Mihaela C. Cristea

Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer

PURPOSE A 2006 randomized trial demonstrated a 16-month survival benefit with intraperitoneal and intravenous (IP/IV) chemotherapy administered to patients who had ovarian cancer, compared with IV chemotherapy alone, but more treatment-related toxicities. The objective of this study was to examine the use and effectiveness of IP/IV chemotherapy in clinical practice. PATIENTS AND METHODS Prospective cohort study of 823 women with stage III, optimally cytoreduced ovarian cancer diagnosed at six National Comprehensive Cancer Network institutions. We examined IP/IV chemotherapy use in all patients diagnosed between 2003 and 2012 (N = 823), and overall survival and treatment-related toxicities with Cox regression and logistic regression, respectively, in a propensity score-matched sample (n = 402) of patients diagnosed from 2006 to 2012, excluding trial participants, to minimize selection bias. RESULTS Use of IP/IV chemotherapy increased from 0% to 33% between 2003 and 2006, increased to 50% from 2007 to 2008, and plateaued thereafter. Between 2006 and 2012, adoption of IP/IV chemotherapy varied by institution from 4% to 67% (P < .001) and 43% of patients received modified IP/IV regimens at treatment initiation. In the propensity score-matched sample, IP/IV chemotherapy was associated with significantly improved overall survival (3-year overall survival, 81% v 71%; hazard ratio, 0.68; 95% CI, 0.47 to 0.99), compared with IV chemotherapy, but also more frequent alterations in chemotherapy delivery route (adjusted rates discontinuation or change, 20.4% v 10.0%; adjusted odds ratio, 2.83; 95% CI, 1.47 to 5.47). CONCLUSION Although the use of IP/IV chemotherapy increased significantly at National Comprehensive Cancer Network centers between 2003 and 2012, fewer than 50% of eligible patients received it. Increasing IP/IV chemotherapy use in clinical practice may be an important and underused strategy to improve ovarian cancer outcomes.

A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer

Germline variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09–2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31–7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.

Interdisciplinary Palliative Care for Patients With Lung Cancer

CONTEXT Palliative care, including symptom management and attention to quality of life (QOL) concerns, should be addressed throughout the trajectory of a serious illness such as lung cancer. OBJECTIVES This study tested the effectiveness of an interdisciplinary palliative care intervention for patients with Stage I-IV non-small cell lung cancer (NSCLC). METHODS Patients undergoing treatments for NSCLC were enrolled in a prospective, quasi-experimental study whereby the usual care group was accrued first followed by the intervention group. Patients in the intervention group were presented at interdisciplinary care meetings, and appropriate supportive care referrals were made. They also received four educational sessions. In both groups, QOL, symptoms, and psychological distress were assessed at baseline and 12 weeks using surveys which included the Functional Assessment of Cancer Therapy-Lung and the Lung Cancer Subscale, the 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, and the Distress Thermometer. RESULTS A total of 491 patients were included in the primary analysis. Patients who received the intervention had significantly better scores for QOL (109.1 vs. 101.4; P < 0.001), symptoms (25.8 vs. 23.9; P < 0.001) spiritual well-being (38.1 vs. 36.2; P = 0.001), and lower psychological distress (2.2 vs. 3.3; P < 0.001) at 12 weeks, after controlling for baseline scores, compared to patients in the usual care group. Patients in the intervention group also had significantly higher numbers of completed advance care directives (44% vs. 9%; P < 0.001), and overall supportive care referrals (61% vs. 28%; P < 0.001). The benefits were seen primarily in the earlier stage patients vs. those with Stage IV disease. CONCLUSION Interdisciplinary palliative care in the ambulatory care setting resulted in significant improvements in QOL, symptoms, and distress for NSCLC patients.

Use and Effectiveness of Neoadjuvant Chemotherapy for Treatment of Ovarian Cancer

Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute-designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease ( Ptrend < .001), and from 41% to 62% in stage IV disease ( Ptrend < .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P < .001) and from 27% to 61% ( P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have ≥ 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P ≤ .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or ≤ 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients.

Practical considerations in ovarian cancer chemotherapy

Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer.

Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival

Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes. We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y; P < 0.01) and had fewer poorly differentiated tumors (67% vs. 82%; P < 0.05). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08). Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease. This may reflect important differences between BRCA genotypes and should be validated in larger studies.

