Patient reported outcomes after risk-reducing surgery in patients at increased risk of ovarian cancer.

OBJECTIVE: To describe the quality of life of women at an increased risk of ovarian cancer undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). METHODS: Patients evaluated in our gynecologic oncology ambulatory practice between January 2018-December 2019 for an increased risk of ovarian cancer were included. Patients received the EORTC QLQ-C30 and PROMIS emotional and instrumental support questionnaires along with a disease-specific measure (PROM). First and last and pre- and post-surgical PROM responses in each group were compared as were PROMs between at-risk patients and patients with other ovarian diseases. RESULTS: 195 patients with an increased risk of ovarian cancer were identified, 155 completed PROMs (79.5%). BRCA1 or BRCA2 mutations were noted in 52.8%. Also included were 469 patients with benign ovarian disease and 455 with ovarian neoplasms. Seventy-two at-risk patients (46.5%) had surgery and 36 had both pre- and post-operative PROMs. Post-operatively, these patients reported significantly less tension (p = 0.011) and health-related worry (p = 0.021) but also decreased levels of health (p = 0.018) and quality of life <7d (0.001), less interest in sex (p = 0.014) and feeling less physically attractive (p = 0.046). No differences in body image or physical/sexual health were noted in at-risk patients who did not have surgery. When compared to patients with ovarian neoplasms, at-risk patients reported lower levels of disease-related life interference and treatment burden, less worry, and better overall health. CONCLUSIONS: In patients with an increased risk of ovarian cancer, RRBSO is associated with decreased health-related worry and tension, increased sexual dysfunction and poorer short-term quality of life. Patients with ovarian neoplasms suffer to a greater extent than at-risk patients and report higher levels of treatment burden and disease-related anxiety.

A Population-based Study of Survival Impact of New Targeted and Immune-based Therapies for Metastatic or Unresectable Melanoma.

AIMS: New targeted drugs and immune therapies reported since 2010 for metastatic or unresectable melanoma (MM) have shown improved survival in randomised trials. We studied the uptake of these new drugs and their impact on population-based survival. MATERIALS AND METHODS: This was a retrospective, population-based cohort study of all patients treated for MM in Ontario 2007-2015. Provincial administrative sources covering the whole population identified palliative systemic therapy, radiotherapy and metastasis surgery. Temporal trends in utilisation and survival were investigated, as was survival of treatments predefined as 'new drugs' (BRAF or MEK inhibitors, anti-CTLA4 and anti-PD-1 antibodies). RESULTS: We identified 2793 treated MM patients. First treatment was systemic therapy (46%), radiotherapy (41%) and metastasis surgery (14%). Systemic treatment increased from 53% of patients (2007) to 75% (2015). New drug treatments increased from <6% of known first-line regimens in 2007 to 82% in 2015. One and 2 year overall survival was 28% and 15%, respectively, for all MM 2007-2009, rising to 46% and 35% for 2014-2015 (adjusted hazard ratio 0.56, 95% confidence interval 0.49-0.63, P < 0.0001). Survival gains were observed primarily among those cases initially treated with systemic therapy, which became dominated by the use of new drugs over the study period (2 year overall survival 16% 2007-2009 versus 44% 2014-2015; adjusted hazard ratio 0.46, 95% confidence interval 0.38-0.56, P < 0.0001). CONCLUSIONS: Utilisation of new targeted drugs and immune therapies for MM has increased considerably in routine practice 2007-2015. Consistent with the results of clinical trials, adoption was associated with substantial increases in survival of patients in the general population.

Barriers to participation in clinical trials: a physician survey.

