Dose-dense Chemotherapy Research Articles

Dose-dense adjuvant chemotherapy in premenopausal breast cancer patients: A pooled analysis of the MIG1 and GIM2 phase III studies

BackgroundNo evidence exists to recommend a specific chemotherapy regimen in young breast cancer patients. We performed a pooled analysis of two randomised clinical trials to evaluate the efficacy of adjuvant dose-dense chemotherapy in premenopausal breast cancer patients and its impact on the risk of treatment-induced amenorrhoea. Patients and methodsIn the MIG1 study, node-positive or high-risk node-negative patients were randomised to 6 cycles of fluorouracil/epirubicin/cyclophosphamide every 2 (dose-dense) or 3 (standard-interval) weeks. In the GIM2 study, node-positive patients were randomised to 4 cycles of dose-dense or standard-interval EC or FEC followed by 4 cycles of dose-dense or standard-interval paclitaxel. Using individual patient data, the hazard ratio (HR) for overall survival by means of a Cox proportional hazards model and the odds ratio for treatment-induced amenorrhoea through a logistic regression model were calculated for each study. A meta-analysis of the two studies was performed using the random effect model to compute the parameter estimates. ResultsA total of 1,549 patients were included. Dose-dense chemotherapy was associated with a significant improved overall survival as compared to standard-interval chemotherapy (HR, 0.71; 95% confidence intervals [CI], 0.54–0.95; p = 0.021). The pooled HRs were 0.78 (95% CI, 0.54–1.12) and 0.65 (95% CI, 0.40–1.06) for patients with hormone receptor-positive and -negative tumours, respectively (interaction p = 0.330). No increased risk of treatment-induced amenorrhoea was observed with dose-dense chemotherapy (odds ratio, 1.00; 95% CI, 0.80–1.25; p = 0.989). ConclusionDose-dense adjuvant chemotherapy may be considered the preferred treatment option in high-risk premenopausal breast cancer patients.

Switching from standard to dose-dense chemotherapy in front-line treatment of advanced ovarian cancer: a retrospective study of feasibility and efficacy

BackgroundCurrent standard neoadjuvant treatment for advanced ovarian cancer is 3-weekly platinum-based chemotherapy (CP3w).Patients unable to have interval debulking surgery (IDS) or with significant residual disease have a poor outcome to CP3w treatment. We investigated the outcome in patients who were switched to dose-dense chemotherapy.Methods:We retrospectively analysed 30 patients treated at UCLH in 2009–2013, who switched to dose-dense chemotherapy after neoadjuvant CP3w, having achieved a poor response/progressed and unable to proceed to IDS (n=21), or had >1 cm residual disease after IDS (n=9). Treatment was 3-weekly carboplatin and weekly paclitaxel (n=23), or both drugs weekly (n=7). For comparison, we included 30 matched patients treated with CP3w followed by IDS (n=24, without or ≤1 cm residual disease; n=6, with >1 cm residual disease). Time to progression (TTP) and overall survival (OS) were measured from the date of diagnosis until progression (CT scan or CA-125) and death from any cause, respectively.ResultsBaseline characteristics were similar in both groups. The response rate to dose-dense chemotherapy was 70% (Gynecological Cancer Intergroup criteria). In the dose-dense group, 24 patients had tumour progression and 16 died; the corresponding numbers in the control group were 24 and 11. Median TTP was 15.8 months with dose-dense therapy, higher than expected for this patient group, and the same as in the control group (15.7 months) undergoing IDS, p=0.27. Median TTP in patients with residual disease postsurgery was 16.5 months (dose-dense) and 10.8 months (controls), p=0.02. TTP in dose-dense patients who did not have surgery was 10.4 months. Median OS was 31.3 (dose-dense) and 59.6 months (controls), p=0.06. Dose-dense chemotherapy was well tolerated: only three patients interrupted treatment due to toxicity.ConclusionSwitching to dose-dense chemotherapy in patients who failed to respond to CT3w neoadjuvant chemotherapy appears to be an effective strategy and requires further investigation.

