A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients.

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5-0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5-1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.

Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients.

Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.

Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study.

BACKGROUND: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. PURPOSE: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). METHODS: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. RESULTS: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. CONCLUSIONS: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.

Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab.

AIM: To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. PATIENTS & METHODS: Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. RESULTS: One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4-16.8) and 10.2 months (95% CI: 8.8-11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29-0.66, p < 0.0001). CONCLUSION: The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome.

A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases.

BACKGROUND: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s). METHODS: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria. RESULTS: Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively. CONCLUSIONS: This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study.

BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.

High safety profile and activity of oral vinorelbine in an elderly patient with metastatic breast cancer.

Visceral metastases of breast cancer have been commonly treated with "aggressive" anthracyclines/taxanes-based chemotherapy. In contrast, this case report concerns an elderly patient with advanced breast cancer (pleural effusion, peritoneal carcinosis, and bone metastases) who firmly declined intravenous chemotherapy and was treated for a long time (28 months) with oral vinorelbine. The oral formulation of this drug had activity and a high safety profile, enabling the patient's wishes to be respected.

Early and Complete Response of Bone Metastases, Documented by FDG-PET/CT Scan, in a Patient With NSCLC.

In this case report we describe the case of a patient with multiple bone metastases of NSCLC, adenocarcinoma with exon 21 point-mutation of EGFR, treated with gefitinib. After only 3 months, FDG-PET/CT scan showed a complete response of bone metastases and right hylar adenopathy. Implications for need of early use of FDG-PET/CT scan after gefitinib treatment are discussed.

Activity and safety of erlotinib as second- and third-line treatment in elderly patients with advanced non-small cell lung cancer: a phase II trial.

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Efficacy of this drug was documented in the BR.21 trial showing that adenocarcinoma, female gender, Asian ethnicity and never-smoker status are predictive of clinical response to erlotinib. Retrospective studies documented the same benefits for elderly patients as young patients in terms of response, progression-free survival, and overall survival. The primary aim of our trial was to confirm these findings in a prospective way; the secondary aim was to identify if the aforementioned clinical characteristics may be predictive of response even in elderly patients. The trial included 31 patients with pretreated stage IIIB (2) and IV (29) non-small cell lung cancer (NSCLC). Median age was 75 years (range: 65-85). Twenty-seven patients were current/former-smokers and four never-smokers. Twenty-three patients are evaluable for response. Objective response rates were reported in five patients (16%). Five patients had stable disease (16%) and 13 progressive disease (43%). Seven patients had a "clinical benefit" from erlotinib (22.5%; 95% C.I.: 7.9-37.2%). Grade 3 skin rash was recorded in three patients (10%). Median survival was 9 months (range 1-30). Median time to progression was 3 months (range: 1-24 months). Our study confirmed erlotinib activity and safety as second- and third-line treatment in elderly patients with advanced NSCLC, especially in terms of median survival. Even though this trial does not allow us to draw a definitive conclusion about the role of a particular clinical characteristic predictive of response, the "clinical benefit" was documented especially in females, in patients with adenocarcinoma histology and skin rash, confirming previous retrospective data.

Weekly paclitaxel in elderly patients (aged > or = 70 years) with advanced non-small-cell lung cancer: an alternative choice? Results of a phase II study.

PURPOSE: Paclitaxel and platinum-based chemotherapy is considered to be a standard approach for locally advanced and metastatic non-small-cell lung cancer (NSCLC). In recent years, weekly paclitaxel has been widely used for its safety profile, especially in breast and ovarian cancer. Otherwise, only a few studies are available in NSCLC. The aim of our study was to investigate the activity and safety of weekly paclitaxel in elderly patients with locally advanced (stage IIIB) and metastatic (stage IV) NSCLC. PATIENTS AND METHODS: Twenty-seven patients entered the study; 10 had stage IIIB disease (5 "wet" and 5 "dry"), and 17 had stage IV disease. Median age was 73 years (range, 70-83 years). Sixteen patients (59%) presented with comorbidities. The schedule was weekly paclitaxel 80 mg/m2 for 6 weeks with 2 weeks of rest (1 cycle). RESULTS: All patients were evaluable for response and toxicity; a median of 1 cycle was administered (range, 1-5 cycles). Partial responses were recorded in 9 patients (37.5%; 33.3%, according to intention-to- treat analysis; 95% CI, 15.5%-51.1%); 7 had stable disease (29%), and 8 had progressive disease (33.5%). Median time to progression was 5 months (range, 1-23 months), and median survival was 12 months (range, 1-36 months). Grade 2/3 asthenia was the main toxicity in 7 patients (29%); a hypersensitivity reaction presented in 1 patient. No other episode of grade 3/4 toxicity was recorded. CONCLUSION: Our study confirmed that paclitaxel 80 mg/m2 weekly is active in patients with locally advanced and metastatic NSCLC with a good safety profile; this schedule might be considered an alternative choice to gemcitabine or vinorelbine as first-line treatment in elderly patients, particularly patients with comorbidities. Phase III studies that compare these third-generation drugs are warranted to draw definitive conclusion about the best approach in these patients.