Background: Clinical trials are vital for evidence-based cancer care. Oncologist engagement in clinical trials has an effect on patient recruitment, which in turn can affect trial success. Identifying barriers to clinical trial participation might enable interventions that could help to increase physician participation. Methods: To assess factors affecting physician engagement in oncology trials, a national survey was conducted using the online SurveyMonkey tool (SurveyMonkey, San Mateo, CA, U.S.A.; http://www.surveymonkey.com). Physicians associated with the Canadian Cancer Clinical Trials Network and the Canadian Cancer Trials Group were asked about their specialty, years of experience, barriers to participation, and motivating interventions, which included an open-ended question inviting survey takers to suggest interventions. Results: The survey collected 207 anonymous responses. Respondents were predominantly medical oncologists (46.4%), followed by radiation oncologists (24.6%). Almost 70% of the respondents had more than 10 years of experience. Significant time constraints included extra paperwork (77%), patient education (54%), and extended follow-up or clinic visits (53%). Timing of events within trials was also a barrier to participation (55%). Most respondents favoured clinical work credits (72%), academic credits (67%), a clinical trial alert system (75%), a regular meeting to review trial protocols (65%), and a screening log to aid in patient accrual (67%) as motivational strategies. Suggested interventions included increased support staff, streamlined regulatory burden, and provision of greater funding for trials and easier access to ancillary services. Conclusions: The present study confirms that Canadian oncologists are willing to participate in clinical research, but face multiple barriers to trial participation. Those barriers could be mitigated by the implementation of several interventions identified in the study.

OV21/PETROC: a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer.

Background: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). Patients and methods: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL). Results: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone. Conclusion: In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy. Clinical trial number: clinicaltrials.gov, NCT01622543.

Real-world evidence in the treatment of ovarian cancer.

INTRODUCTION: 'Real-world evidence (RWE)' refers to information on the utilization and outcome of new therapies and technologies in clinical practice. RWE may include single institution cohort studies, population-based health services studies, or (inter)national data on survival and mortality. This paper reviews RWE on the impact of treatment in ovarian cancer. MATERIALS AND METHODS: A literature review of publications addressing population level survival outcomes of new surgical and systemic treatment interventions in ovarian cancer was undertaken. In addition, literature and international cancer registry trends in ovarian cancer survival, mortality and incidence rates were compiled. These latter were utilized to make inferences on the relative impact of new treatments as well as changing incidence rates on observed mortality trends. RESULTS: The last four decades have seen new systemic and surgical treatments introduced into practice for ovarian cancer based on randomized trial evidence. However, there has been little published on population level uptake and survival outcomes of those interventions. Exceptions were population studies on intraperitoneal chemotherapy and neoadjuvant chemotherapy. One paper demonstrated modest uptake of intraperitoneal chemotherapy and evidence of improved survival. Cancer registry statistics revealed falling incidence rates (∼1%-2% per year) for ovarian cancer across Europe, North America and elsewhere over the last three to four decades. Mortality rates also declined by ∼1%-2% per year over this period. Population 5-year relative survival estimates also improved over this period [from 33.7% in 1975 to 46.2% in 2008 (SEER data)]. CONCLUSIONS: There are few RWE studies of specific treatments in ovarian cancer. Trends in relative survival and population mortality have shown improvements. Mortality changes can be explained in part by reductions in ovarian cancer incidence rates (speculated to be due to use of oral contraceptives and reduction in postmenopausal hormone use). However, it is plausible that at least some of the mortality reduction is related to improved survival of patients with the introduction of effective new treatments.

Mental health services use by melanoma patients receiving adjuvant interferon: association of pre-treatment mental health care with early discontinuation.

BACKGROUND: Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. METHODS: This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. RESULTS: Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). CONCLUSIONS: Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered.

Multigene expression profile testing in breast cancer: is there a role for family physicians?

BACKGROUND: Family physicians (fps) play a role in aspects of personalized medicine in cancer, including assessment of increased risk because of family history. Little is known about the potential role of fps in supporting cancer patients who undergo tumour gene expression profile (gep) testing. METHODS: We conducted a mixed-methods study with qualitative and quantitative components. Qualitative data from focus groups and interviews with fps and cancer specialists about the role of fps in breast cancer gep testing were obtained during studies conducted within the pan-Canadian canimpact research program. We determined the number of visits by breast cancer patients to a fp between the first medical oncology visit and the start of chemotherapy, a period when patients might be considering results of gep testing. RESULTS: The fps and cancer specialists felt that ordering gep tests and explaining the results was the role of the oncologist. A new fp role was identified relating to the fp-patient relationship: supporting patients in making adjuvant therapy decisions informed by gep tests by considering the patient's comorbid conditions, social situation, and preferences. Lack of fp knowledge and resources, and challenges in fp-oncologist communication were seen as significant barriers to that role. Between 28% and 38% of patients visited a fp between the first oncology visit and the start of chemotherapy. CONCLUSIONS: Our findings suggest an emerging role for fps in supporting patients who are making adjuvant treatment decisions after receiving the results of gep testing. For success in this new role, education and point-of-care tools, together with more effective communication strategies between fps and oncologists, are needed.

