What proportion of patients with stage 3 ovarian cancer are potentially cured following intraperitoneal chemotherapy? Analysis of the long term (≥10 years) survivors in NRG/GOG randomized clinical trials of intraperitoneal and intravenous chemotherapy in stage III ovarian cancer.

OBJECTIVE: Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS. METHODS: Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS. RESULTS: Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23-28%) and LTDFS ≥10 years was 18% (95% CI, 16-20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p < 0.001). Younger age (p < 0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis. CONCLUSIONS: Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes.

The Evolving Arena of Ovarian Cancer Maintenance Therapy.

Based on the results of several phase 3 randomized trials, "maintenance therapy" (prolonged treatment after an initial response to cytotoxic chemotherapy) has assumed a critical role in the routine care of advanced epithelial ovarian cancer. While earlier data had provided support for this therapeutic concept in disease management (e.g., multiple cycles of single-agent paclitaxel following a clinical complete response to a platinum/paclitaxel regimen), more recent data has revealed both the efficacy and safety of the anti-angiogenesis agent, bevacizumab, and several PARP inhibitors when employed in this clinical setting.

Differences in presentation and survival of Asians compared to Caucasians with ovarian cancer: An NRG Oncology/GOG Ancillary study of 7914 patients.

PURPOSE: To compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer. METHODS: Ancillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed. RESULTS: Of 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p < 0.001), and were more likely to be of clear cell (15.8% vs. 6.2%, p < 0.001) and mucinous (3.3% vs. 1.9%, p < 0.001) histology. Asians had an improved 5-year disease-specific survival of 54.1% compared to 46.1% for Caucasians, p = 0.001. In multivariate analysis, the Asian race remained a significant prognostic factor for all-cause survival (HR: 0.84; 95% CI: 0.72-0.99; p = 0.04). Other factors predictive of improved survival included younger age, better performance status, optimal cytoreduction, earlier stage, non-clear cell histology, and lower grade tumors. CONCLUSION: Asians enrolled into phase III ovarian cancer clinical trials were younger, with better performance status, earlier-stage of disease, and have a greater number of clear cell and mucinous tumors. After adjusting for these prognostic factors, Asians have a better survival compared to Caucasians.

Self-forgiveness is associated with reduced psychological distress in cancer patients and unmatched caregivers: Hope and self-blame as mediating mechanisms.

This study examined the association between self-forgiveness and psychological distress and tested whether self-blame and hope mediated these associations equally for both patients and caregivers. Participants were 38 patients and 44 unmatched caregivers receiving care at a national cancer hospital. Participants completed measures of self-forgiveness, self-blame, hope, and psychological distress. Self-forgiveness was inversely associated with self-blame and psychological distress and positively associated with hope. Self-forgiveness was indirectly associated with psychological distress through hope but not self-blame and more strongly for caregivers than patients. Group differences between patients and caregivers in associations are intriguing and may have implications for improved psychosocial care of cancer patients and support of caregivers.

Maintenance chemotherapy in the management of epithelial ovarian cancer.

The fundamental goal of maintenance therapy of cancer is to extend a clinically meaningful survival endpoint (overall, symptom-free, progression-free) while at the same time not substantially interfering with a patient's quality of life. Several phase 3 randomized trials in ovarian cancer involving different anti-neoplastics (e.g., paclitaxel, anti-angiogenic agents, olaparib) have revealed an improvement in progression-free survival with generally acceptable side effect profiles, and as a result represent in appropriately selected patients a rational therapeutic strategy.

Evaluating the Utility of a 'N-of-1' Precision Cancer Medicine Strategy: The Case for 'Time-to-Subsequent-Disease Progression'.

