (CI) 4.5 - 7.5) and 14.7 months (95% CI 8.4 - 21), respectively. Fourteen patients (28%) experienced grade 3 - 4 neutropenia and 7 (14%) experienced febrile neutropenia during the combination treatment. During the maintenance phase, the most frequent grade 3 - 4 adverse event was hypertension. Neither grade 3 - 4 thrombocytopenia nor toxic death was observed. CONCLUSIONS: The studied regimen achieved a similar efficacy to other regimens containing platinum doublets. The data provide further evidence that bevacizumab may be used in combination with multiple standard platinum-based doublets in this setting.

Management of lung cancer-associated anaemia: the Spanish Lung Cancer Anaemia Survey (SLCAS).

BACKGROUND: The purpose of the Spanish Lung Cancer Anaemia Survey (SLCAS) was to thoroughly investigate lung cancer-associated anaemia management, and describe the profile of lung cancer patients in relation to anaemia incidence and tumour type in Spain. PATIENTS AND METHODS: This survey collected data from 1089 randomly recruited patients gathered by 50 Spanish physicians at 38 sites. In addition, a qualitative assay was performed through 16 one-to-one and 2 one-to-two interviews, and a discussion group of 4 cancer specialists participating in the survey. RESULTS: Lung cancer patients undergoing chemotherapy treatment had haemoglobin (Hb) levels <12.0 g/dl in 58.0% of the cases, in contrast to 39.0% of patients receiving no chemotherapy. Anaemia was treated in 53.0% of patients with Hb<12 g/dl (45.0% epoetin, 3.9% transfusion, 4.1% iron). Mean Hb level trigger was 9.7 g/dl for administration of epoetin and 8.2 g/dl for blood transfusion. CONCLUSIONS: SLCAS reveals a significant change in the management of anaemia and clinical practice pattern in the use of erythropoiesis-stimulating agents (45.0% vs. 18.0%) and much less use of blood transfusions (3.9% vs. 15.0%) since the European Cancer Anaemia Survey performed five years ago.

Combination therapy with docetaxel and low dose of cisplatin in elderly patients with advanced non-small cell lung cancer: multicenter phase II study.

PURPOSE: To determine the efficacy and safety of the combination therapy with docetaxel and cisplatin (CDDP) at low doses in elderly patients with advanced NSCLC. PATIENTS AND METHODS: A total of 42 patients aged > or =70 years with previously untreated advanced NSCLC received docetaxel 75 mg/m(2) plus CDDP 50 mg/m(2) on day 1. The regimen was repeated every 21 days. Patients received a minimum of three courses unless progressive disease was detected. RESULTS: By intent-to-treat analysis, the overall response rate was 31% (95% CI, 17.8-47.2%). A total of 18 patients (43%) had stable disease and 11 (26%) progressed. Median time to progression was 5.2 months. Overall median survival was 8.9 months, with 1-year actuarial survival rate of 41%. Eastern Cooperative Oncology Group performance status was improved in 18 patients (43%). The chemotherapy regimen was well tolerated. A total of 11 patients (26%) had grade 3/4 adverse events: 7 (17%) neutropenia (one of them was diagnosed with febrile neutropenia), 3 (7%) asthenia, 3 (7%) nausea/vomiting, 1 (2%) diarrhea, 1 (2%) thrombocytopenia and 1 (2%) neurotoxicity. No death due to toxicity was seen. CONCLUSION: The combination of low-dose CDDP and docetaxel for elderly patients with advanced NSCLC is an efficient and well-tolerated chemotherapeutic approach.

Biweekly administration of docetaxel and vinorelbine as second-line chemotherapy for patients with stage IIIB and IV non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 013-02).

The current report aims to evaluate the efficacy and safety profile of a biweekly administration of docetaxel and vinorelbine to patients with advanced non-small cell lung cancer, who had previously been treated for this disease. In a prospective, multicenter, open-label, phase II trial, patients received 40 mg/m of docetaxel and 20 mg/m of vinorelbine on days 1 and 15, every 28 days. Treatment continued for up to a maximum of six cycles, unless disease progression or unacceptable toxicity occurred, or consent was withdrawn. Fifty patients were enrolled in the study and they received 174 cycles of chemotherapy, with a median of three cycles per patient. All patients were evaluated for efficacy and toxicity in an intention-to-treat analysis. The overall response rate was 10% [95% confidence interval (CI): 1-19], including one complete response (2%) and four partial responses (8%). Previous chemotherapy of 80% of the responders included paclitaxel. Median time to disease progression was 2.7 months (95% CI: 2.2-4.3) and median overall survival was 6.5 months (95% CI: 2.5-9.2). The survival rates at 1 and 2 years were 18% (95% CI: 7-29) and 4% (95% CI: 0-10), respectively. The most frequent severe toxicities were neutropenia (20% of patients) and leukopenia (8% of patients). Other toxicities appeared in 4% or fewer of the patients. Biweekly administration of docetaxel and vinorelbine is feasible as a second-line treatment for non-small cell lung cancer patients, but its level of activity and toxicity does not suggest any advantage compared with the results obtained with single-agent docetaxel in the same setting.

Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma.

