Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083).

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer.

The aim of this study was to evaluate the safety and efficacy of combined treatment with trastuzumab (T), gemcitabine (gem) and vinorelbine (vin) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab. Eligible patients had HER-2/neu-positive disease (IHC 2+ or 3+), performance status (PS) or=2 metastatic sites. Of the patients, 7 (23.3%) had received trastuzumab as first-line therapy. Treatment was well-tolerated with grade 4 neutropenia in 6 patients, grade 3 thrombocytopenia and grade 3 anemia in 1 patient, and grade 3 asthenia in 4 patients. Fifteen patients obtained an objective response (response rate, 50%; C.I. 95%, range, 31.3-68.7%). Among the patients with HER-2/neu 3+, the response rate was 73.3%. Noteworthy were 4 objective responses observed in patients with brain metastasis. Also, 7 patients had stable disease (23.3%). Median progression-free survival was 7 months (range 5-10), and median overall survival was 15 months (range 5-33). T-gem-vin is a safe and active regimen in this subgroup of patients with poor prognosis, and the efficacy of such a schedule was particularly satisfactory in patients with HercepTest 3+.

Is tailored therapy feasible in oncology?

Tailored therapy aims to cure a patient who suffers from a specific disease with an effective and safe drug, based on the complex interactions among patient's characteristics, disease physiopathology and drug metabolism. Genomic and proteomic technologies represent promising new useful tools to understand cancer biology and molecular basis of interindividual differences of anticancer drugs efficacy. Genomic profiling seems to be able to re-classifying cancer into new molecular and prognostic homogeneous subgroups. By individual polymorphisms it is possible to identify the patients at higher risk for severe toxicity from those that may gain benefit from a particular treatment. The clinical use of targeted therapy is hampered by several questions, including: optimal biological dose, availability of surrogate biomarkers predictive of activity, schedule of administration, tumor histotype and stage to treat and modalities of combination with chemo/radiotherapy. In addition, further efforts are needed to improve the reliability of genomic and proteomic technologies. These unsolved issues presently make tailored therapy an open challenge.

Multiorganic dissemination of a colorectal signet ring cell carcinoma with fulminant clinical course.

Mucinous colorectal cancer with signet ring cell aspects is a rare form of adenocarcinoma representing about 2-5% of large bowel neoplasms. The tumor frequently presents with late-stage or peritoneal spreading. It can often affect young patients and diffusely infiltrate through all layers of the intestinal wall. Local recurrence and distant metastases are common in spite of surgical operation and adjuvant treatment, conditioning a poor prognosis. At the present, early diagnosis and complete resection are the most important approaches to improve the outcome. In our report we describe a case of a 41-yr-old patient with very aggressive untreated metastatic colorectal signet ring cell carcinoma. The fulminant tumor progression was really unexpected and misled every possible medical interpretation, leading to rapid worsening of the patient's clinical conditions and no chance for chemotherapy treatment. The tumor mimicked the picture observed in the acute leukemia, developing diffuse infiltration in all serosal membranes, liver, lung, kidneys, multiple lymph nodes, and meninges, as revealed by the post-mortem medical report.

Combined therapy with weekly irinotecan, infusional 5-fluorouracil and the selective COX-2 inhibitor rofecoxib is a safe and effective second-line treatment in metastatic colorectal cancer.

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged > or =18 to < or =75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m(2) per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m(2) and further dose escalations were planned by increments of 12.5 mg/m(2) up to 125 mg/m(2). Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m(2), and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.

The combination of the selective cyclooxygenase-2 inhibitor celecoxib with weekly paclitaxel is a safe and active second-line therapy for non-small cell lung cancer: a phase II study with biological correlates.