109P Impact of FDG PET-CT in response evaluation of different molecular subtypes of locally advanced breast cancers post dose dense neoadjuvant chemotherapy

109P Impact of FDG PET-CT in response evaluation of different molecular subtypes of locally advanced breast cancers post dose dense neoadjuvant chemotherapy

Dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube, or primary peritoneal carcinomas.

Weekly dose-dense paclitaxel with carboplatin every 3weeks (dose-dense TC) provides good efficacy, and neoadjuvant chemotherapy is common for advanced-stage disease. However, it is unclear the efficacy and safety of dose-dense TC as neoadjuvant chemotherapy. Therefore, we evaluated neoadjuvant dose-dense TC chemotherapy for advanced-stage ovarian carcinoma. We retrospectively reviewed cases of ovarian carcinoma that were not suited for primary debulking surgery (2003-2014). The patients received neoadjuvant dose-dense TC chemotherapy, followed by interval debulking surgery and adjuvant chemotherapy. We identified 74 patients (mean age 60years, range 39-85years). The FIGO stages were IIIC (39/74, 52.7%) and IV (34/74, 45.9%). Fifty-six patients (75.6%) had a performance status of 0-1. The adverse events were grade 3/4 neutropenia (55.4%), anemia (44.6%), thrombocytopenia (21.6%), and peripheral neuropathy (8.1%); no treatment-related deaths were observed. Among the 66 patients who underwent debulking (89.2%), 55 patients (74.3%) achieved optimal debulking and 47 patients (63.5%) achieved complete resection. The median progression-free and overall survivals were 19.0months (95% CI 16.2-23.7months) and 55.1months (95% CI 44.6months to not estimable), respectively. A performance status of 2-3 was independently associated with poor prognosis (hazard ratio 3.84; p=0.001). Neoadjuvant dose-dense TC chemotherapy was effective (complete resection in >60% of cases) and tolerable for advanced-stage ovarian carcinoma.

Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer

Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Recommandations en onco-urologie 2016-2018 du CCAFU : Tumeurs germinales testiculaires

IntroductionThe purpose of the oncologic comitee of the french association of urology was to establish guidelines proposed by the external genital organ group, for the diagnosis, treatment and follow-up of the germ cell tumours of the testis. Material and MethodsThe multidisciplinary working group studied 2013 guidelines, exhaustively reviewed the literature, and evaluated references and their level of proof in order to attribute grades of recommandation. ResultsThe initial workup of testicular cancer is based on clinical, laboratory (AFP, total hCG, LDH) and imaging assessment (scrotal ultrasound and chest, abdomen and pelvis computed tomography).Inguinal orchiectomy is the first line treatment allowing characterization of the histological type, local staging and identification of risk factors for micrometastases. The management of stage I tumors is based on surveillance or on a risk-adapted approach with explaining to the patient the benefits/disadvantages of active treatment or watchful waiting as a function of the risk of relapse.Treatment options for stage I seminomas comprise: surveillance, chemotherapy (1cycle of carboplatin) or para-aortic radiotherapy.Treatment options for stage I nonseminomatous germ cell tumours comprise: surveillance, chemotherapy (1cycle of BEP) or staging retroperitoneal lymphadenectomy. The management of metastatic tumors essentially comprises chemotherapy with 3, 4 cycles of BEP or dose-dense chemotherapy according to the IGCCCG. Radiotherapy may be indicated in seminomas with lymph node metastasis < 3cm. Review 3 to 4 weeks postchemotherapy is essentially based on tumor marker assays and chest, abdomen and pelvis computed tomography. Surgical retroperitoneal lymph node dissection is indicated for all residual NSGCT masses > 1cm and for persistent residual seminoma masses > 3cm with 18F- FDG PET- CT uptake. ConclusionsGood Germ cell tumors specific survival rates (99% CSI, 85% CSII, III) are based on precise initial staging, adapted and strictly defined treatment and close surveillance.© 2016 Elsevier Masson SAS. All rights reserved.

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study

In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications.

