Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial.

PURPOSE: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. PATIENTS AND METHODS: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. RESULTS: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. CONCLUSIONS: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious. See related commentary by Gonzalez-Ochoa and Oza, p. 2563.

Fractionated 9°Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria.

PURPOSE: We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated (90)Y-ibritumomab tiuxetan ((90)Y-IT) as initial therapy of follicular lymphoma (FL). PATIENTS AND METHODS: A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of (90)Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m(2)) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). RESULTS: Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. CONCLUSION: Fractionated RIT using (90)Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index.

BACKGROUND: TSH secretion in hypopituitary patients may be decreased due to TSH deficiency but it also remains under feedback inhibition by free thyroxine (fT4). We propose a TSH index (TSHI), as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, to provide a true estimate of pituitary thyrotroph function and any pathological pituitary suppression. METHODS: A total of 9519 thyroid function tests (TFTs) (Bayer Immuno-1) in 4064 patients of our institution were examined, including 444 patients investigated for hypopituitarism. Based on the physiological log-linear relationship between fT4 and TSH, we estimated the amount of feedback-induced change in log TSH per change in fT4, which allowed the extrapolation of log TSH to a fixed fT4 of 0, defining the TSHI. TSHIs were compared with other measures of pituitary function. RESULTS: Feedback inhibition was estimated to cause a 0.1345 decrease in log TSH (mU/l) for 1 pmol/l increase in fT4 concentration, therefore TSHI = log TSH + 0.1345 x fT4. Patients with lower peak-stimulated GH and cortisol concentrations had a significantly lower TSHI (P < 0.0001). TSHIs measured before pituitary stimulation tests predicted highly significantly the risk of test failure (P = 0.0002). Of all potential fT4-TSH combinations within the current reference ranges, 21.9% were identified as abnormal on the basis of the TSHI. CONCLUSION: The TSHI provides an accurate estimate of the severity of pituitary dysfunction in hypopituitary patients based on simple TFTs. It predicts the probability of pituitary stimulation test failure and extends the diagnosis of TSH deficiency into areas of the normal TFT reference ranges.

Tumor expression of major vault protein is an adverse prognostic factor for radiotherapy outcome in oropharyngeal carcinoma.

PURPOSE: Vaults are multi-subunit structures that may be involved in nucleo-cytoplasmic transport, with the major vault protein (MVP or lung resistance-related protein [LRP]) being the main component. The MVP gene is located on chromosome 16 close to the multidrug resistance-associated protein and protein kinase c-beta genes. The role of MVP in cancer drug resistance has been demonstrated in various cell lines as well as in ovarian carcinomas and acute myeloid leukemia, but nothing is known about its possible role in radiation resistance. Our aim was to examine this in head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Archived biopsy material was obtained for 78 patients with squamous cell carcinoma of the oropharynx who received primary radiotherapy with curative intent. Immunohistochemistry was used to detect MVP expression. Locoregional failure and cancer-specific survival were estimated using cumulative incidence and Cox multivariate analyses. RESULTS: In a univariate and multivariate analysis, MVP expression was strongly associated with both locoregional failure and cancer-specific survival. After adjustment for disease site, stage, grade, anemia, smoking, alcohol, gender, and age, the estimated hazard ratio for high MVP (2/3) compared with low (0/1) was 4.98 (95% confidence interval, 2.17-11.42; p = 0.0002) for locoregional failure and 4.28 (95% confidence interval, 1.85-9.95; p = 0.001) for cancer-specific mortality. CONCLUSION: These data are the first to show that MVP may be a useful prognostic marker associated with radiotherapy resistance in a subgroup of patients with HNSCC.

Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy.

PURPOSE: To investigate whether delivering an increased radiation dose to the tumor-bearing region of the bladder alone would improve local disease control without increasing treatment toxicity. METHODS AND MATERIALS: A total of 149 patients with unifocal T2-T3N0M0 bladder carcinoma were randomized between whole bladder conformal radiotherapy (WBRT, 52.5 Gy in 20 fractions, n = 60) and partial bladder conformal RT (PBRT) to tumor alone with 1.5-cm margins within either 4 weeks (PBRT4, 57.5 Gy in 20 fractions, n = 44) or 3 weeks (PBRT3, 55 Gy in 16 fractions, n = 45). The response was assessed cystoscopically after 4 months. RESULTS: The 5-year overall and CFS rate was 58% and 47%, respectively, for the whole population. The CR rate was 75% for WBRT, 80% for PBRT4, and 71% for PBRT3 (p = 0.6), with a 5-year local control rate of 58%, 59%, and 34%, respectively (p = 0.18). Solitary new tumors arose within the bladder, outside the irradiated volume, in 6 (7%) of 89 patients who underwent PBRT. The 5-year overall survival and cystectomy-free survival rate was 61% and 49% for WBRT, 60% and 50% for PBRT4, and 51% and 41% for PBRT3 (p = 0.81 and p = 0.59). The treatment toxicity was mild and equivalent across the three trial arms. CONCLUSION: The reduction in treatment volume allowed delivery of an increased radiation dose without a reduction in local tumor control or the development of excess toxicity. However, this dose-escalated partial bladder approach did not result in significantly improved overall survival.