PURPOSE: The selection of effective schedules of treatment for metastatic non-small cell lung cancer still remains a challenge for the oncologist. The present multicentric phase II study was designed in order to investigate the activity and safety of the combination of weekly paclitaxel and celecoxib as second-line treatment for non-small cell lung cancer. As a secondary endpoint, the possible correlation of biomarkers with objective response was investigated in a subset of patients. PATIENTS AND METHODS: Patients with platinum-refractory non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0-2 entered the present phase II study. Paclitaxel was administered at the dose of 80 mg/m(2) i.v. weekly for 6 weeks, followed by a 2-week rest, and celecoxib, 400 mg p.o. b.i.d. administered continuously. A cycle consisted of 8 weeks of treatment. Determination of circulating vascular endothelial growth factor and interleukin 6 was performed at baseline and every two cycles. RESULTS: Fifty-eight patients were enrolled: median age, 60 years (range, 30-77 years); male/female ratio = 44/14; performance status, 0, 31 patients; 1, 25 patients; and 2, two patients. Predominant histotype was adenocarcinoma (34 cases), and most patients had at least two sites of disease. According to the intent-to-treat analysis, 14/58 objective responses (24.1%) and 24/58 (41.3%) stabilizations of disease were observed, with a median duration of 4 months (range, 2-22+ months) and 5 months (range, 1-13 months), respectively. Median time to progression and median overall survival were 5 and 11 months, respectively. One-year survival was 42.5%. The main toxicity was neuropathy (4% of grade 3). Preliminary results suggest that decrease in serum vascular endothelial growth factor level is significantly associated with clinical response. DISCUSSION: Combination of celecoxib and weekly paclitaxel is safe and active new regimen in pretreated non-small cell lung cancer. Toxicity appears not to be worsened by the addition of celecoxib. According to preliminary results, serum vascular endothelial growth factor level seems to be predictive of response, suggesting that it should be further investigated as a surrogate marker of response.

Safety and activity of the combination of pegylated liposomal doxorubicin and weekly docetaxel in advanced breast cancer.

BACKGROUND: The present study was designed with the aim of evaluating the tolerability and activity of pegylated liposomial doxorubicin (PLD) in combination with weekly docetaxel as first line treatment of advanced breast cancer. PATIENTS AND METHODS: Fifty-seven patients entered the study. PLD was administered at escalating doses starting from 30 mg/m2, on day 1; docetaxel was administered at the fixed dose of 35 mg/m2 on days 2 and 9. A cycle of therapy consisted of 21 days. RESULTS: The MTD was achieved at the dose of 40 mg/m2 of PLD, being febrile neutropenia and palmar-plantar-erythrodisesthesia (PPE) the dose-limiting toxicities (DLTs), so that the fixed dose of PLD for the Phase II study was 35 mg/m2. Forty-two consecutive patients received treatment at the established dose for a total of 194 cycles: among these, three patients were withdrawn for severe allergic reaction at the first administration of PLD. Hematological toxicity was moderate, the most common grade 1-3 non-hematological toxicities were stomatitis and PPE, occurring in 20 (47.5%) and 16 (38%) patients, respectively. No cardiac toxicity was recorded. According to the intent to treat analysis a major objective response was observed in 59.5% of patients (95% CI, 43.3-74.4%), with a median time to progression of 9 months and an estimated overall survival at 18 months of 62%. CONCLUSION: The combination of PLD and weekly docetaxel is an effective first-line therapy for patients with advanced breast cancer. PPE and mucositis are the most relevant side effects of such a combination.

Thalidomide prolongs disease stabilization after conventional therapy in patients with recurrent glioblastoma.

Thalidomide shows antiangiogenic activity and it has been successfully employed in various tumors. Considering the poor therapeutic options for glioblastoma and the role of angiogenesis in malignant glioma cells growth, we investigated the therapeutic activity of thalidomide in patients affected by recurrent glioblastoma. Inclusion criteria were: recurrent glioblastoma pretreated with surgery and radiotherapy, age >/=18 years, adequate performance status, hematological, renal, and hepatic functions. Exclusion criteria included severe underlying diseases, neuropathy or concurrent radiotherapy. Eighteen patients entered the study, 17 of whom were assessable for toxicity and response. Most of patients were pretreated with chemotherapy (77.8%). Thalidomide was well tolerated: the most common side effects were constipation (76.5% of patients), somnolence (47%), and peripheral neuropathy (11.8%). One minimal response (MR) and 8 stable disease (SD) were observed, with an overall clinical benefit of 52.9%. Median time to progression and median overall survival (OS) for responders was 25 weeks (range 12-40) and 36 weeks (range 16-64), respectively. In conclusion, thalidomide induces modest side effects and it may be considered a valid therapeutic option for patients with recurrent glioblastoma.