206P - Bevacizumab plus dose-dense neoadjuvant FEC followed by docetaxel chemotherapy in patients with HER2-negative breast cancer: a multicentre, phase 2 study by the Hellenic Oncology Research Group

Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting improves the proportion of patients with HER2-negative breast cancer who achieve pathological complete response. We aimed to assess the addition of bevacizumab to dose-dense neoadjuvant chemotherapy. We enrolled women with operable HER2-negative breast cancer (T1c-T4 and N0-3). Patients underwent treatment every 2 weeks (with pegfilgrastim support) of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), cyclophosphamide (500 mg/m2), and bevacizumab (10 mg/kg) for 4 cycles followed by docetaxel (75 mg/m2) and bevacizumab for 4 cycles. After surgery, patients received adjuvant radiotherapy, and hormone therapy (if indicated). The primary endpoint was pathological complete response in breast and the axilla, and safety of the combination. A two-stage trial design was planned with 15 and 33 patients to enroll, respectively. The trial was terminated early due to slow accrual and follow-up is ongoing. Between Oct, 2011, and Apr, 2015, we enrolled 34 patients, of whom 3 didn't undergo surgery, leaving 31 patients in the primary endpoint analysis. After neoadjuvant therapy, 5 (16.1%) of 31 patients achieved a pathological complete response according to centralized review. No patient discontinued treatment due to adverse events. The most frequent grade 3–4 toxicities were neutropenia (23.5%), nausea and vomiting (5,8%), and febrile neutropenia (2,9%). Only one patient developed grade III bevacizumab-related toxicity (hypertention). One patient died of pneumonia after cycle 8 and before surgery, which was thought to be unrelated to bevacizumab. After 25,2 months of median follow-up (range: 2,3-43,3) five patients experienced a disease relapse (16,1%). Our results seem to indicate that the addition of bevacizumab to dose-dense neoadjuvant chemotherapy with FEC and docetaxel, although safe and feasible, does not provide clinical benefit to patients with non-metastatic HER2-negative breast cancer. Translational research to identify patients who might benefit from bevacizumab is needed.

Rationale and design of the multidisciplinary team IntervenTion in cArdio-oNcology study (TITAN)

BackgroundCancer is the leading cause of premature death in Canada. In the last decade, important gains in cancer survival have been achieved by advances in adjuvant treatment. However, many oncologic treatments also result in cardiovascular "toxicity". Furthermore, cardiac risk factors such as hypertension, dyslipidemia, and diabetes mellitus are known to contribute to the progression of cardiac damage and clinical cardiotoxicity. As such, for many survivors, the risk of death from cardiac disease exceeds that of recurrent cancer. While provision of care by multidisciplinary teams has been shown to reduce mortality and hospitalizations among heart failure patients, the effect of assessments and interventions by multidisciplinary specialists in cancer patients receiving cardiotoxic chemotherapy regimens is currently unknown. Accordingly, we will examine the effect of a multi-disciplinary team interventions in the early assessment, identification and treatment of cardiovascular risk factors in cancer patients receiving adjuvant systemic therapy. Our main hypothesis is to determine if the incidence of LV dysfunction in cancer patients undergoing adjuvant therapy can be reduced through a multidisciplinary team approach.Methods/designThis is a randomized study comparing intensive multidisciplinary team intervention to usual care in the prevention of LV remodeling in patients receiving anthracycline or trastuzumab-based chemotherapy. Main objectives include early detection strategies for cardiotoxicity using novel biomarkers that reflect myocardial injury, remodeling and/or dysfunction; early identification and intensive treatment of cardiovascular risk factors; and early intervention with supportive care strategies including nutritional and pharmacist counselling, exercise training and cardiology team support. Secondary objectives include correlation of novel biomarkers to clinical outcomes; correlation of multidisciplinary interventions to adverse clinical outcomes; relationship of multidisciplinary interventions and chemotherapy dose density; preservation of lean muscle mass; and patient reported outcomes (symptom intensity and quality of life).DiscussionCardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, TITAN will be the first randomized trial examining the utility of multidisciplinary team care in the prevention of cardiotoxicity. We expect our results to inform comprehensive and holistic care for patients at risk for negative cancer therapy mediated sequelae.Trial registrationClinicalTrials.gov, NCT01621659 Registration Date 4 June 2012.

