A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial.

BACKGROUND: There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine carcinoma. These patients generally have poor performance status and low tolerance to combination therapy. In this trial, we aim to evaluate the efficacy and safety of temozolomide given every other week in patients with advanced platinum-pretreated NENs G3. PATIENTS AND METHODS: This trial is an open-label, non-randomized, phase II trial. Patients with platinum-pretreated metastatic neuroendocrine carcinoma were treated with 75 mg/m2/day of temozolomide for 7 days, followed by 7 days of no treatment (regimen one week on/one week off). The primary endpoint was the overall response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and tolerability. This study is registered with ClinicalTrials.gov, NCT04122911. RESULTS: From 2017 to 2020, 38 patients were enrolled. Among the patients with determined Ki67, 12 out of 36 (33.3%) had a Ki67 index <55% and the remaining 24 out of 36 (66.6%) had an index ≥55%. Overall response rate was 18% (7/38), including one complete response and six partial responses. The median PFS was 5.86 months [95% confidence interval (CI) 4.8 months-not applicable) and the median OS was 12.1 months (95% CI 5.6-20.4 months). The 1-year PFS rate was 37%. No statistically significant difference in median PFS [hazard ratio 1.3 (95% CI 0.6-2.8); P = 0.44] and median OS [hazard ratio 1.1 (95% CI 0.5-2.4); P = 0.77] was observed among patients with Ki67 <55% versus ≥55%. Only G1-G2 adverse events were registered, the most common being G1 nausea, diarrhea and abdominal pain. CONCLUSION: One week on/one week off temozolomide shows promising activity in patients with poorly differentiated NEN. The good safety profile confirmed the possibility of using this scheme in patients with poor performance status.

Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Metronomic temozolomide as second line treatment for metastatic poorly differentiated pancreatic neuroendocrine carcinoma.

Neuroendocrine Neoplasms (NEN) are a group of heterogeneous malignancies derived from neuroendocrine cell compartment, with different roles in both endocrine and nervous system. Most NETs have gastroentero-pancreatic (GEP) origin, arising in the foregut, midgut, or hindgut. The 2010 WHO classification divides GEP-NETs into two main subgroups, neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), according with Ki-67 levels. NET are tumors with low (<20 %) Ki-67 value, and NECs, including small cell lung carcinomas and Merkel Cell carcinomas, are all NETs with high Ki-67 levels (>20 %-G3). Poorly differentiated neuroendocrine carcinomas (NEC) are usually treated with cisplatin-based chemotherapy regimens. Here we present a case of a patient with pancreatic NEC progressing after cisplatin and etoposide, treated with temozolomide as palliative, second line treatment. According with the poor Performance Status (PS = 2) and to reduce the toxicity of the treatment was chosen an intermittent dosing regimen of metronomic temozolomide (75 mg/m(2)/day-one-week-on/on-week-off). MGMT resulted methylated. On July 2014 the patient started the treatment. On August 2014 the patient obtained a significant clinical benefit (PS = 0) and the total body CT scan performed on October 2014 showed a RECIST partial response on all the sites of disease. No drug-related side effects were reported by the patient. After 18 months of therapy the treatment continues without significant toxicity, and with further remission of the metastases. Treatment with metronomic "one-week-on/on-week-off" Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pNEC with MGMT methylation.

Biweekly oxaliplatin combined with oral capecitabine (OXXEL regimen) as first-line treatment of metastatic colorectal cancer patients: a Southern Italy Cooperative Oncology Group phase II study.

Oxaliplatin 100 mg/m(2) iv on day 1, and capecitabine 1,000 mg/m(2) orally bid from day 1 (evening) to day 11 (morning) were administered every 2 weeks (OXXEL regimen) to 38 patients as first-line treatment for metastatic colorectal carcinoma. A total of 318 cycles were administered, with a median of 8 (range, 4-12) cycles per patient. Response rate (RR) was 45% (95% confidence interval (CI), 29%-62%), with 7 complete responses and 10 partial responses; furthermore, 12 patients showed a stable disease, so that a disease control was achieved in 29 (76%) patients. RR was greater among patients with performance status 0 (52%), without weight loss (52%), younger than 65 years (50%), and previously unexposed to adjuvant chemotherapy (48%), while no correlation was found with the actually delivered oxaliplatin dose intensity. Overall, haematological side effects were negligible, with no case of grade 4 toxicity, and only one patient suffering from an episode of grade 3 neutropenic fever. Severe anaemia occurred in 4 (11%) patients, and grade 3 neuropathy affected 9 (24%) patients. Median progression-free survival was 7.9 (95% CI, 6.2-9.6) months, and median overall survival has not been reached yet. In conclusion, the OXXEL regimen resulted safe and active, and it deserves further evaluation in metastatic colorectal cancer patients.

Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial.

PURPOSE: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma. PATIENTS AND METHODS: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m(2) on day 1, l-FA 250 mg/m(2) intravenously plus 5-FU 850 mg/m(2) on day 2 (IRIFAFU); or OXA 100 mg/m(2) on day 1, l-FA 250 mg/m(2) plus 5-FU 1050 mg/m(2) on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m(2) and 5-FU to 850 mg/m(2) [OXAFAFU low dose (ld)]. RESULTS: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade > or =3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU. CONCLUSIONS: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.

Addition of either irinotecan or methotrexate to bolus 5-fluorouracil and high-dose folinic acid every 2 weeks in advanced colorectal carcinoma: a randomised study by the Southern Italy Cooperative Oncology Group.

PURPOSE: The purpose of this study was to compare the activity and toxicity of the combination of irinotecan (IRI) plus folinic acid (FA)-modulated 5-fluorouracil (5-FU) i.v. bolus with a regimen of double modulation of 5-FU with methotrexate (MTX) and FA in patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Two-hundred and thirty-four patients were enrolled: 118 patients received IRI 200 mg/m2 (90-min i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and 5-FU 850 mg/m2 (i.v. bolus) on day 2 (IRIFAFU), and 116 patients received MTX 750 mg/m2 (2-h i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and FU 800 mg/m2 (i.v. bolus) on day 2 (MTXFAFU). Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles. Response rate (RR) was the main end point of the study; responses were assessed every four cycles and confirmed after 2 additional months of treatment. RESULTS: RR was significantly greater with IRIFAFU (36%) than with MTXFAFU (20%) (P <0.001). Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity (P = 0.028). Median progression-free survival was longer with IRIFAFU than with MTXFAFU (7.2 months compared with 4.8 months; P = 0.048). Median survival time (MST) did not differ between the two arms (14.7 months compared with 14.8 months, respectively). Patients not receiving second-line chemotherapy, however, lived longer when treated in the first-line with IRIFAFU (MST 11.9 months compared with 6.4 months; P = 0.038). IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia (40% compared with 9%; P = 0.001) and diarrhoea (13% compared with 4%; P = 0.024), but a significantly lower incidence of stomatitis (3% compared with 12%; P = 0.007), than the comparative regimen. CONCLUSIONS: IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens. IRIFAFU, however, seems easier to administer, because it does not require infusional catheter or pump devices, and it is less expensive. It may represent a new option for treating advanced colorectal carcinoma.

A comparison of two GM-CSF schedules to counteract the granulo-monocytopenia of carboplatin-etoposide chemotherapy.

In order to obtain the beneficial effects from granulocyte-macrophage colony-stimulating factor (GM-CSF) on granulo-monocyte recovery with the minimum dose and toxicity, we compared the effect of two different GM-CSF schedules (5 micrograms/kg/day subcutaneously, days 5 to > 18 versus days 12 to > 18 on the cytopenias which follow cytostatic treatment with carboplatin (400 mg/m2 intravenous (i.v.) day 1) and etoposide (100 mg/m2 i.v. days 1 to > 3). 13 patients entered the study for a total of 36 evaluable cycles. The cytostatic treatment produced a neutropenia that persisted for up to day 22 (absolute neutrophil count (ANC) < 1000/microliters in 25% and ANC < 2000 in 50% of control cycles). Early GM-CSF administration markedly increased the leucocyte nadir and produced two waves of leucocytosis: an early one, linked to marrow reserve release and presumably of no value to the patients; and a delayed one, due to marrow precursor and progenitor cell proliferation, in which the granulomonocytosis was associated with a marked eosinophilia. The delayed GM-CSF administration markedly increased the leucocyte nadir and accelerated granulo-monocyte recovery (with an only modest eosinophilia), so that chemotherapy could be repeated every 21 days in all the patients.

Interleukin-3 in vivo: kinetic of response of target cells.