Interleukin-2 (IL-2) is a lymphokine produced by T cells whose main function is to stimulate the growth and cytotoxic response of activated T lymphocytes. It has been used to stimulate the immune system for the treatment of multiples tumors. This article is intended to review the reports published from 1990 to 2004 on the IL-2 treatment of tumors other than melanoma and renal carcinoma. A literature search was made in various databases (MEDLINE, EMBASE and BioAssay), focused on IL-2 clinical efficacy in such tumors. A selection was made over 150 publications reporting on administration of IL-2 in multiple tumors: lung carcinoma (small cell and non-small cell), colorectal, gastric, pancreatic, ovarian and breast cancer, sarcomas, hepatocarcinoma, mesothelioma, and brain, urological, and head and neck tumors. IL-2 was mainly used in metastatic disease, associated with other immunotherapy or chemotherapy schedules. We conclude that adjuvant IL-2 may be of value in early stages combined with standard treatment for colon and pancreas cancers. In other neoplasms, the indication for adjuvant IL-2 has been sporadic and does not allow conclusions to be drawn. Assessment of the efficacy of IL-2 combined with chemotherapy as treatment for advanced stages is complex, due to the lack of a control, and the variety of dosages and schemes. The activity of IL-2 in monotherapy or in association with immunotherapy is clinically relevant in hepatocarcinoma, mesothelioma and in malignant overflows as palliative treatment. Randomized trials would be required in order to be able to draw conclusions about its indication in other tumors.

Docetaxel plus fractionated cisplatin is a safe and active schedule as first-line treatment of patients with advanced non-small cell lung cancer: results of a phase II study.

This phase II trial evaluated the efficacy and safety of docetaxel 85 mg/m(2) (day 1) and cisplatin 80 mg/m(2) (administered as 40 mg/m(2) doses each on days 1 and 2) every 3 weeks as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Forty-two NSCLC patients were enrolled, most of them with stage IV disease (74%). A total of 195 chemotherapy cycles were administered (median 6, range 1-6). All patients were considered evaluable for efficacy and toxicity in an intention-to-treat (ITT) analysis. The overall response rate was 48% (95% CI, 33-64), including one CR (3%) and 19 PRs (45%). Stable disease was found in 6 patients (14%). The median time to disease progression was 4.9 months (95% CI, 4.0-5.7) and the median overall survival was 10.5 months (95% CI, 5.1-16.0). The survival rates at 1 and 2 years were 36.0% (95% CI, 19.9-52.0) and 18.0% (95% CI, 3.9-32.1), respectively. Overall, the combination showed an excellent safety profile. Severe hematological toxicities were uncommon: neutropenia (5% of patients, 1% of cycles) and febrile neutropenia (2% of patients, 0.5% of cycles). Asthenia (12%) was the only grade 3/4 non-hematological toxicity that affected more than 10% of patients. There were no toxic deaths. In conclusion, docetaxel plus fractionated cisplatin as first-line treatment of advanced NSCLC patients showed similar efficacy as the same combination with higher doses of docetaxel but where cisplatin was administered in a single dose. This new schedule shows promise in its excellent hematological and non-hematological toxicity profile. A randomized phase III trial is needed to confirm these results.

Biweekly docetaxel as second-line chemotherapy of patients with advanced non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 006-00).

This phase II trial assessed the antitumoral activity and toxicity of docetaxel 50 mg/m (1-h i.v. infusion) administered every 2 weeks as second-line treatment in 45 patients with advanced non-small cell lung cancer (NSCLC). A total of 251 infusions (median 4 per patient) were administered. The actual and relative median dose intensity values were 24.2 mg/m/week and 0.97, respectively. Thirty-seven patients were evaluable for tumor response. The overall response rate was 20% [95% confidence interval (CI) 8-32%] and included one complete response (2%) and eight partial responses (18%). Stable disease was found in seven patients (16%). With a median follow-up of 4 months, the median time to disease progression was 2.8 months (95% CI 1.9-3.7), the median overall survival was 4.0 months (95% CI 3.4-4.6) and the 1-year survival rate was 23% (95% CI 9-37). The every-2-weeks docetaxel schedule was well tolerated. Grade 3/4 non-hematological toxicities showed rates of 5% or less of patients and 2% or less of cycles. The main grade 3/4 hematological toxicity was neutropenia (16% of patients and 8% of cycles). No febrile neutropenia was found. Nevertheless, one toxic death was reported. We conclude that the biweekly docetaxel schedule showed an antitumoral activity similar to that found with the every-3-weeks or weekly docetaxel schedule in a second-line setting for advanced NSCLC. This antitumoral effect was associated with a marked reduction in hematological toxicity, therefore suggesting that this new docetaxel schedule might be useful in the design of combined second-line schedules for treating NSCLC.

Hiperaldosteronismo primario aislado causado por carcinoma córtico-suprarrenal / Primary aldosteronism arising from adrenocortical carcinoma

OBJETIVOS: Presentar el caso de un varón de 39 años con carcinoma córtico-suprarrenal e hiperaldosteronismo primario como única manifestación endocrina. MÉTODO-RESULTADOS: Tras la evaluación hormonal y radiológica completa, se practicó suprarrenalectomía y nefrectomía derecha (pT2pN0M0, estadio II), normalizándose la tensión arterial y las cifras de potasio y aldosterona. El paciente recibió terapia adyuvante con carboplatino y etopósido. Después de un intervalo libre de enfermedad de 15 meses se diagnosticaron metástasis pulmonares, sin recidiva local hasta 5 meses después, momento en que también reapareció hipertensión arterial e hiperaldosteronismo primario. No hubo otras alteraciones endocrinas. Se instauró tratamiento con espironolactona y 5-FU y adriamicina sin respuesta tumoral y el paciente falleció a los 3 años por complicaciones de metástasis endobronquiales. CONCLUSIONES: El carcinoma suprarrenal con hiperaldosteronismo primario aislado es excepcional por lo que no existe gran experiencia en su diagnóstico y tratamiento. Aunque no existen estudios controlados, en estadios localmente avanzados parece razonable la terapia adyuvante con fármacos, como la combinación de cisplatino y etopósido (VP-16), alternativos al mitotano (o,pDDD), pues aunque puede ser útil cuando existe hipercortisolismo su eficacia como agente antitumoral ha sido más discutida (AU)