F01* - Dose-dense adjuvant chemotherapy, treatment-induced amenorrhea and overall survival in premenopausal breast cancer patients: a pooled analysis of the MIG1 and GIM2 phase 3 studies

F01* - Dose-dense adjuvant chemotherapy, treatment-induced amenorrhea and overall survival in premenopausal breast cancer patients: a pooled analysis of the MIG1 and GIM2 phase 3 studies

F17 - The STAR score predicts prognosis in Luminal-like breast cancer patients independently from dose-dense adjuvant chemotherapy

F17 - The STAR score predicts prognosis in Luminal-like breast cancer patients independently from dose-dense adjuvant chemotherapy

Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies.

Large operable or locally advanced breast cancers (BCs) are usually treated with neoadjuvant chemotherapy (CT) before surgery. However, there is no evidence to support an improvement in efficacy with dose-dense (DD) CT in this setting. We, therefore, carried out a meta-analysis to investigate whether DD-CT was more effective than the reference (every 3 weeks anthracyclines±taxanes) standard-dose CT as neoadjuvant treatment for BC. We searched Pubmed, SCOPUS, EMBASE, the Web of Science, CINAHL, and the Cochrane Central Register of Controlled Trials for randomized trials comparing conventional versus DD neoadjuvant CT for BC. Odds ratios (ORs) for pathologic complete responses (ypT0N0M0: pCR) and hazard ratios (HRs) of death and recurrence [overall survival (OS), and disease-free survival (DFS)] were estimated and pooled. A QUADAS-2 report for all studies included in the final analysis was tabulated for the risk of bias and applicability. A total of six randomized trials fulfilled the inclusion criteria. The pooled rates of the pCR were 13.5 and 9.2% in the experimental and control arms. A significant increase in the pCR [OR=1.55, 95% confidence interval (CI) 1.18-2.02, P=0.001] was noted with neoadjuvant DD-CT. However, the patients who received DD-CT did not have significantly better DFS and OS rates (DFS: HR=0.88, 95% CI 0.76-1.01, P=0.06; OS: HR=0.89, 95% CI 0.78-1.02, P=0.08). Even with the limitation of a relatively short follow-up period, this meta-analysis shows that DD neoadjuvant CT, despite not leading to a significant increase in survival, increases by 46.7% the possibility of achieving a pCR in operable and locally advanced BC. This treatment should thus be considered one of the backbone treatments of choice when neoadjuvant therapy is planned.

Adherence to Hematologic Hold Parameters in Carboplatin and Dose-Dense Paclitaxel Chemotherapy for Ovarian Malignancies: A Survey of NCCN Member Institutions.

To determine the adherence to hematologic chemotherapy hold parameters for the carboplatin and dose-dense paclitaxel chemotherapy regimen in patients with ovarian, fallopian tube, or primary peritoneal cancers. This is a quality assessment survey study. All 26 NCCN Member Institutions were contacted electronically. Hematologic chemotherapy hold parameter values (absolute neutrophil count [ANC] and platelet count) on days 1, 8, and 15 of each cycle were queried. These hold parameters were compared with published data supporting the use of dose-dense chemotherapy regimens in ovarian cancer. The overall survey response rate was 85% (22/26 sites). Of responders, 27% (6 sites) were fully adherent with all hematologic hold parameters and 64% (14 sites) used hold parameters that differed from the published protocol. Specifically, all of these sites use hold parameters higher than those recommended in the literature. Two centers did not have center-specific hold parameters. Carboplatin and dose-dense paclitaxel chemotherapy has been shown to increase progression-free survival and overall survival in patients with stage II-IV ovarian, fallopian tube, or primary peritoneal cancers. However, our study found that two-thirds of queried sites had hold parameters higher than those in the published protocol. Using more stringent hold parameters may lead to compromised clinical outcomes. Further research is necessary to determine the optimal strategy to increase individual site adherence to chemotherapy hematologic hold parameters as specified in published trials.

An update on current and emerging therapies for epithelial ovarian cancer: Focus on poly(adenosine diphosphate-ribose) polymerase inhibition and antiangiogenesis.

