Months Of Neoadjuvant Chemotherapy Research Articles

Incidence and Risk Factors for Central Venous Catheter-Related Venous Thromboembolism in Breast Cancer Patients Under Neoadjuvant Chemotherapy: the Caveccas (Catheter Veineux Central et Cancer du Sein) Study

Background: Symptomatic Catheter Related Thrombosis (CRT) occurs in 3-5% of cancer patients with Central Venous Catheters (CVC) and, overall, the incidence of CRT could reach 30% when including asymptomatic cases (1). In women with Breast Cancer (BC), the most frequent cancer in females world-wide, the high risk of Venous Thromboembolism (VTE) during chemotherapy may be related in part to CRT (2). We therefore designed the CAVECCAS (Cathéter VEineux Central et CAncer du Sein) study to analyze CRT incidence and CRT risk factors in BC patients with CVC receiving (neo)adjuvant chemotherapy (NAC).Methods: CAVECCAS is a prospective, multicenter cohort study of patients with non metastatic invasive BC undergoing insertion of a single lumen CVC for at least 3 months of NAC. All included patients with signed informed consent between September 2008 and December 2011 underwent repeated double-blind Doppler US evaluation before (D0) and at 7, 30 and 90 days (D) after CVC insertion. In case of VTE symptoms, diagnosis was confirmed by venography, ultrasonography and/or computed tomography. Venous blood samples were systematically drawn before and 2 days after CVC insertion to determine D-Dimers levels (VIDAS® D-Dimer Exclusion™), Platelet-derived MPs (Pd-MPs) and Pd-MPs expressing phosphatidyl serin (Pd-MP/PS+) levels (3), thrombin generation (Calibrated Automated Thrombogram assay®, Stago) and endogenous thrombin potential (ETP). After completing recruitment and follow-up (D90), a nested case-control study analyzed additional individual thrombophilic risk factors (Antithrombin, Protein C and Protein S levels, presence of Factor V and Factor II Leiden mutations, presence of antiphospholipid, anticardiolipin and antiβ2GP1 antibodies) using two controls without CRT from the CAVECCAS cohort matched for TNM status with each symptomatic or asymptomatic CRT patient.Statistical analysis used Fisher or Wilcoxon tests for univariate analysis; step down selection procedure with p-values < 0.10 for multivariate models; conditional logistic model to study the occurrence of CRT based on thrombophilia testing (open-source software R Version 2.15.2 (2012-10-26).Results(expressed as median and inter-quartile range [IQR] for quantitative data and numbers and percentages for categorical data). 524 patients with non metastatic BC (85% ductal carcinoma, 12.2% Lobular carcinoma, 2.8% other) with respective T0/T1/T2/T3/T4 staging (0.5%/47.6%/43.3%/8.0%/0.7%), SBR 1/2/3 grading (11.2%/53%/35.8%), 49.2 % having node involvement and 79.5% steroid hormone receptors, were analyzed. During follow-up, the overall CRT incidence rate was 2.18 cases/100 patient-months, with 14 symptomatic and 46 asymptomatic patients, 27, 10 and 9 of the asymptomatic CRT being respectively diagnosed on D8, 30 and day 90 US. In univariate analysis, increased age (>50 years) (OR, 1.80; 95% CI, 1.01-3.22; p=0.048), BMI> 30 kg/m² (OR, 2.64; 95% CI, 1.46-4.76; p=0.001) and comorbidities (OR, 2.05; 95% CI, 1.18-3.56; p=0.011) were associated with CRT. CRT was less frequent in ductal (OR, 0.55; 95% CI, 0.28-1.07; p=0.078) versus lobular carcinoma (OR, 2.53; 95% CI, 1.32-4.85; p= 0.005). In multivariate analysis, BMI>30 kg/m² (OR, 2.66: 99%CI, 1.46-4.84, p=0.001) and lobular carcinoma histology (OR, 2.56; 95%CI, .32-4.96, p=0.005) remained CRT risk factors. Pd-MPs (981.5 [518-2147] vs 758.5 [416.5-373] /mL; p<0.0001) and Pd-MP/PS+(778 [409-1851] vs 730 [380.5-412]/mL; p=0.021) levels decreased after CVC insertion versus baseline, while D-Dimers levels increased (454[294.2-757] vs 586 [366-842] ng/mL; p<0.0001), as did all thrombin generation parameters increased except ETP (1322 [1052-582] vs 1304 [1063-652] nM/min; p=0.023). None of these biomarkers appeared significant predictors for CRT.Conclusion: In this large sample size study with serial measurements of clinical parameters and biomarkers for thrombosis, only obesity and lobular carcinoma histology appeared strong risk factors for CRT in non metastatic BC treated with NAC. Further studies will elucidate how individual stratification of BC patients may identify those who may benefit from CRT prophylaxis.1) Debourdeau P and Farge D et al. J Thromb Haemost 2013; 11:71-802) Walker AJ et al. Blood 2016;127(7):849-573) Robert S et al J Thromb Haemost 2009;7:190-7 DisclosuresNo relevant conflicts of interest to declare.