First application of the Automated QUantitative Analysis (AQUA) technique to quantify PTEN protein expression in ovarian cancer: A correlative study of NCIC CTG OV.16.

BACKGROUND: Platinum resistance is a dominant cause of poor outcomes in advanced ovarian cancer (OC). A mechanism of platinum resistance is the inhibition of apoptosis through phosphatidylinositol 3 kinase (PI3K) pathway activation. The role of phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, as a tumor biomarker is unclear. Quantitative analysis of PTEN expression as an alternative to immunohistochemistry has not been considered. PATIENTS AND METHODS: In 238 patient tumors from the NCIC-CTG trial OV.16, PTEN protein expression was quantified by Automated QUantitative Analysis (AQUA). Cox model was used to study the association between PTEN expression and clinical outcomes using a minimum p-value approach in univariate analysis. Multivariate analysis was used to adjust for clinical and pathological parameters. RESULTS: PTEN scores (range 13.9-192.3) of the 202 samples that passed quality control were analyzed. In univariate analysis, there was a trend suggesting an association between PTEN expression by AQUA as a binary variable (low ≤61 vs high >61) and progression free survival (HR=0.77, p=0.083), and in multivariate analysis, this association approached significance (HR=0.74, p=0.059). The relationship between quantitative PTEN expression and PFS differed (p=0.01 for interaction) by the extent of surgical debulking (residual disease (RD) <1cm or ≥1cm), with a numerically superior PFS in patients with high PTEN (23.5 vs 14.9m) only when RD<1cm (p=0.19). There was no association between PTEN levels and overall survival. CONCLUSIONS: AQUA is a novel method to measure PTEN expression. Further study of PTEN as a biomarker in OC is warranted.

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†.

BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.

Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199).

OBJECTIVE: HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. METHODS: Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue. RESULTS: Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. CONCLUSION: Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.

Performance of multinomial designs in comparison with response-based designs in non-randomized phase II trials of targeted cancer agents.

BACKGROUND: In phase II trials of cytotoxic agents, a multinomial phase II design incorporating early progression and response end points was shown to perform more efficiently than designs based only on response. We undertook a study to evaluate the performance of these designs in trials of targeted agents using the actual phase II data. PATIENTS AND METHODS: Using best response data from sequentially enrolled patients in 15 NCIC Clinical Trials Group and 7 European Organization for Research and Treatment of Cancer trials of targeted agents, we determined that trials would have been stopped at the end of stage I of accrual by applying rules generated by the multinomial and Fleming designs. Two variants of the multinomial design were studied: to stop accrual after stage I of enrolment, Variant A required either response or progression criteria to be met, whereas Variant B required that both response and progression criteria to be met. RESULTS: Using early progression, null/alternate hypotheses of 60% and 40% (60/40), the multinomial A variant recommended early stopping more often than the Fleming design. In most of the cases, this recommendation was correct given the final trial outcome. In contrast, the multinomial B variant never led to recommendations for early stopping and changing progression hypotheses did not improve the performance of this design. CONCLUSIONS: The multinomial A design using 60/40 hypotheses carried out better than the Fleming design in appropriately stopping trials of inactive targeted agents early. The multinomial B design was not useful for early stopping decisions. The multinomial A design may be favored over response-based designs in phase II trials of targeted agents.

Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer.

OBJECTIVE: The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). METHODS: Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. RESULTS: Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. CONCLUSIONS: Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.

First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)--a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG.

BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

Health-related quality of life in recurrent platinum-sensitive ovarian cancer--results from the CALYPSO trial.