Epithelial ovarian cancer is the leading cause of death from gynecologic tumors in western countries. Newly diagnosed epithelial ovarian cancer patients usually have good initial response to combination of platinum-based and taxane-based chemotherapy. However, most patients eventually experience relapses, and responses to subsequent therapies are generally short-lived. Intraperitoneal chemotherapy has been shown to improve survival outcomes, but toxicities and logistics limit its acceptance. Dose-dense schedule of paclitaxel combined with carboplatin remains controversial, and more studies are needed to validate this approach. About 15% of epithelial ovarian cancer patients carry gene mutations in BRCA1 and/or BRCA2. The development of poly(adenosine diphosphate-ribose) polymerase inhibitors represents a novel therapeutic strategy, in which poly(adenosine diphosphate-ribose) inhibition leads to the formation of double-stranded DNA breaks that cannot be accurately repaired in BRCA1- or BRCA2-mutated tumors, thus leading to tumor cell death. This principle of synthetic lethality can be demonstrated by olaparib, an oral agent that inhibits the repair of single strand DNA breaks during DNA replication, causing defective homologous recombination and hence tumor cell death. Currently, many poly(adenosine diphosphate-ribose) inhibitors are in different phases of development. Furthermore, mechanisms of defective homologous recombination pathway may include other genetic and epigenetic abnormalities in addition to either germline or somatic BRCA1 and/or BRCA2 mutations, making these pathways as potential therapeutic targets. The clinical pharmacology, clinical efficacy, safety, administration issues of olaparib and current clinical development of poly(adenosine diphosphate-ribose) inhibitors are described in this article, along with an overview on the treatment options (including intraperitoneal chemotherapy and dose-dense chemotherapy) for epithelial ovarian cancer. On the other hand, overexpression of the vascular endothelial growth factor and increased angiogenesis are associated with the development and progression of epithelial ovarian cancer. Although there are some expected toxicities associated with antiangiogenesis, combination of bevacizumab and systemic chemotherapy improves the progression-free survival and response rate compared to chemotherapy alone. The clinical efficacy of adding bevacizumab and its safety for advanced epithelial ovarian cancer is also reviewed, with emerging data on antiangiogenesis therapy.

Achievements, Investigations in Gynecologic Oncology Explored

Achievements, Investigations in Gynecologic Oncology Explored

Interval cytoreductive surgical outcome following administration of standard versus dose-dense neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer

Objectives: Given the benefit of dose-dense platinum/taxane chemotherapy compared with standard every-3-week treatment after primary cytoreductive surgery, we sought to evaluate the utilization of dose-dense chemotherapy (DDC) in the neoadjuvant setting. Methods: With institutional review board approval, we identified all stage III/IV ovarian cancer patients who received initial treatment at our institution, and received neoadjuvant chemotherapy (NACT) from January 2008 to May 2013. We excluded cases treated with upfront surgery, low-grade histology, and early-stage disease. Clinicopathologic data were abstracted from medical records. DDC was defined as receiving at least 1 cycle of platinum with weekly paclitaxel. Standard chemotherapy (SC) was defined as receiving no DDC, and at least 1 cycle of an every-3-week platinum/taxane regimen. Appropriate statistical tests were performed. Results: A total of 154 patients received NACT. Of these, 5 (3%) did not undergo interval cytoreductive surgery (IDS) because of progression of disease; all 5 received SC. Of the remaining 149 cases, 23 (15%) received DDC and 126 (85%) received SC. There were no differences in age, CA-125 levels at diagnosis, or baseline albumin between the 2 groups. Seventy-three (49%) of 149 patients had stage IV disease: 64 (51%) of 126 who received SC and 9 (39%) of 23 who received DDC (P = .37). During NACT, the median number of DDC cycles administered was 3 (range, 1–7) compared with 4.5 cycles for the SC patients (range, 3–7) (P = .03). Carcinomatosis was present before IDS in 19 (83%) of 23 DDC patients compared with 109 (87%) of 124 SC patients (P = .74). At the time of IDS, 1 (4%) of 23 DDC patients exhibited a complete clinical response intraoperatively compared with 15 (12%) of 126 SC patients (P = .5). All 7 complete pathologic responses were in the SC group. All patients treated with DDC achieved less than 1 cm visible residual disease at IDS compared with 108 (86%) of 126 who received SC (P = .08). At IDS, 14 (61%) of 23 DDC patients achieved complete gross resection compared with 68 (54%) of 126 SC patients (P = .14). Conclusions: DDC patients had similar clinical features, but received fewer NACT cycles before IDS compared with standard dosing. DDC patients had a similar rate of optimal and complete gross resection at IDS compared with SC, and all DDC patients achieved less than 1 cm visible residual disease. Our data support the consideration of dose-dense neoadjuvant chemotherapy, and future investigation of the long-term oncologic outcomes with this approach.