Pain and its treatment in hospitalized patients with metastatic cancer.

GOALS: The aim of this prospective study was to assess the quality of pain management hospitalized cancer patients. PATIENTS AND METHODS: In a quantitative and qualitative evaluation from six oncology centers in Italy, all consecutive cancer patients complaining of pain and hospitalized during the same 2 weeks were requested to fill in a McGill pain questionnaire (MPQ), a present pain intensity scale (PPI), and a hospital anxiety and depression acale (HADS), and to answer a questionnaire focused (QF) on the quality of medical and nursing care. The healthcare provider's antalgic prescriptions were assessed by an index of pain management (IPM). MAIN RESULTS: Of 120 patients with pain admitted to oncology divisions (65 men and 52 women; mean age 57 years, range 21-79 years), 117 completed the questionnaires. The quantitative evaluation (PPI) showed a significant pain reduction between admission and discharge pain levels-from 2.65 to 1.50 ( p<0.001). While a significant reduction of anxiety (HADS) was also found-from 10.24 to 9.11 ( p<0.001)-depression did not improve (9.83 and 9.72). The most relevant information from qualitative evaluation (QF) was: in 37.6% of patients, pain level was higher overnight; 47% waited for spontaneous decrease of pain intensity before asking for nurse or physician intervention; 69% asked for nurse help when pain level was really high. The health care response to patients' pain was not completely satisfactory, since analgesic prescription was adequate in 56.52% but inadequate in 43.47%. CONCLUSIONS: Pain control in hospitalized cancer patients is not completely satisfactory. The physician's attitude is to underestimate and undertreat pain, while nurses are not adequately trained for timely intervention despite published guidelines for pain management. The findings of this study support the concern of inadequate knowledge and inappropriate attitudes regarding pain management, even in cancer patients hospitalized in medical oncology divisions.

Thalidomide: a new anticancer drug?

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.

Prognostic and predictive indicators in operable breast cancer.

Because of its biological heterogeneity and wide spectrum of responsiveness to different treatments, breast cancer is a complex disease of difficult clinical management. Over the past several years, knowledge of the molecular mechanisms regulating normal and aberrant cell growth leading to cancer has been enhanced. These advances have enabled the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. Axillary nodal status, age, tumor size, pathologic grade, and hormone receptor status are the established prognostic and/or predictive factors for selection of adjuvant treatments. The role of new biomarkers, such as p53, HER2/neu, angiogenesis, and the proliferation index value, is promising; however, the clinical value of their determination must be provided by prospective clinical studies.

The combination of gemcitabine and vinorelbine is an active regimen as second-line therapy in patients with metastatic breast cancer pretreated with taxanes and/or anthracyclines: a phase I-II study.

PURPOSE: To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes. Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m2 and vinorelbine was given at the fixed dose of 25 mg/m2, both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m2 per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30-70) and median performance status (PS, ECOG score), 1 (range 0-2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively. RESULTS: The optimal schedule for the combination was gemcitabine 800 mg/m2 and vinorelbine 25 mg/m2. The maximum tolerated dose of gemcitabine was 1000 mg/m2, with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3-9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28-57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone. CONCLUSIONS: The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline-based schedules or with combinations of anthracyclines and taxanes.

[Innovative treatment in oncology]. / Terapie innovative in oncologia.

The improved knowledge of the key molecular mechanisms involved in cell transformation and tumor progression allows to the identification of new therapeutic targets for anticancer therapy. Several molecular-targeting compounds have been developed, capable to selectively interfire with tumorangiogenesis, receptors with tyrosin-chinase activity, specific tumor growth factors. A rationale selection of the patients as well as an appropriate monitoring of pharmacodynamics effects of molecular-targeting compounds need of the availability of surrogate markers, assessable in tumor tissue of circulating blood.