BACKGROUND: In the CALYPSO trial, carboplatin-pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings. MATERIALS AND METHODS: HRQoL was measured with the EORTC QoL-QC30 questionnaire and OV28 ovarian cancer module. Mean change scores from baseline in HRQoL subscales (five functional scales and global health status) in each arm and the proportion of patients improved or worsened were calculated every 3 months until 12 months. RESULTS: Compliance was 90% at baseline and 76%, 64%, 57% at 3, 6, and 9 months, respectively. Baseline HRQoL showed already impaired global scores (mean 62/100) and considerable symptom burden (90% of patients reporting nonzero scores). Global QoL and abdominal symptom scores improved over time in both arms; at 6 months, 36% of patients met criteria for improved symptoms. Treatment with CD resulted in less peripheral neuropathy (9.8 versus 24.2), fewer other chemotherapy side-effects (9.5 versus 16.2), and less impact on body image (3.8 versus 10.4) versus CP (all P<0.02) at 6 months. CONCLUSIONS: These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.

Effect of chemotherapy delays and dose reductions on progression free and overall survival in the treatment of epithelial ovarian cancer.

INTRODUCTION: Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS). METHODS: A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS. RESULTS: One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range=0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n=51), thrombocytopenia (n=45), and neuropathy (n=18). There were no differences detected in PFS or OS between groups. CONCLUSIONS: There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.

Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179).

BACKGROUND: The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus. MATERIALS AND METHODS: Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration. RESULTS: Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs. CONCLUSION: Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.

Optimal assessment of response in ovarian cancer.

Objective tumor response and progression, measured by standard criteria such as RECIST 1.1, are important measures of change in tumor size that are utilized as endpoints in phase II and III clinical trials. In ovarian cancer, RECIST criteria, which are based on anatomical tumor size, have been supplemented by CA125 response and progression criteria developed by the Gynecologic Cancer InterGroup. CA125 progression has been integrated with objective criteria into a composite definition of progression often used in the front-line setting, whereas response criteria are generally intended for use in recurrent disease trials. In terms of the performance of these endpoints in clinical trials, objective response, when used to assess the activity of new drugs in phase II trials in recurrent ovarian cancer, has proven to be helpful in identifying agents that have subsequently been shown to improve overall or progression-free survival in randomized trials. Thus, objective response has utility as an endpoint for new drug screening trials. Progression-free survival is often used as the primary (or co-primary) efficacy endpoint in studies of first-line therapy in ovarian cancer. Data from historical studies of platinum-based chemotherapy regimens indicate that improvements in progression-free survival generally translate into overall survival gains, indicating it may qualify as a surrogate endpoint for overall survival. It is not yet clear if this relationship will hold true in randomized trials of targeted agents, making it important to continue to assess overall survival in such studies. Finally, the routine monitoring of CA125 in patients after completion of front-line treatment as part of the standard of care has come under question with the publication of the results of a large European study; therefore, the use of CA125 progression as an endpoint in clinical trials will also likely be debated in the coming years.

Phase ii/iii study of intraperitoneal chemotherapy after neoadjuvant chemotherapy for ovarian cancer: ncic ctg ov.21.

Three large randomized clinical trials have shown a survival benefit in women with stage iii epithelial ovarian cancer (eoc) who receive intraperitoneal (IP) chemotherapy after optimal primary debulking surgery. The most recent Gynecologic Oncology Group study, gog 172, showed an improvement in median overall survival of approximately 17 months. That result led to a U.S. National Cancer Institute (nci) clinical announcement recommending that IP chemotherapy be considered for this group of women with eoc. However, IP chemotherapy is associated with increased toxicity, and rates for completion of treatment are low (42% in gog 172). The optimal IP regimen and duration of treatment has yet to be defined. Women undergoing chemotherapy before optimal debulking surgery were not included in the studies or in the nci clinical announcement. The National Cancer Institute of Canada Clinical Trials Group has developed a protocol for a randomized phase ii/iii study which will examine whether IP platinum-taxane-based chemotherapy benefits women who have received neoadjuvant chemotherapy before optimal surgical debulking. To address whether the less systemically toxic carboplatin can be substituted for cisplatin IP, the first phase of the study will have 3 arms: 1 intravenous-only, and 2 IP-containing regimens. At the end of the first stage, and provided that IP therapy is feasible to administer in this patient population, one of the IP regimens, either IP carboplatin or IP cisplatin, will proceed into a phase iii comparison with the intravenous arm. This exciting new study has gathered international support.