Possible surrogate marker for an effective dose-dense chemotherapy in treating ovarian cancer

ObjectiveTo dissect the correlated hematologic markers that reflect the clinical outcome or treatment response in patients receiving dose-dense chemotherapy with a combination of platinum (cisplatin or carboplatin) and paclitaxel. Materials and MethodsFrom 2009 to 2014, we enrolled 55 ovarian cancer patients (total 67 courses) including first-line, persistent, platinum-sensitive, or platinum-resistant disease in MacKay Memorial Hospital, Taipei, Taiwan. Weekly pretreatment complete blood counts and calculated ratios [platelet/neutrophil ratio, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), neutrophil/monocyte ratio, platelet/monocyte ratio, lymphocyte/monocyte ratio] during dose-dense chemotherapy were collected. By grouping these hematologic biomarkers into three different response subgroups (responsive, stable, and nonresponsive) according to CA125 trend, the data were analyzed using one-way analysis of variance, and using post hoc-Tukey test for comparing each other. A p value < 0.05 was considered to be statistically significant. ResultsAbsolute counts of lymphocytes and platelets, PLR, platelet/neutrophil ratio, platelet/monocyte ratio (all p < 0.001), and NLR (p=0.013) had statistically significant differences. Moreover, using box-and-whisker plot, absolute count of lymphocyte, PLR, and NLR showed most remarkable discrepancy in responsive, stable, and nonresponsive patients. Subgroup analysis for primary, platinum-sensitive, and platinum-resistant patients further revealed that PLR and NLR were significantly correlated to the outcome of dose-dense chemotherapy. ConclusionLower PLR or lower NLR had better treatment response for dose-dense chemotherapy and are possible markers for representing treatment response in dose-dense chemotherapy. For a clinician, this is useful for timing when to switch to another chemotherapy regimen.

Improved outcomes following the use of dose-dense paclitaxel-based neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma

Objectives: Prior trials have demonstrated improved survival when dose-dense paclitaxel (DDP) is given in combination with carboplatin every 3 weeks as adjuvant therapy after primary debulking in epithelial ovarian carcinoma (EOC). The use of a DDP-based regimen has not been well studied in the neoadjuvant chemotherapy (NACT) setting. The purpose of this study is to compare outcomes of advanced EOC patients receiving NACT with DDP to those receiving taxane every 3 weeks before interval debulking surgery (IDS). Methods: This was a retrospective review of all patients who received NACT for advanced EOC between June 2012 and July 2015 at our institution. Patient demographics, chemotherapy-related toxicity, and IDS outcomes were compared between the patients who received DDP and those who received taxane. All patients received carboplatin every 3 weeks. The Fisher exact test was used to determine statistical significance. Results: Seventy-five EOC patients were treated with NACT. Of these, 27 (36%) were treated with DDP and 48 (64%) were treated with standard taxane. Patient demographics of the 2 groups were similar. Median number of NACT cycles was similar between the cohorts (2.9 DDP vs 4.1 taxane). Five DDP patients (19%) were unable to complete chemotherapy and were switched to standard taxane. Toxicity, predominantly hematologic and gastrointestinal (GI), was greater in the DDP group. However, there were no episodes of febrile neutropenia in either group, and the percentage of patients requiring blood transfusion was similar—26% DDP vs 15% taxane (P = .24). GI symptoms were manageable. After IDS, 11 patients (41%) in the DDP group had no residual disease compared with 11 patients (23%) in the taxane group (P = .12). Three patients (11%) in the DDP group had a pathologic complete response compared with 1 (2%) in the taxane group (P = .13). Conclusions: Although associated with an increase in toxicity, DDP appears in this preliminary study to facilitate higher rates of no residual disease and pathologic complete response than taxane at the time of IDS. These results warrant further investigation of DDP for patients with advanced EOC undergoing NACT and assessment of its impact on long-term outcomes.Table 1Demographics and Outcomes.