It is increasingly recognized that cancer is a highly heterogeneous group of illnesses even within a particular organ site (e.g., breast, lung, colon, etc.). This observation presents a serious challenge to the traditional concept of phase 3 randomized trials designed to define therapeutic efficacy of a novel treatment strategy. For while 10% of the patients with a common malignancy (e.g., non-small-cell lung cancer) may be sufficient to consider such an effort, enrolling a sufficient number of patients into a clinical trial in a timely manner to define clinical utility would be extremely difficult if the population in question represented only 1% of this population, and essentially impossible if one wished to explore the benefits of treatment in a rarer neoplasm (e.g. ovarian cancer). Therefore, in the new era of precision cancer medicine, alternative research designs are imperative. One option would be to compare the time-to-disease progression of an individual cancer patient following treatment with a novel therapeutic to the time-to-disease progression for that specific patient on her/his immediately preceding treatment. The rationale for this strategy and early experience with this innovative approach to evaluating the efficacy of anticancer therapy is highlighted in this report.

Initial experience with genomic profiling of heavily pretreated breast cancers.

BACKGROUND: Rapidly evolving advances in the understanding of theorized unique driver mutations within individual patient's cancers, as well as dramatic reduction in the cost of genomic profiling, have stimulated major interest in the role of such testing in routine clinical practice. The aim of this study was to report our initial experience with genomic testing in heavily pretreated breast cancer patients. METHODS: Patients with primary or recurrent breast cancer managed at any of our five hospitals and whose malignancy had failed to respond to therapy or had progressed on all recognized standard-of-care options were offered the opportunity to have their cancer undergo next-generation sequencing genomic profiling. RESULTS: Of a total of 101 patients, 98 (97 %) had at least one specific genomic alteration identified. A total of 465 different somatic genetic abnormalities were revealed in this group of patients. Although 52 % of patients were found to have an abnormality for which an U.S. Food and Drug Administration (FDA)-approved drug was available, 69 % of patients had an FDA-approved agent for an indication other than breast cancer. The most common genomic alterations of potential clinical consequence were PIK3 (25 %), FGFR1 (16 %), AKT (11 %), PTEN (10 %), ERBB2 (8 %), JAK2 (6 %), and RAF1 (5 %). CONCLUSIONS: Almost all advanced breast cancers possess at least one well-characterized genomic alteration that might be actionable at the clinical level. Further, in most cases, a plausible argument can be advanced for the potential biological and clinical relevance of an FDA-approved antineoplastic agent not currently indicated in the treatment of breast cancer.

The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis.

BACKGROUND: Extensive clinical experience suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) may play an important role in the management of colorectal cancer patients with peritoneal carcinomatosis (CRCPC). However, there remains no established nonsurgical process to rationally select patients for this management, either for inclusion/stratification in clinical trials or as a component of standard of care. The Peritoneal Surface Disease Severity Score (PSDSS) was introduced as a basis to improve patient selection. METHODS: The American Society of Peritoneal Surface Malignancies conducted a retrospective review of 1,013 CRCPC patients. The PSDSS was evaluated on 3 specific criteria obtained before surgery (symptoms, extent of peritoneal dissemination, and primary tumor histology). Overall survival was analyzed according to four tiers of disease severity, and a comparison was made between patients who underwent cytoreductive surgery + HIPEC and those who did not. RESULTS: The PSDSS was calculated on 884 patients (87 %). The median survival of 275 patients not undergoing CRS/HIPEC based on their PSDSS-I (n = 8), II (n = 80), III (n = 55), and IV (n = 132)-was 45, 19, 8, and 6 months, respectively. The median survival of 609 patients who underwent CRS/HIPEC based on their PSDSS-I (n = 75), II (n = 317), III (n = 82), and IV (n = 135)-was 86, 43, 29, and 28 months, respectively. CONCLUSIONS: These data support that the PSDSS, undertaken before surgery, is capable of defining CRCPC populations who have a statistically defined high or considerably lower likelihood of long-term survival after CRS/HIPEC. The PSDSS can be quite useful in the decision to enter CRCPC patients into, and their stratification within, clinical trials.

The incidence of genitourinary and gastrointestinal complications in open and endoscopic gynecologic cancer surgery.