Neoadjuvant chemotherapy with low dose of pegylated liposomal doxorubicin plus weekly paclitaxel in operable and locally advanced breast cancer.

To determine the activity and safety of a schedule with a low dose of pegylated liposomal doxorubicin (PLD) and weekly paclitaxel in operable and locally advanced breast cancer patients. Thirty-five patients with histologically confirmed, operable, and locally advanced breast cancer entered the study. The median age was 59 years (range 31-74 years). The schedule was biweekly PLD at the dose of 15 mg/m for four administrations and weekly paclitaxel at the dose of 80 mg/m for eight administrations. All patients were evaluable for response and toxicity. Twenty-six patients responded (74%): three (8%) had a complete response and 23 (66%) had a partial response, seven (23%) remained stable, and one experienced progression (3%). Fifteen of 27 operable patients (55%) underwent conservative surgery. Three patients (9%) had a pathological complete response and the disappearance of infiltrating disease was documented in three other patients. The main toxicity was hand-foot syndrome (grade 3 in four patients; 11%). Other nonhematological grade 3 toxicities included stomatitis in three patients (8%) and liver toxicity in one patient (3%). Grade 3-4 neutropenia was documented in another three patients and dose reduction was necessary in two patients. The fourth administration of PLD was suspended in four patients for grade 2-3 hand-foot syndrome. No symptoms were related to impairment of cardiac function and no death related to toxicity occurred. The combination of biweekly PLD and weekly paclitaxel was active in operable and locally advanced breast cancer with a manageable safety profile.

A phase II study of single-agent oral vinorelbine in patients with pretreated advanced non-small-cell lung cancer.

PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m(2) once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m(2) once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m(2) weekly are warranted.

Safety profile and activity of lower capecitabine dose in patients with metastatic breast cancer.

PURPOSE: Capecitabine is an orally administered precursor of 5'-deoxy-5-fluorouridine that was rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue. The drug enables chronic dosing that mimics continuous infusion of 5-FU. Phase II trials of capecitabine at 1250 mg/m2 twice daily for 14 days followed by 7 days of rest, is active in anthracycline- and taxane-pretreated patients; the main toxicity is palmar-plantar erythrodysesthesia, diarrhea, and nausea. To overcome these side effects, the dose has been reduced to 1000 mg/m2 twice daily with a better therapeutic profile and encouraging efficacy. The aim of our study was to confirm safety and activity of capecitabine at lower doses in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-seven patients with advanced breast cancer entered the study. The first 7 patients were treated with capecitabine 1250 mg/m2 twice daily (for 14 days followed by 7 days of rest) and the next 30 patients with capecitabine 1000 mg/m2. The median age was 62 years (range, 38-87 years). Thirteen patients were chemotherapy naive and 24 were pretreated with chemotherapy (9 patients, 1 line; 15 patients, > or = 2 lines). Anthracyclines and/or taxane schedules were administered in 22 patients. Soft tissue metastases were documented in 36 patients; visceral metastases in 24 patients; visceral and soft tissue metastases in 23 patients. RESULTS: Thirty patients were evaluable for response (5 at "higher" dose and 25 at "lower" dose) and all for toxicity. Overall objective response rate was 57% (5 complete responses and 12 partial responses); 95% CI, 39%-74%; stable disease 20% and progressive disease 23%. Eight of 13 chemotherapy-naive patients (61.5%) and 9 of 24 pretreated patients (37.5%) responded to capecitabine, according to the intent-to-treat principle (6 of 9 responses were obtained at a lower dose). Three responses at the "higher" dose and 14 at the "lower" dose were reported. Median time to progression was 7 months (range, 1-38 months) and median overall survival was 19 months (range, 2-47 months). Toxicity was as follows: grade 2/3 palmar-plantar erythrodysesthesia in 9 patients (24%), grade 2/3 asthenia in 7 patients (19%), grade 2 vomiting in 4 patients (11%), grade 2 renal toxicity in 1 patient, grade 2 skin reaction in 1 patient, and suspected cardiac toxicity in 1 patient. CONCLUSION: Our study confirmed that a lower dose of capecitabine has a good toxicity profile and is active in patients with MBC.