Henry G. Kaplan

Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma.

PURPOSE Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety. RESULTS Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). CONCLUSION Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.

Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Impact of Triple Negative Phenotype on Breast Cancer Prognosis

Abstract:  Triple negative (TN) [estrogen receptor (ER), progesterone receptor (PgR)] (ER−/PgR−/Her2/neu−) breast cancer (BC) is an aggressive disease without tumor‐specific treatment options. Our objective is to evaluate the relative contribution of combined Her2/neu (Her2) and hormone receptor (HR) status to BC progression. A prospective primary BC cohort of 1550 patients at our institution, stage I–IV, from 1998 to 2003 were categorized by HR and Her2 status into ER+/PgR+/Her2− (HR+/Her2−) (n = 1134), ER+/PgR+/Her2+ [triple positive (TP)] (n = 138), ER−/PgR−/Her2− (TN) (n = 183), and ER−/PgR−/Her2+ (HR−/Her2+) (n = 95). Clinical variables were chart abstracted and vital and disease status updated annually. Log‐rank tests and Cox regression analyses were used to assess associations with survival. Patient age ranged from 21 to 88 years and average length of follow‐up was 4.24 years. Overall survival at 5 years was 94% (HR+/Her2−), 91% (TP), and 81% (TN and HR−/Her2+) (log rank test = 22.22, p < 0.001). Disease‐specific survival at 5 years was 98% (HR+/Her2−), 93% (TP), 88% (TN), and 86% (HR−/Her2+) (log rank test = 25.85, p < 0.001) and 5‐year relapse‐free survival was 95% (HR+/Her2−), 89% (TP), 84% (TN), and 76% (HR−/Her2+) (log rank test = 20.29, p < 0.001). In a model adjusted for age, race, TNM stage, and treatment using HR+/Her2− patients as the reference group, recurrence risk was 1.98 for TP (95% CI = 1.02 to 3.84), 2.32 for TN (95% CI = 1.32 to 4.08), and 4.25 for HR−/Her2+ patients (95% CI = 2.33, 7.75). A hierarchy of BC phenotypes defined by HR and Her2 status exists with progressively worse disease outcomes by category.

Metastatic Adenocarcinoma After Augmentation Gastrocystoplasty

PURPOSE Augmentation gastrocystoplasty has been proposed as an alternative to enterocystoplasty because of potential benefits, including decreased risk of mucus production, stone formation and urinary tract infections. Although cancer has rarely been reported in this patient population, it is a well recognized potential risk of all augmentation cystoplasties. To define better the risk of malignancy associated with gastric augmentation and the appropriate surveillance protocol for these patients, we describe our experience in 2 patients with metastatic adenocarcinoma following gastrocystoplasty. MATERIALS AND METHODS We retrospectively reviewed the charts of all patients who had undergone augmentation gastrocystoplasty between 1990 and 1994. Of the 72 patients identified 2 were diagnosed with a primary malignancy arising from the augmented bladder. Charts were reviewed for medical history, clinical outcomes and pathology. RESULTS Two patients were identified with a primary bladder malignancy after gastrocystoplasty. Both patients had metastatic disease at initial presentation. Neither patient had a history of gross hematuria, recurrent urinary tract infections or pain before initial presentation. Mean patient age at augmentation was 5.5 years. Mean age at diagnosis of malignancy was 19.5 years, with a mean time from augmentation of 14 years. CONCLUSIONS Although the risk of bladder cancer is low after gastric augmentation, the effects may be life threatening. Therefore, we advocate routine annual surveillance with cystoscopy, bladder biopsy and upper tract imaging in all patients who have undergone augmentation gastrocystoplasty.

T1N0 Triple Negative Breast Cancer: Risk of Recurrence and Adjuvant Chemotherapy

Abstract:  Adjuvant treatment of T1N0 breast cancer (BC) has evolved in recent years with chemotherapy options dependent on tumor size and cellular characteristics. Our goal is to describe the difference in outcome between T1N0 triple negative (TriNeg) and estrogen/progesterone receptor positive/her2/neu‐negative BC. From our institute’s registry, we identified primary BC patients diagnosed from 1998 to 2005, estrogen/progesterone receptor negative (ER−/PR−)/her‐2/neu negative (her2−) (TriNeg = 110) and ER+/PR+/her2− (HR+/her2− = 919). Clinical diagnosis and treatment variables were chart abstracted. Vital and disease status were updated annually. Pearson chi‐squared tests were used for bivariate analysis. Hazard ratios were calculated using the Cox proportional hazards model. Average patient age was 59 years, range 23–93 years and average length of follow‐up was 4.22 years. T‐stage distribution for HR+/her2− patients was 9% T1a (>0.1, ≤0.5 cm), 34% T1b (>0.5 cm, ≤1 cm), 57% T1c (>1 cm, ≤2 cm) and for TriNeg, 6% T1a, 21% T1b, and 73% T1c. Sixty‐five per cent of T1b and 73% T1c TriNeg patients received chemotherapy versus 7% of T1b and 32% of T1c HR+/her2− patients with TriNeg patients more likely to receive doxorubicin/cyclophosphamide/paclitaxel combined therapy. Recurrence rates were the following, T1b: 8.7%, TriNeg (2/23) versus 0%, HR+/her2− (0/315) and T1c: 8.8%, TriNeg (7/80) versus 2.1%, HR+/her2− (11/523). Five year relapse‐free survival was 98% in the HR+/her2− group and 89% in the TriNeg group (log rank test = 27.77, p < 0.001). The hazard ratio for recurrence in the TriNeg group was 6.57 (95% CI = 2.34, 18.49) adjusted for age, tumor size, and adjuvant chemotherapy. Triple negative T1N0 patients have greater recurrence risk in spite of more aggressive therapy by both number treated and adjuvant chemotherapy type even in a low‐risk category. New treatment modalities specific for triple negative disease are urgently needed.