OBJECTIVES: The purpose of this study was to examine the incidence of genitourinary and intestinal tract injuries in an effort to identify which factors might predispose a patient to developing one of these surgical complications. METHODS: We retrospectively evaluated the charts of gynecologic cancer patients who were treated at a single medical institution from January 2002 to February 2011. The following study variables were noted for evaluation: age, BMI, cancer origin, disease recurrence, a history of pelvic surgery, surgery type, operative approach and injury classification (genitourinary or gastrointestinal). RESULTS: In our group of 1,618 patients, a total of 47 (2.9%) gastrointestinal and 18 (1.1%) genitourinary tract injuries were encountered. There were no intraoperative-related deaths but 2 patients expired 1 month after surgery. Logistic regression indicated that surgery type, undergoing an open procedure, cancerous involvement of the bowel or genitourinary tract and a history of pelvic surgery were significant predictors of operative injury occurrence [χ(2) (28) = 167.22; p < 0.001]. CONCLUSIONS: We ascertained a relatively low incidence of gastrointestinal and genitourinary complications. Nevertheless, undergoing an open procedure, a history of pelvic surgery and surgical involvement of the bowel or genitourinary tract were predictive of an increased risk for these aforementioned injuries.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.

Dangers of "confirmatory" cancer trials that fail to actually test the original hypothesis.

The concept of "confirmatory" studies is a standard and important component of the overall clinical trials strategy in oncology. However, it is critical that such studies are similar enough in basic design and how they are conducted that they actually have the realistic potential to confirm, or refute, objectively the findings of the original study. In this commentary, two examples of clinical studies in the gynecologic oncology arena suggested by some to serve as "confirmatory" trials for the original reports demonstrate both the dangers and potential inappropriateness of such conclusions.

Cardiotoxicity of antineoplastic agents: what is the present and future role for imaging?

As antineoplastic treatment options expand at an increasing rate, both traditional and novel agents continue to be limited by their cardiotoxic effects. While functional decline becomes clinically apparent at late states of toxicity, little is known about early stages during which treatment or prevention may still be an option. Several imaging modalities,including echocardiography, multiple gated acquisition, and cardiac magnetic resonance imaging have the ability to identify cardiac effects before they produce clinical symptoms.Here we discuss the current and future role of cardiac imaging in the assessment of cardiotoxicity of antineoplastic agents. effects on cardiac tissue, resulting in myocardial cellular damage,and ultimately lead to a wide range of effects including electrophysiological abnormalities, symptomatic heart failure(HF), and even death. This represents a limiting factor in the therapy of several otherwise treatable neoplasms [2].The cardiotoxicity of antineoplastic agents raises several important questions regarding the actual prevalence of cardiac toxicity, the ability to effectively treat or prevent such effects with pharmaceutical interventions, and the availability of a means for early diagnosis. Here, we focus on the latter, specifically examining current and potential future imaging strategies to detect the cardiac effects of chemotherapeutic agents.

Chemoradiation in the management of cervix cancer: current status and future directions.

Cytotoxic chemotherapy has been shown to have only a very modest impact on outcome in recurrent, persistent, or metastatic cervix cancer. Despite this fact, when cisplatin is administered concurrently with external beam radiation as a 'chemosensitizing' strategy, both progression-free and overall survival have been shown in multiple evidence-based randomized trials to be improved compared to the delivery of radiation alone. Ongoing research in this area has focused on improving the drug component of this strategy and on following the concurrent chemoradiation with systemic ('adjuvant') therapy.

Current standards of care for chemotherapy of optimally cytoreduced advanced epithelial ovarian cancer.

There has been limited change in evidence-based primary chemotherapeutic management of optimal residual advanced ovarian cancer for more than a decade. The backbone of therapy remains a platinum agent (generally carboplatin) and a taxane (generally paclitaxel). Phase 3 randomized trial data provide support for the use of weekly paclitaxel in this setting (compared to the traditional every 3-week schedule) and the addition of bevacizumab as a component of primary management. Recently available data provide increasingly solid support for a role of regional platinum administration in at least a subset of patients with optimal residual advanced ovarian cancer and an important retrospective analysis has suggested a novel biomarker that may predict for the utility (or lack thereof) of this method of drug delivery.

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study.

OBJECTIVE: CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer. METHODS: GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival. RESULTS: CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p=0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p<0.0001). CONCLUSIONS: No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.