Interdisciplinary Palliative Care Intervention in Metastatic Non-Small-Cell Lung Cancer

OBJECTIVE Challenges and barriers continue to hinder the integration of palliative care models into comprehensive, ambulatory oncology care. This article aims to describe how symptoms, distress, and quality of life (QOL) data from the usual care phase of a National Cancer Institute-supported Program Project informed the development of an interdisciplinary, tailored palliative care intervention for patients with metastatic non-small-cell lung cancer (NSCLC). METHODS Patients receiving usual care for metastatic NSCLC were recruited into this prospective longitudinal study over a 1-year period. A total of 130 patients with stage IV NSCLC were accrued, and 114 patients had evaluable data. Research nurses assisted patients in completing the clinical section of the data forms, and patients completed surveys and self-reports at baseline and 6, 12, and 24 weeks. RESULTS Patients ranged in age from 40 to 84 years, and 61% were Caucasian non-Hispanic. Sixty-six former (N = 59) and current smokers had an average of 38 pack-year history of smoking. The Karnofsky Performance Status, Instrumental Activities of Daily Living, and Cognitive scores deteriorated significantly (P = .001, .009, and .042, respectively). Social Activity was stable, whereas Social Support increased significantly. Overall symptom distress score and Total symptom score both significantly increased at 24 weeks (P = .003 and .017, respectively). Physical Well-Being decreased significantly (P = .036), whereas the Functional Assessment of Cancer Therapy-Lung, Functional Assessment of Chronic Illness Therapy-Spirituality Subscale, and Distress scores remained statistically stable over time. CONCLUSIONS Patients with metastatic NSCLC continue to experience high symptom burden and diminished physical well-being over time while receiving cancer treatments. An interdisciplinary palliative care intervention is currently being tested to improve symptom burden and overall QOL.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

Background:Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.Methods:Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7–1.4 mg m−2 and CP 60–75 mg m−2. Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m−2, CP 60 mg m−2) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.Results:On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m−2, 60 mg m−2); G 3 anorexia/fatigue/hypokalemia (1.2 mg m−2, 60 mg m−2); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m−2, 60 mg m−2). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m−2, 60 mg m−2); G 4 mucositis (1.4 mg m−2, 60 mg m−2); and G 3 hypokalemia (1.2 mg m−2, 75 mg m−2). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m−2 (days 1, 8) and CP 75 mg m−2 (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).Conclusions:On the 21-day cycle, eribulin mesylate 1.2 mg m−2, administered on days 1 and 8, in combination with CP 75 mg m−2, administered on day 1 is well tolerated and showed preliminary anticancer activity.

Overcoming immunosuppression to enhance a p53MVA vaccine

A Phase I trial of a p53-targeting modified vaccinia Ankara (p53MVA) vaccine in patients afflicted with refractory gastrointestinal cancers demonstrated enhanced T-cell recognition of p53 following vaccination. However, this effect was transient suggesting that p53MVA requires combination with immunomodulatory agents to deliver clinical benefit. Here, we outline our rationale for combining p53MVA with immunomodulatory chemotherapy in a forthcoming trial.

The impact of lung cancer surgery on quality of life trajectories in patients and family caregivers

OBJECTIVES Family caregivers (FCGs) play an important role in the quality of life (QOL) of lung cancer patients. FCGs experience significant psychological distress related to their caregiving role, but there is relatively little data about FCG QOL after cancer surgery. We sought to describe QOL trajectories for patients and their FCGs after lung cancer surgery. METHODS This is a secondary analysis of a larger, prospective QOL study, testing the effectiveness of an interdisciplinary palliative care intervention for lung cancer patients and FCGs in a single institution. The intervention included interdisciplinary care planning and formal education sessions for both patients and FCGs. This subset analysis included patients who underwent surgery and had a matching FCG with complete QOL data (41 pairs of patients and caregivers out of 112 surgical patients). Patient QOL was assessed with the Functional Assessment of Cancer Therapy-Lung tool. FCG QOL was assessed with the FCG version of the City of Hope QOL tool. Psychological distress was assessed using the Distress Thermometer. RESULTS Psychological distress levels were highest for patients (3.8/10) and FCGs (5.1/10) before surgery. Distress levels decreased among patients at six (2.9/10) and 12 weeks (2.2/10, p=0.001) later, but remained elevated among FCGs (4.2/10 and 4.4/10, p=0.157). Compared with usual care, patients in the intervention group reported improved physical and functional QOL outcomes at 12 weeks (p<0.01), but there was no significant benefit seen for FCGs in any domain (p>0.05). CONCLUSIONS FCGs of lung cancer patients experience significant psychological distress. FCGs continue to have impaired QOL 3 months after surgery. The trajectory of QOL for FCGs does not mirror that of patients. Our palliative care intervention showed improved QOL outcomes for this subset of patients but was not effective for their FCGs. TRIAL REGISTRATION NCI sponsored, trial identifier NCT00823667 https://clinicaltrials.gov/show/NCT00823667.