Impact of Mammography Detection on the Course of Breast Cancer in Women Aged 40–49 Years

PURPOSE To analyze trends in detection method related to breast cancer stage at diagnosis, treatments, and outcomes over time among 40-49-year-old women. MATERIALS AND METHODS i This study was institutional review board approved, with a waiver of informed consent, and HIPAA compliant. A longitudinal prospective cohort study was conducted of women aged 40-49 years who had primary breast cancer, during 1990-2008, and were identified and tracked by a dedicated registry database (n = 1977). Method of detection--patient detected (PtD), physician detected (PhysD), or mammography detected (MamD)--was chart abstracted. Disease-specific survival and relapse-free survival statistics were calculated by using the Kaplan-Meier method for stage I-IV breast cancer. RESULTS A significant increase in the percentage of MamD breast cancer over time (28%-58%) and a concurrent decline in patient and physician detected (Pt/PhysD) breast cancer (73%-42%) (Pearson x(2) = 72.72, P < .001) were observed over time from 1990 to 2008, with an overall increase in lower-stage disease detection and a decrease in higher-stage disease. MamD breast cancer patients were more likely to undergo lumpectomy (67% vs 48% of Pt/PhysD breast cancer patients) and less likely to undergo modified radical mastectomy (25% vs 47% of the Pt/PhysD breast cancer patients) (P < .001). Uncorrected for stage, 13% of MamD breast cancer patients underwent surgery and chemotherapy versus 22% of Pt/PhysD breast cancer patients (P < .001), and 31% of MamD breast cancer patients underwent surgery, radiation therapy, and chemotherapy versus 59% of Pt/PhysD breast cancer patients (x(2) = 305.13, P < .001). Analyzing invasive cancers only, 5-year relapse-free survival for MamD breast cancer patients was 92% versus 88% for Pt/PhysD patients (log-rank test, 12.47; P < .001). CONCLUSION Increased mammography-detected breast cancer over time coincided with lower-stage disease detection resulting in reduced treatment and lower rates of recurrence, adding factors to consider when evaluating the benefits of mammography screening of women aged 40-49 years.

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Leukemia incidence following primary breast carcinoma treatment

The results of randomized clinical trials have suggested that after receiving radiotherapy and/or chemotherapy, patients with primary breast carcinoma have an increased risk of developing leukemia. In the current study, the authors set out to assess the reported association between breast carcinoma treatment and leukemia risk.

Hepatitis Caused by Halothane Sniffing

Excerpt Halothane has been identified as the cause of hypersensitivity-mediated hepatitis (1). Repeated use of this agent has frequently caused hepatotoxicity in humans (2, 3) and laboratory animal...

Improved Prognosis of Women Aged 75 and Older with Mammography-detected Breast Cancer

PURPOSE To evaluate the characteristics and outcomes of women aged 75 years and older with mammography-detected breast cancer, an age group not represented in mammography screening effectiveness studies. MATERIALS AND METHODS We conducted a HIPAA-compliant, prospective cohort study with waiver of informed consent in patients with primary breast cancer, aged 75 years and older, with stage 0-IV disease from 1990 to 2011, identified and tracked with our registry database (n = 1162). Details including stage, treatment, outcomes, and method of detection (by patient, physician, or mammography) were noted from the chart at the time of diagnosis. Kaplan-Meier estimation was used to compare invasive disease-specific survival rates. RESULTS Among patients with breast cancer aged 75 years and older, mammography detection of cancers increased over time, from 49% to 70% (P < .001). Mammography-detected cases were more often stage I (62%), whereas patient- and physician-detected cases were more likely stage II and III (59%). Over time, from 1990 to 2011, the incidence of stage II cancers decreased by 8%, the incidence of stage III cancers decreased by 8%, and the incidence of stage 0 cancers increased by 15% (P < .001). Patients with mammography-detected invasive breast cancer were more often treated with lumpectomy and radiation and underwent fewer mastectomies and less chemotherapy than patients with cancer detected by patients and physicians (P < .001). Mammography detection was associated with significantly better 5-year disease-specific survival for invasive breast cancer (97% vs 87% for patient- and physician-detected cancer [P < .001], respectively). CONCLUSION Mammography-detected breast cancer in women 75 years and older was diagnosed at an earlier stage, required less treatment, and had better disease-specific survival than patient- or physician-detected breast cancer. These findings indicate that the same benefits of mammography detection observed in younger women extend to older women.