Utilization and Toxicity of Alternative Delivery Methods of Adjuvant Chemotherapy for Ovarian Cancer.

Compared with conventional intravenous platinum and taxane-based chemotherapy for ovarian cancer, both intraperitoneal chemotherapy and more frequent dose-dense intravenous chemotherapy have been associated with improved survival in some studies. We examined the utilization and toxicity of these three methods of chemotherapy delivery in women with ovarian cancer. We performed a population-based study and analyzed data on women with ovarian cancer who underwent primary surgery followed by platinum and taxane-based chemotherapy from 2009 to 2013 who were recorded in the MarketScan database. Adjuvant chemotherapy was classified as: intraperitoneal chemotherapy, dose-dense chemotherapy (weekly administration of chemotherapy), or standard chemotherapy (every 3 weeks). Hospitalizations and emergency department visits for chemotherapy-associated complications and costs were recorded and compared using χ tests. A total of 5,892 patients, including 4,135 (70.2%) who received standard chemotherapy, 859 (14.6%) who received intraperitoneal chemotherapy, and 898 (15.2%) treated with dose-dense chemotherapy, were identified. From 2009 to 2013, use of intraperitoneal chemotherapy remained constant (16.3-16.3%), whereas use of dose-dense therapy increased (8.7-18.1%) (P<.001). Hospitalizations for chemotherapy-associated complications occurred in 21.3% of women receiving standard chemotherapy, 34.7% of patients treated with intraperitoneal therapy, and in 25.2% of those receiving dose-dense treatment (P<.001); emergency department visits occurred in 18.3%, 26.3%, and 20.3%, respectively (P<.001). The largest differences in hospitalizations and emergency department visits were seen for gastrointestinal toxicities and electrolyte disorders. The per-patient costs of hospitalization were higher for intraperitoneal chemotherapy than other treatment modalities. Intraperitoneal chemotherapy was used in less than 15% of women with ovarian cancer, whereas use of dose-dense chemotherapy is increasing. Although we did not examine survival, intraperitoneal chemotherapy is significantly more toxic than the other methods of treatment.

Improved outcomes with dose-dense paclitaxel-based neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma

ObjectiveWe compared tolerability, toxicity, response, and interval debulking surgery (IDS) outcomes between patients who received weekly dose-dense paclitaxel (DDP) and every three-week platinum to standard every three-week taxane plus platinum neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC). MethodsWe conducted a retrospective study of patients receiving NACT at our center between June 1, 2012 and July 31, 2015. Patients with stage III/IV EOC who received at least one cycle of DDP (weekly paclitaxel plus every three-week carboplatin) or standard taxane (every three-week paclitaxel or docetaxel plus carboplatin) therapy were included. Abstracted data included demographics, tolerability, grade 3/4 toxicity, response, and IDS outcomes. Fisher's exact and student t-test were used for statistical significance. ResultsTwenty-one patients received DDP and 40 received standard taxane. Tolerability was comparable. More patients receiving DDP experienced grade 3 or 4 toxicity when considered in aggregate (86% vs. 40%; p=0.001). Pathologic complete response (pCR) was achieved in 14% of DDP patients versus 3% of standard (p=0.11). 48% of patients in the DDP group were debulked to no residual disease (NRD) versus 28% in the standard group (p=0.16). ConclusionsWhile associated with an increase in severe toxicity compared to standard three-week taxane, DDP appears to facilitate higher rates of pCR and NRD for patients receiving NACT in this preliminary study. These results warrant further investigation of DDP for patients with advanced EOC and assessment of impact on long-term survival outcomes.