The impact of staging laparoscopy on treatment strategy in advanced ovarian cancer

Introduction: Complete primary cytoreductive surgery (PCS) is the most important prognostic factor for progression free survival (PFS) and overall survival (OS) in patients with advanced (FIGO stage III) ovarian cancer (AOC). In patients with poor general conditions or with heavy disease burden, complete PCS is difficult to achieve. Various patterns of abdominal disease spread represent biological aggressiveness affect prognosis and demands visual evaluation before planning treatment strategy. Beside imaging methods, laparoscopic pretreatment evaluation of resectability was proposed to more accurately identify those patients that can not be completely resected. In such cases neoadjuvant chemotherapy (NACT), followed with interval debulking surgery (IDS) is proposed. We present the preliminary results of treatment with NACT and IDS in patients selected according to laparoscopic evaluation of resectability. Methods: 2 years retrospective analysis (2011–2013) of 41 patients with clinical signs of AOC, where according to gyn-oncology consultative team, laparoscopy was proposed as a diagnostic and staging procedure. After evaluation of respectability, PCS by laparotomy was performed. Metastatic process of intestinal mesenterium and/or serosa was considered unresectable and NACT was started followed by IDS. Evaluation of laparoscopic procedures and impact on treatment strategy is presented through PFS analysis between the subgroup that had PCS and those started with NACT, followed with IDS. Results: Ascites together with elevated tumor markers, with or without pelvic mass were the most common clinical sign in population studied. 32 patients presented in Stage IIIC and 9 in stage IV. Laparoscopic staging included evaluation of omental infiltration, peritoneal and diaphragmatic carcinosis, intestinal mesenteric or serosal involvement, bowel infiltration, and liver superficial metastasis as well as amount of pelvic disease. In all stage IV patients only laparoscopy was performed. According to laparoscopic staging in stage III patients, conversion to laparotomy for PCS and adjuvant chemotherapy was performed in 21 patients; while in 12 neodjuvant chemotherapy was started. Laparoscopic procedures were: unilateral or bilateral adnexectomy (N = 18); omental biopsy (N = 21), peritoneal biopsy (N = 21); and cytology specimen (N = 15). Average start of chemotherapy was 10 days (7–14) after surgery No major intraoperative complications were registered. In 2 patients laparotomy was performed because of obstructive ileum on day 3 and 5 after laparoscopy. During the mean follow up of 21 (8–33) months 3/21 patients died in PCS subgroup and 5/12 in NACT subgroup; all in the first 8 months after surgery. PFS were 27.80 (19.41–36.19) months for complete PCS; 13.62 (8.54–18.7) months for suboptimal PCS and 15.80 (8.6–22.99) months for NACT with IDS. Estimated OS were 35.6 (30.09–41.26) months for complete PCS, 31.85 (26.35–37.35) months for suboptimal PCS and 31.33 (25.48–37.18) months for NACT with IDS. Conclusions: According to our results, laparoscopy as a staging procedure have a certain impact on treatment strategy in AOC by selecting patients where tumor biology disables complete PCS and making them candidates for NACT. Our preliminary analysis of PFS and estimated OS in this selected group demonstrates that this strategy is not inferior towards suboptimal PCS and adjuvant chemotherapy, but more cases should be analyzed for more definitive conclusions.

Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial.

5500 Background: First line treatment of advanced ovarian cancer (OC) is accepted to be primary surgery (PS) followed by adjuvant platinum-based chemotherapy (P-CT). However, the EORTC55971 trial suggested neoadjuvant chemotherapy (NACT) is an alternative, showing increased optimal debulking rates and reduced surgical complications without detriment to survival. CHORUS (CRUK 07/009) is the 2nd phase III randomized controlled trial to investigate timing of initial surgery in OC. Methods: Patients (pts) with clinical FIGO stage III-IV OC (pelvic mass, extrapelvic metastases and CA125/CEA ratio &gt;25) were randomized to standard treatment (PS followed by 6 cycles P-CT) or NACT (3 cycles P-CT either side of surgery). CHORUS was designed to demonstrate non-inferiority of NACT, excluding a 6% absolute detriment in 3yr survival from 50% expected with PS (1-sided alpha 10%). Primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), toxicity and quality of life. Results: 550 women (276 PS, 274 NACT) were randomized from 74 centres (72 UK, 2 NZ) between Mar 2004 and Aug 2010. Baseline characteristics were well balanced: median age 65yrs, median tumor size 80mm, 25% FIGO stage IV, 19% WHO PS 2. Median follow-up was 3yrs, 410 pts have died. Treatment data are summarized in the Table. 3yr survival in the control arm was 32%. Intention to treat analysis showed a median OS of 22.8 months for PS vs 24.5 months for NACT (hazard ratio (HR) 0.87 in favor of NACT, 80% CI 0.76 – 0.98) and median PFS of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). OS results represent a 5% absolute benefit in 3yr survival for NACT to 37% and the upper 80% CI allows us to exclude a survival benefit for PS. Conclusions: NACT was associated with increased optimal debulking, less early mortality and similar survival in this poor prognosis group. CHORUS results are consistent with EORTC55971 and strengthen evidence that NACT is a viable alternative to PS. Clinical trial information: ISRCTN74802813. [Table: see text]

Does aggressive primary debulking surgery influence survival in ovarian cancer?

5561 Background: Evidence comparing outcomes in patients receiving primary debulking surgery (PDS) to those receiving neoadjuvant chemotherapy (NACT) for advanced stage ovarian carcinoma is conflicting. We conducted a retrospective survival analysis of all patients with stage IIIC and IV serous ovarian cancer treated at our institute by either PDS or NACT. Methods: Data was extracted from patient synoptic OR reports and medical records between January 2003 and December 2011. Survival comparisons between patients receiving NACT and PDS were made according to aggressiveness of surgery and residual disease following surgery. Aggressive surgery was defined by one of the following procedures; pelvic peritonectomy, any bowel resection, diaphragm resection, diaphragm peritonectomy and splenectomy. Results: Out of 342 patients, 143 (41%) had NACT and 199 (59%) had PDS. Patients undergoing PDS had a median survival (MS) of 58 months compared to 34 months for NACT. Patients undergoing PDS with &gt; 10mm and &lt;10mm residual disease, had a MS of 33 and 55 months, respectively; whereas those with microscopic disease have not yet reached their MS. In the NACT group, MS for &lt; and &gt; 10 mm residual disease was 30 months for both, compared with 39 months for those with microscopic disease. Within the PDS group, those undergoing limited surgery had a MS of 48 months whereas MS has not been reached for those undergoing aggressive surgery. Over 60% of patients undergoing PDS with microscopic residual were alive at 7 years. In the NACT group, there was no difference in survival according to extent of surgery. Conclusions: Patients withPDS, whether debulked to &lt; 10mm or to microscopic disease have a significant and lengthy survival advantage over patients receiving NACT.

