Biosimilar medicines in oncology: single-center experience with biosimilar G-CSF.

AIMS: A biosimilar medicine is one with proven similarity to a reference biological product for which the patent has expired and whose active ingredient is produced or derived from a living organism. Recombinant granulocyte colony-stimulating growth factors (G-CSF) are used for the prophylaxis of febrile neutropenia. MATERIALS & METHODS: In this observational, single-center study, a total of 48 patients with solid tumors were treated with a new biosimilar G-CSF (Zarzio(®)) for 4-14 days from the day following the end of chemotherapy. RESULTS: Between October 2010 and July 2011, biosimilar G-CSF was administered as primary prophylaxis in 37 patients and as secondary prophylaxis in 11 patients in our clinic. The median length of G-CSF administration was 7 days (range: 1-12 days). Three cases of febrile neutropenia were reported: two in patients with prostate adenocarcinoma and one in a patient with pulmonary squamous cell carcinoma and multiple secondary skeletal lesions. These patients were treated with antibiotics and improved within 24 h without the need for hospitalization. Nonfebrile grade 4 neutropenia was observed in a further six patients. CONCLUSION: Our experience indicates that the use of biosimilar G-CSF is safe and effective at reducing neutropenic complications in patients with solid tumors and may be associated with cost savings.

Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index.

BACKGROUND: Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score. METHODS: We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012). RESULTS: In the training cohort (n = 217), the median age was 69 years (range: 32-89), and the primary tumours were non-small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60-3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31-3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13-2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0006) within the external cohort. CONCLUSION: Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs.

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice.

BACKGROUND: Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors. METHODS: We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, ß-blockers, metformin and other oral antidiabetics, opioids. RESULTS: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and ß-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death. CONCLUSION: We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.

Bisphosphonates and oral cavity avascular bone necrosis: a review of twelve cases.

BACKGROUND: Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy and for the prevention of skeletal complications associated with bone metastases. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. PATIENTS AND METHODS: The data for twelve patients, referred to either an oral and maxillofacial surgeon or to an oral medicine specialist for the management of clinically apparent chronic oral osteonecrosis of unknown etiology, were reviewed. All had received cancer-related therapy simultaneously with bisphosphonate management. RESULTS: The typical presenting symptoms were pain and exposed bone at the site of a previous tooth extraction. In most patients, the lesions initially occurred after dental extraction or other odontostomatological procedures, while five had a spontaneous event. Biopsy of the involved area showed the presence of necrotic lacunae, with infiltration of lymphocytes and histiocytes. In nine cases, there was histological or cytological diagnosis of suspicious osteomyelitis. No correlation was observed between the intraoral lesions and myelosuppression secondary to antineoplastic therapy. CONCLUSION: Based on the patients' respective histories, clinical presentations and responses to surgical and antibiotic treatments, it appears that the pathogenesis of this osteonecrotic process is most consistent with localized vascular insufficiency. In our opinion, the mechanism by which bisphosphonates compromise bone vascularity may be related to their effect on the osteoclasts. The potent bisphosphonate-mediated inhibition of osteoclast function serves to decrease bone resorption and inhibit normal bone turnover remodeling, resulting in microdamage accumulation and a reduction in some mechanical properties of the bone.

Clinical experience with bevacizumab in colorectal cancer.

Angiogenesis, the process of generating new capillary blood vessels, is a fundamental requirement for normal physiological processes including embryogenesis, reproductive function and wound healing. Angiogenesis is also implicated in various pathological conditions including age-related retinal macular degeneration, diabetic retinopathy, rheumatoid arthritis, psoriasis and cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the best characterized of the pro-angiogenic growth factors, and multiple strategies have been developed to inhibit this pathway. Bevacizumab, a monoclonal antibody developed against VEGF, has shown initial preclinical and clinical activity. This review discusses the critical role of VEGF and summarizes the available data on the use of bevacizumab in colorectal cancer.

Testis metastasis as an initial manifestation of an occult gastrointestinal cancer.

Metastatic epithelial malignant tumor involving the spermatic cord and epididymis is rare and the prognosis of these patients is poor. Usually gastrointestinal cancers show diffusion to liver, lung and bone. Several routes by which a colorectal cancer can metastasize to the testis have been reported in literature. Herein we report a case of an occult gastrointestinal cancer with an intrascrotal metastasis in an adult patient with possible spread through the spermatic veins due to primary intestinal carcinoma. In the case of a testicular mass or hydrocele evidence in a patient with an unusual age for primary testis tumor, a diagnosis of metastatic cancer should be considered.

Alfa-epoietin and anaemia in gynaecological cancer.

The incidence and severity of anaemia in gynaecological cancer patients depends on several factors including age, histology and tumor stage, site of neoplasm and treatment. At present, two principal opinions are available for the management of chronic anaemia in cancer patients: blood transfusions and treatment with recombinant human Erythropoietin (rHuEPO). Clinical studies showed that rHuEPO can ameliorate chronic and chemotherapy-induced anaemia and reduce transfusions in patients with various malignant diseases. In this review we discuss the role of alfa-epoetin in the management of gynaecological and breast cancers.

[Hamartomatous polyposis syndromes]. / Sindromi poliposiche amartomatose.

Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Peutz-Jeghers syndrome and juvenile polyposis are both characterized by the presence of hamartomatous polyps and increased risk of malignancy in the gastrointestinal tract. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease.

Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients.

BACKGROUND: To evaluate the modifications of circulating angiogenic factors, metalloproteinases and acute-phase cytokines after the first single zoledronic acid (ZA) intravenous infusion. EXPERIMENTAL DESIGN: Eighteen consecutive breast cancer patients with bone metastases were evaluated for circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinase 1 (MMP-1), metalloproteinase 2 (MMP-2), interleukins 1beta, 6 and 8 (IL-1beta, IL-6, IL-8), interferon gamma, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta1 just before and 2 and 7 days after ZA infusion. RESULTS: The MMP-2 basal value showed a statistically significant decrease 48 h after ZA (p = 0.01), being at 7 days higher than the day 2 value (p = 0.03). The VEGF basal value showed a statistically significant decrease 48 h after ZA infusion (p = 0.03), increasing above the basal level at 7 days (p = 0.07). The bFGF basal level almost significantly decreased 2 days after infusion (p = 0.06), being at 7 days higher than the basal value (p = 0.09). Comparing the day 2 values with basal ones, the linear regression model showed a significant positive correlation between IL-8 and bFGF (p = 0.02), IL-8 and TNF-alpha (p < 0.0001), bFGF and TNF-alpha (p = 0.01), MMP-1 and TNF-alpha (p = 0.02). CONCLUSIONS: ZA could exert an antiangiogenic activity and inhibition of tumor cell bone invasiveness by a transient reduction of VEGF, bFGF and MMP-2 circulating levels after infusion.