Francesca Galli

Estimating the risk of chemotherapy toxicity in older patients with cancer: The role of the Vulnerable Elders Survey-13 (VES-13).

OBJECTIVE Some parameters of the Comprehensive Geriatric Assessment (CGA) are predictive of chemotherapy toxicity. The Vulnerable Elders Survey-13 (VES-13) is a short instrument that has been tested as a means of identifying patients who need a full CGA, but its ability to predict chemotherapy toxicity is still unclear. We performed a pooled analysis of four published clinical trials studying VES-13 as a means of diagnosing vulnerability, in order to evaluate its accuracy in predicting the risk of grade 3/4 toxicity in older patients undergoing chemotherapy. MATERIALS AND METHODS The study involved patients aged ≥ 66 years with a diagnosis of solid or hematological cancer, all of whom were administered VES-13. The number of medications taken by each patient, their comorbidities, their Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score and index, the type of chemotherapy and treatment line, and their Mini Mental State Evaluation (MMSE), and Mini Nutritional Assessment (MNA) scores were recorded. Information was available concerning the grades 3-4 hematological and non-hematological toxicities experienced by each patient. RESULTS The study involved 648 patients aged ≥ 66 years (mean age 76.2±4.5, range 66-90) of whom 336 (51.9%) were female. VES-13 identified 287 patients (44.3%) as vulnerable. Grades 3-4 hematological and non-hematological toxicities were more prevalent in the vulnerable subjects (35.2% vs 20.8%, p<0.0001, and 18.5% vs 10.8%, p=0.0055), who were also at higher risk of both (adjusted ORs 2.15, 95% CI 1.46-3.17, p<0.001); and 1.66 (95% CI 1.02-2.72, p=0.043). CONCLUSIONS VES-13 could be considered to be a good candidate for future prospective studies to assess older patients with cancer at risk of toxicity.

Genetic markers for toxicity of adjuvant oxaliplatin and fluoropyrimidines in the phase III TOSCA trial in high-risk colon cancer patients

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II–III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3–4 CTCAE toxicity events (grade 2–4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Long-term results of fertility-sparing treatment compared with standard radical surgery for early-stage epithelial ovarian cancer

Background:The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC).Methods:A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS).Results:A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P<0.001) and shorter CSS (P=0.001). The type of treatment did not influence CSS or RFI in any grade group. We also found a significant association between low-grade tumours and younger age.Conclusions:Fertility-sparing surgery is an adequate treatment for patients with stage I EOC. The clinical outcome of patients with G3 tumours, which is confirmed to be the most important prognostic factor, is not determined by the type of treatment received.

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

BACKGROUND Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. PATIENTS AND METHODS Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. CONCLUSION Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

Radiosurgery for intracranial meningiomas: A systematic review and meta-analysis

BACKGROUND Radiosurgery(RS), both in single and multiple sessions, have been performed for intracranial meningiomas. Different aspects are still controversial on this field. The aim of this systematic review is to summarize the current literature on long-term efficacy and safety of RS for meningiomas. METHODS Online databases were searched for studies published until April 2015. The primary outcomes were disease control and progression-free-survival(PFS). The secondary outcomes were symptom control and radiation-induced toxicity. RESULTS The estimate of disease control rate ranged from 87.0% to 100.0% at 5 years and from 67.0% to 100.0% at 10 years. The PFS rate ranged 78.0%-98.9% and 53.1%-97.2% at 5 and 10 years, respectively. The overall symptom control was 92.3%, the overall toxicity was 8.1%. CONCLUSIONS RS can be considered a safe and effective treatment. Efforts are needed in standardizing the definition of local and symptom control and toxicity in order to properly compare different treatment schedules.

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

Background:Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity.Methods:The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used.Results:FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.Conclusions:This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Nonresponsiveness and Susceptibility of Opioid Side Effects Related to Cancer Patients’ Clinical Characteristics: A Post-Hoc Analysis

The response to opioids is not always positive in cancer patients. A considerable proportion of patients do not respond (nonresponders [NRs]) or experience severe toxicity. The aim of this analysis was to assess the role of demographic characteristics, pain features, comorbidities, and ongoing therapy on the lack of efficacy and on the occurrence of severe adverse drug reactions (ADRs).