Socioeconomic factors may contribute to neoadjuvant chemotherapy use in metastatic epithelial ovarian carcinoma

Objective. To identify patient characteristics which predict receipt of neoadjuvant chemotherapy (NCT) versus standard therapy (ST) in metastatic ovarian cancer. Methods. A retrospective matched case control study was conducted of 52 women treated with NCT compared to 104 women who received standard treatment from 1996 to 2007. The t test was used for comparison of means between the groups, and the χ 2 test was used for categorical data. Multivariable analysis was performed with logistic regression models and only two-tailed analyses with a P value < 0.05 were considered statistically significant. Results. Age, employment and marital status, and insurance alone did not affect treatment allocation ( P = NS). However, non-Hispanic White (NHW) patients were more as likely to receive ST ( P < 0.05). When insurance was stratified by ethnicity, NHW patients were twice as likely to have private insurance (OR = 2.29, CI = 1.16–4.53). Furthermore, medically compromised (MC) patients who were NHW were almost three times more likely to receive ST (OR = 2.72, CI = 1.02–5.00). In multivariate analysis, only MC and publically funded women were more likely to receive NCT (OR 3.83 CI = 1.35–11.11); P = 0.01). During surgery, patients receiving NCT were found to have smaller tumors and less ascites, and were more likely to be optimally debulked with lower estimated blood loss and shorter hospital stays. The median survival for ST was 55.8 months versus 26 months for NCT ( P < 0.001). Conclusions. Non-clinical factors such as publically funded status and non-Hispanic White race may influence the allocation of NCT for women with metastatic ovarian cancer.

Letter from the Chair of the ACCWS

Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear.Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin.Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy.Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.

Reversal of adverse effects of neoadjuvant chemotherapy on bone turnover in pre- and post-menopausal women with zoledronic acid

556 Background: Ovarian failure secondary to adjuvant chemotherapy is known to have an adverse effect on bone mineral density and to increase bone turnover markers. The effects of chemotherapy with growth factor support in the absence of hormonal changes have not been described. The impact of zoledronic acid on these changes was also explored. Methods: We evaluated bone turnover markers in 82 women undergoing neoadjuvant chemotherapy for localized stage II/III breast cancer at initial diagnosis prior to treatment and after 4 cycles of epirubicin (75mg/m2)-docetaxel (75mg/m2) with pegylated G-CSF support with or without zoledronic acid. 47% of patients were post-menopausal and all groups were balanced for other variables. Women were randomized to receive zoledronic acid 4 mg IV every 3 weeks concurrently with chemotherapy (n=41) versus no bisphosphonate treatment (n=41). Bone turnover markers included: urinary N-telopeptide (NTx), serum bone specific alkaline phosphatase (BAP)and osteocalcin (OSTEO). Results: Women, regardless of menopausal status, who received no bisphosphonate had statistically significant increases in NTx, from baseline after 3 months of neoadjuvant chemotherapy using multivariable mixed repeated measures (p=0.0213). Women who received zoledronic acid concurrently with neoadjuvant chemotherapy had statistically significant decreases in NTx (p&lt;0.0001), BAP (p&lt;0.0001) and OSTEO (p=0.0295) from baseline. This is the first demonstration that anthracycline-taxane chemotherapy with growth factor support increased bone turnover markers in both post-menopausal and pre-menopausal women independent of hormone therapy, radiation therapy and surgery. Conclusions: Neoadjuvant chemotherapy with anthracycline- taxane and growth factor support increased bone resorption markers in both post-menopausal and pre-menopausal women. Zoledronic acid given concurrently with each cycle of chemotherapy reversed this increase in bone turnover markers. No significant financial relationships to disclose.

Dose-dense neoadjuvant treatment of women with breast cancer utilizing docetaxel, vinorelbine and trastuzumab with growth factor support

