Giovanni Randon

Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer

Purpose This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy. Methods Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.450.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%). Conclusions The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.

Metformin: a modulator of bevacizumab activity in cancer? A case report

Recurrent type I endometrial cancer (EC) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced EC treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed EC G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong 18F-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findings—albeit limited to a single case—suggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation.

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

Background Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Squamous Cell Carcinoma of the Oral Cavity in a Woman With a 9-Year History of Ovarian Cancer: Is Exposure to Pegylated Liposomal Doxorubicin a Factor?

Pegylated liposomal doxorubicin (PLD) is now being used for a variety of cancers and shows a better toxicity profile and, in some instances (e.g., ovarian cancer), more activity than free doxorubicin. Because this improved tolerance allows maintenance use, possible emerging long-term side effects such as secondary neoplasia should be considered carefully. We are reporting the case of a platinum-sensitive patient (interval free: 29 months) who has developed moderately differentiated squamous cell carcinoma (SCC) of the oral cavity after exposure to PLD. No major risks for SCC were found. There was no history of smoking or alcohol consumption, and the neoplastic tissue was negative for human papillomavirus as well as for p16 expression. The cumulative dose of PLD was 683 mg/m2, which is considerably lower than those of 11 patients reported in literature [1–6] with doses ranging from 750 mg/m2 to more than 3,000 mg/m2, although the latter was administered over a remarkable period of time (5 years). Briefly, this 65-year-old woman underwent optimal debulking surgery in April 2004 for stage IIIC serous ovarian carcinoma (ER positive, PR positive, MIB1 20%, HER2 90%, grade 2/3, stage IIIC related to abdominal lymph nodes). She underwent adjuvant therapy with eight cycles of paclitaxel-carboplatin and four cycles alternated with the addition of PLD, was enrolled in ICON5 [7] (30 mg/m2 of PLD every 6 weeks; cumulative dose: 114.4 mg/m2), and had a negative second-look exploratory reassessment in September 2004. In February 2007, she had a recurrent tumor in the liver that was initially treated with tamoxifen until May 2008, followed by second-line PLD-oxaliplatin until December 2008 (cumulative dose: 508.2 mg/m2). Oxaliplatin was discontinued after three cycles because of phlebitis. In February 2009, brain magnetic resonance imaging showed an intra-axial supratentorial mass of secondary origin. The patient underwent radical neurosurgery and then was treated with local brain radiotherapy at 20 Gy (five administrations). Since then, she has done exceptionally well. Cyclophosphamide was given as third-line therapy until July 2010, when a positron emission tomography-computed tomography (PET-CT) scan revealed retroperitoneal lymph node pathological captation confirmed by a further PET-CT scan in January 2012. Lumbo-aortic lymphadenectomy was performed in May 2012. She was treated with letrozole until April 2012, followed by tamoxifen, which was discontinued in November 2012, and lumbo-aortic radiotherapy (45 Gy, 25 administrations). In November 2012, liver recurrence was documented by ultrasonography, and she was again treated with PLD (two cycles; cumulative dose: 60mg/m2) until December 2012, obtaining partial response. The patient started complaining of an oral cavity lesion, which was initially underestimated by the patient, who used to wear orthodontic braces. The lesion was removed in December 2012, and histological examination showed SCC (pT1pN0pM0, grade 2). Submandibular ultrasonography was negative for lymph node metastases. PLD was discontinued, and the patient is now being treated with gemcitabine-carboplatin with no change in response. In October 2013, another surgical check of same area of the tongue lesion confirmed persistence or local recurrence of grade 2 SCC. As recently outlined by Muggia [6], it seems reasonable to avoid prolonged exposure to PLD while we await further molecular biology analysis to help identify patients at major risk of developing PLD-related secondary malignancies or the advent of new strategies for reducing these PLD oral effects, such as clinical trials with N-acetylcysteine or other measures for inhibiting potentially carcinogenic activation of “free radicals” from chronic exposure to anthracyclines and their metabolites.

Clinical and molecular determinants of extrahepatic disease progression (ePD) in initially unresectable, liver limited metastatic colorectal cancer (mCRC).

e15511Background: In the last years, availability of active upfront systemic regimens, development of surgical techniques and diffusion of locoregional treatments (LrTx) increased the therapeutic o...

581PMetronomic capecitabine plus cyclophosphamide in unresectable or relapsed pseudomyxoma peritonei

and showed longer time to complications (18m vs 1m, p1⁄4 0.004). In patients treated with BV, complications were similar in SEMS and surgery (40% vs 31%, RR 1.28, p1⁄4 0.5) and perforation was also similar (13% vs 19%, RR 1.46, p1⁄4 0.4). The incidence of perforation in the SEMS group was similar between BV and chemotherapy alone (13% vs 9%, p1⁄4 0.2). In patients without systemic therapy, complications were higher in the surgery group compared to SEMS (50% vs 25%, RR 1.34, p1⁄4 0.1), also the incidence of perforation (20% vs 6%, RR 1.57, p1⁄4 0.2), but not statistically significant. SEMS and surgery showed similar OS (14m vs 15m, p1⁄4 0.5). Treatment with BV increased OS in SEMS group (18 months vs 7 months, p1⁄4 0.001) and surgery group (20 months vs 4 months, p1⁄4 0.001) compared to patients without subsequent medical treatment. In the multivariate analysis, patients treated with subsequent medical treatment showed a statistically significant longer OS [HR 0.43, CI95% 0.19-0.94, p1⁄4 0.02] and patients who had complications, showed a shorter OS (HR 2.45, CI95% 1.17-5.12, p1⁄4 0.01).

“Systemic strategy at the patient’s service”: a congress report on supportive care in oncology

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