A phase II randomised (calibrated design) study on the activity of the single-agent trabectedin in metastatic or locally relapsed uterine leiomyosarcoma

BackgroundPatients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS.MethodsEligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m2 or calibration Arm B: gemcitabine 900 mg/m2 and docetaxel 75 mg/m2. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%.ResultsOverall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2–45). No difference in PFS by the number of previous chemotherapy lines emerged. Median OS = 20.6 months (IQR: 8–36.4). In Arm B, the PFS-6 = 51.5% (95% CI: 33.5–69.2). No toxic deaths occurred. In Arm A, only 4 patients interrupted treatment for toxicity.ConclusionsTrabectedin is active and well tolerated, retaining similar efficacy across one to three previous lines of chemotherapy.

A comparison between the administration of oral prolonged-release oxycodone-naloxone and transdermal fentanyl in patients with moderate-to-severe cancer pain: a propensity score analysis

Background Opioids are the most important pharmacological treatment for moderate-to-severe cancer pain, but side effects limit their use. Transdermal fentanyl (TDF) and oral prolonged-release oxycodone-naloxone (OXN-PR) are effective in controlling chronic pain, with less constipation compared to other opioids. However, TDF and OXN-PR have never been directly compared. Patients and methods Cancer patients with moderate-to-severe chronic pain were consecutively enrolled in two prospective 28-day trials, received either TDF or OXN-PR, and were assessed at baseline and after 7, 14, 21, and 28 days. The primary endpoint was 28-day analgesic response rate (average pain intensity decrease ≥30% from baseline). Other outcome measures included opioid daily dose changes over time; need for adjuvant analgesics; number of switches; premature discontinuation; presence and severity of constipation; and other adverse drug reactions. To compare the efficacy and the safety of TDF and OXN-PR, we used the propensity score analysis to adjust for heterogeneity between the two patient groups. Results Three hundred ten out of 336 patients originally treated (119 TDF and 191 OXN-PR) were included in the comparative analysis. The amount of responders was comparable after TDF (75.3%) and OXN-PR administration (82.9%, not significant [NS]). The final opioid daily dose expressed as morphine equivalent was 113.6 mg for TDF and 44.5 mg for OXN-PR (p<0.0001). A daily opioid dose escalation >5% was less common after OXN-PR (19.3%) than after TDS administration (37.9%, p<0.0001). Opioid switches and discontinuation were similar in both groups. Severe constipation in the two groups was comparable (32.6% after TDF vs 24.7% after OXN-PR, NS). Nausea, vomiting, and dry mouth were significantly less frequent in the OXN-PR group than in the TDF group. Conclusion Despite a similar analgesic activity in moderate-to-severe cancer pain, OXN-PR is characterized by lower daily dosages, less need for drug escalation, and fewer side effects compared to TDF.

The Glaucoma Italian Pediatric Study (GIPSy): 1-Year Results

Purpose: To investigate the efficacy and safety of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery. Patients and Methods: Children with primary pediatric glaucoma having postsurgical untreated intraocular pressure (IOP) between 22 and 26 mm Hg were eligible. At baseline, patients were administered latanoprost once daily. Depending on IOP reduction, patients were allocated to continuation of latanoprost monotherapy or addition of dorzolamide twice daily, or switch to dorzolamide monotherapy 3 times daily. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered nonresponders. The primary endpoint was the percentage of responders. Study treatment continued for 3 years or until treatment failure. The present article reports the 1-year analysis results. Results: A total of 35 patients (57 eyes) were analyzed. The mean age was 4.0 years (SD, 3.8). In total, 51 eyes were included in the efficacy analysis. In total, 43 eyes (84.3%; 95% confidence interval, 74.3-94.3) were considered responders: 29 on latanoprost monotherapy, 11 on the latanoprost/dorzolamide combination, and only 3 on the dorzolamide monotherapy. The efficacy of pharmacological treatment was inversely related to the age at the time of surgery. IOP reduction was 8.7 mm Hg (SD, 2.2) for latanoprost, 7.5 mm Hg (SD, 1.4) for the latanoprost/dorzolamide combination, and 8.7 mm Hg (SD, 2.1) for the dorzolamide monotherapy. Only mild or moderate local adverse events were noted. None of the patients was withdrawn due to adverse events. Conclusion: Latanoprost alone or in combination with dorzolamide is safe and highly effective in lowering IOP in children postsurgery. Nonresponders were mainly patients with early presentation of the disease.