Human recombinant interleukin-3 (IL-3; Sandoz AG, Basel, Switzerland) was administered for 7 days to patients with neoplastic disease and normal hematopoiesis. The purpose of the study was to assess IL-3 toxicity, to identify target cells, to define their kinetics of response at different dose levels, and to determine if IL-3 in vivo increased the sensitivity of bone marrow (BM) progenitors to the action of other hematopoietic growth factors. A total of 21 patients entered the study; the dosage ranged from 0.25 to 10 micrograms/kg/d. The effect on peripheral blood cells during treatment showed no significant changes in the number of platelets, erythrocytes, neutrophils, or lymphocytes (and their subsets). A mild monocytosis and basophilia occurred. Eosinopenia, present in the first hours of treatment, was followed by a dose-and time-dependent eosinophilia. IL-3 treatment affected BM cell proliferation by increasing the percentage of BM progenitors engaged in the S-phase of the cell cycle. The effect was dose dependent, with the various progenitors showing different degrees of sensitivity. The most sensitive progenitors were the megakaryocyte progenitors (colony-forming unit-megakaryocyte), then the erythroid progenitors (burst-forming unit-erythroid), and finally the granulo-monocyte progenitors (colony-forming unit-granulocyte-macrophage) whose proliferative activity was stimulated at the higher doses of IL-3. Only a slight increase in the proliferative activity of myeloblasts, promyelocytes, and myelocytes was observed, whereas the activity of erythroblasts was unchanged. The priming effect was such that BM progenitors, purified from patients treated with IL-3, produced more colonies in vitro in the presence of granulocyte colony-stimulating factor (G-CSF; granulocyte colonies), IL-5 (eosinophil colonies), and granulocyte-macrophage CSF (GM-CSF; predominantly eosinophil colonies). These data indicate that even in vivo IL-3 acts essentially as a primer for the action of other cytokines. Therefore, optimum stimulus of myelopoiesis will require either endogenous or exogenous late-acting cytokines such as G-CSF, erythropoietin, GM-CSF, and IL-6 for achieving fully mature cells in peripheral blood. If exogenous cytokines are used with IL-3, it is likely that G-CSF will yield more neutrophils, whereas GM-CSF may enhance eosinophils, monocytes, and neutrophils. Attention to the clinical relevance of each cell type will be necessary and should determine the selection of the combination of cytokines.

CEOP/PEB alternating chemotherapy in advanced intermediate and high-grade non-Hodgkin's lymphomas.

BACKGROUND AND METHOD: From February, 1987 to July, 1990, 28 patients (M/F = 16/12; median age = 60.5 yrs) affected by intermediate (22) or high-grade (6) advanced stage (III = 8; IV = 20) NHL were given a median (range 4-10) of 8 cycles of CEOP (Cyclophosphamide, Epirubicin, Vincristine and Prednisone), alternated every 21 days with PEB (Cisplatin, Etoposide, Bleomycin). RESULTS: Nineteen (68%) pts. achieved a CR, 5 (18%) a PR, and 4 (14%) experienced progressive disease (PD); 11/19 CRs subsequently relapsed within a median (range 3-15) time of 8 mos.. After a follow-up ranging from 6 to 42+ (median 18) mos., the 3-year actuarial overall survival (OS) was 51% and shifted to 18% at 42 mos. After 7-42+ (median 19) mos., 14/19 (73%) Crs were still alive with 63% of them predicted to survive at 3 years. The projected 3-year disease-free survival (DFS) for these pts. after 1-36+ (median 8) mos. was 28%. DISCUSSION: CEOP/PEB alternating chemotherapy failed to improve the therapeutic results we obtained in a previous study with CEOP alone. Toxicity was moderate, but higher than expected.

Effects of anthracycline therapy on intestinal absorption in patients with advanced breast cancer.

Although cytotoxic chemotherapy for human cancer has been reported to induce alterations in intestinal permeability, its effects on the absorptive process are still controversial. We have studied mediated and nonmediated absorption in 10 patients with metastatic breast cancer before and after treatment with Adriamycin by the use of specific test sugars given orally and their subsequent urinary recovery, as measured by chromatography. Mediated absorption was investigated by the use of D-xylose and 3-O-methylglucose, while lactulose and L-rhamnose were used to study nonmediated permeation. Lactulose is considered a marker of unmediated paracellular (tight junction) permeation, while L-rhamnose explores passage across cell membranes. The test was performed on patients before and on the second and the eighth days after Adriamycin administration, and only once in 22 age-matched healthy women. Under basal conditions, as well as 2 and 8 days after chemotherapy, D-xylose and 3-O-methylglucose absorption was 35% lower in patients than in controls (P less than 0.001). Lactulose absorption was significantly higher in patients than in controls under basal conditions (P less than 0.001); it reached levels three times higher the second day after chemotherapy, and returned to basal levels by the eighth day. The data suggest an early reversible effect of Adriamycin on cellular tight junctions with resulting increased permeabilization. This effect seems of a toxic nature rather than due to increased cell loss. It is interesting that both nonmediated absorption and mediated absorption were already altered before chemotherapy in cancer patients, suggesting a preexisting functional damage of the intestine. The significance of this alteration as a potential mechanism of cancer cachexia is discussed.