591 Background: The NSABP has confirmed the role of neoadjuvant chemotherapy for the treatment of women with breast cancer. NSABP B18 has demonstrated a relationship between complete pathological response (pCR) and a better survival. Recently Buzdar and colleagues reported a 65% pCR rate with six months of neoadjuvant chemotherapy plus trastuzumab in 23 women with breast cancer. Methods: We report the results of a trial in which women with stage IIB-IIIB and locoregional stage IV (LCRSIV) breast cancer with HER2 overexpression (by fluorescence in situ hybridization) were treated with docetaxel (D) 60 mg/m2 and vinorelbine (V) 45 mg/m2 administered every two weeks with weekly trastuzumab (12 weeks only), G-CSF and quinolone prophylaxis for six cycles prior to surgery. Results: Accrual has been completed and 31 patients (pts) have been enrolled. Age range 27–65. Stage II-12, Stage III-18, LCRSIV-1. Sixty-eight percent of pts had T3 or T4 tumors. Ninety percent of patients had clinically palpable lymph nodes. The average tumor size was 6.6 cm. All patients have completed their preoperative therapy and are evaluable for both clinical and pathological response. Grade 3/4 toxicity has included neutropenic fever 7/31 (23%). There has been no dominant grade 3/4 non-hematologic toxicity. Eight patients have required dose reduction (26%). There were 26 (84%) complete responses (cCr) and 3 (10%) partial responses (PR), one patient with stable disease (3%) and one pt has progressed in the breast only (3%). Pathological data demonstrates a pathologic complete response (pCR) in 14 pts (45%) by NSABP criteria (T0, Tis, NX) and in 12 pts (39%) by other criteria (T0, Tis, N0), 6 additional pts had residual T1a tumors at the time of surgery (65%). Conclusions: The overall clinical response rate is 88% with a cCR rate of 65%. The pCR rate of 45% with 65% of patients having a residual T1a or T0 lesion is among the highest response rates reported with preoperative chemotherapy. This supports the findings of Buzdar and colleagues considering that they treated patients with smaller tumors and utilized six months of therapy including an anthracycline. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, sanofi-aventis Genentech, GlaxoSmithKline, Pierre Fabre, sanofi-aventis Genentech, GlaxoSmithKline, sanofi-aventis

Patterns of Resistance and Incomplete Response to Docetaxel by Gene Expression Profiling in Breast Cancer Patients

Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent. Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 microg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA). From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin. A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment.

Prognostic factors in inflammatory breast cancer and therapeutic implications

223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987. Patients received chemotherapy and radiation treatment according to three consecutive randomised trials. Five- and 10-year survival rates were 41 and 32%, respectively. Disease-free interval rates were 25.5% at 5 years and 19% at 10 years. Parameters significantly linked with a pejorative prognosis in a multivariate analysis were: diffuse erythema, lymph node involvement, chest wall adherence, and age above 50 years. When therapeutic response parameters were included in the multivariate analysis, the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment (at 8 months), complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy, limited erythema at presentation and, less significantly, complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months. In conclusion, patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy. High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials. Detailed information on the biology of this disease should allow the design of new strategies aiming to improve patient management.

Evidence-Based Recommendations Against Neoadjuvant Chemotherapy for Routine Management of Patients with Squamous Cell Head and Neck Cancer

The objective of this study was to determine appropriate recommendations for neoadjuvant chemotherapy in the treatment of head and neck cancer (HNC). Published reports of randomized trials of neoadjuvant versus standard therapy in patients with stage III and stage IV HNC were identified by literature search. The overall trial results were analyzed using three pooling techniques: vote count, weighted median survival, and meta-analysis of published survival data. Excluded from analysis were articles on intra-arterial therapy, studies without a standard treatment control arm, studies that included adjuvant therapy, and abstracts. Twelve studies were evaluable for vote count, 11 for weighted median survival analysis, and 10 for quantitative meta-analysis. By vote count there was no observed survival difference in 7 trials, a trend favoring control in 3, a statistically significant difference favoring control in 1, and a trend favoring neoadjuvant therapy in 1. The weighted median survival was 20.9 months for control versus 20.0 months for neoadjuvant chemotherapy, with consistent trends for resectable and nonresectable disease and for chemotherapy combinations versus single agents. The common odds ratios for deaths at 12, 24, and 36 months were 1.12, 1.27, and 1.11, respectively, all in favor of control treatment. Data generated using rigorous methodological standards indicate that neoadjuvant chemotherapy should not be offered to patients with locally advanced HNC if improved survival is the outcome of interest. It is premature to recommend neoadjuvant chemotherapy to preserve organ function, although patients should be aware of this option and the limitations of the current data.