Dose-dense Group Research Articles

Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

9553 Background: Combination immune-checkpoint inhibitors (ICIs) improved outcomes in a plethora of cancer subtypes. However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events (irAEs), often leading to treatment discontinuation. We evaluated two therapeutic strategies targeting interleukin-6 receptor (IL-6R) to reduce irAEs while enhancing ICls efficacy. Methods: Phase Il trial (NCT04940299) investigating safety/efficacy of frontline tocilizumab (toci; IL-6R inhibitor) combined with ipi 3mg/kg + nivo 1mg/kg Q3 weeks (wks) for 12 wks in advanced melanoma. Initially, toci was given as 162 mg subcutaneously (SQ) bi-weekly for 6 doses (regular dosing regimen; RD). Then, we escalated to a dose dense (DD) regimen (162 mg SQ weekly for 6 wks then bi-weekly for 6 wks; 9 doses total). Primary objective was rate of G 3/4 irAEs. Secondary objectives were objective response rates (ORR) and disease control rate (DCR) per RECIST 1.1. Exploratory objectives involved immune analysis (gene expression, CyTOF, cytokine analysis) on longitudinal blood and tissue samples to identify drivers of auto- vs antitumor immunity. Results: As of Feb 2024, 35 pts were enrolled (25 pts to RD regimen; 10 pts to DD regimen). In RD group, median follow-up is 18 months (6 - 25 months). By 12 wks, 44% of pts developed G 3/4 irAEs including colitis (20%), hepatitis (16%), pancreatitis (12%), type I diabetes and serum sickness (4% each) and 20% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 7.4 wks. 16% of pts discontinued ICIs due to irAEs. ORR was 56% at 12 wks including 40% in pts with high LDH and DCR was 80%. Gene expression analysis showed a trend towards higher expression of IL-17 pathway genes in pts who developed G 3/4 irAEs, suggesting IL-6/Th17 pathway was not sufficiently inhibited. Thus, we enrolled 10 pts into the DD regimen aiming to achieve better inhibition of the IL-6/Th17 pathway. In DD group, median follow-up is 7 months (3 - 13 months). By 12 wks, 40% of pts developed G 3/4 irAEs, including colitis (10%), hepatitis (20%), and uveitis (10%) and 30% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 4.9 wks. 30% of pts discontinued ICIs due to irAEs. ORR was 70% at 12 wks including 75% in pts with high LDH and DCR was 80%. Conclusions: To our knowledge, this is the first study to investigate toci in combination with high dose ipi3/nivo1. Although our cohort is small, preliminary data suggests IL-6R blockade using the DD regimen could decrease the rate of G 3/4 irAEs while maintaining antitumor responses of ipi3/nivo1. A randomized phase ll trial investigating this strategy is underway. Ongoing immune analysis comparing treatment regimens aims to identify distinct pathways involved in auto- vs antitumor immunity and IL-6/Th17 independent pathways of toxicity. Clinical trial information: NCT04940299 .

Heterogeneous treatment effect of dose-dense paclitaxel plus carboplatin therapy for advanced ovarian cancer.

A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m2, non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis.

Efficacy of apatinib combined with temozolomide in the treatment of recurrent high‑grade glioma: A meta‑analysis.

Recurrent high-grade glioma is a refractory disease, and its prognosis is poor. Although the treatment of apatinib combined with temozolomide provides improved efficacy and is able to prolong survival, this conclusion has been based on small samples. In order to clarify this treatment's efficacy, a meta-analysis was performed in the present study. Different databases were screened and finally, 10 studies were included, comprising 357 patients with recurrent high-grade gliomas. The efficacy and prognosis were analyzed using Stata software. The results indicated that the overall objective response rate (ORR) and disease control rate (DCR) of apatinib combined with temozolomide were 0.36 (95% CI, 0.26-0.46) and 0.86 (95% CI, 0.82-0.89), respectively. Subgroup analysis indicated that the overall ORR was 0.43 (95% CI, 0.29-0.57) and 0.26 (95% CI, 0.14-0.38), and the DCR was 0.89 (95% CI, 0.85-0.93) and 0.76 (95% CI, 0.69-0.84) in the treatment of apatinib with temozolomide dose-dense group and the conventional-dose group (5/28 regimen), respectively. Further prognostic analysis indicated that the median overall survival of patients with high-grade glioma treated with apatinib combined with temozolomide was 8.21 months (95% CI, 7.20-9.22 months) and the median progression-free survival was 5.45 months (95% CI, 4.53-6.37). Analysis of the publication bias of the effect size revealed that there was bias in the DCR, while no bias was found in the remaining effect size (ORR, median overall survival and median progression-free survival). After correction by the trim-and-fill method, bias was indicated to have no significant impact on the results. In conclusion, apatinib combined with temozolomide has the effect that, compared with traditional Bevacizumab treatment, it can improve the efficacy in the treatment of recurrent high-grade glioma and improve prognosis. When combining with dose-dense temozolomide, the effect may be better than that of the conventional 5/28 regimen.

Observation Effectiveness of Dose-Dense Neoadjuvant Anthracycline Sequential Weekly Paclitaxel for Triple-Negative Breast Cancer Patients

Introduction/BackgroundTo investigate the differences in pathological response and survival outcomes between dose-dense and conventional-interval neoadjuvant chemotherapy (NAC) in patients with triple-negative breast cancer (TNBC). Patients and MethodsPatients with TNBC who received NAC including epirubicin plus cyclophosphamide followed by weekly paclitaxel were included. A total of 494 patients were divided into either the dose-dense anthracycline (ddEC-wP) group or conventional interval anthracycline (EC-wP) group. ResultsThe breast pathological complete response (bpCR, ypT0/is) rate was 45.3% (n = 101) in the dose-dense group and 34.3% (n = 93) in the conventionally scheduled group, which was a significant difference (P = .013), and in the 251 pN+ cases, the lymph node pathological complete response (LNpCR, ypN0) rate was 57.9% (n = 62) in the dose-dense group and 43.7% (n = 63) in the conventionally scheduled group, which was a significant difference (P = .026) in the univariate analysis. In the multivariate logistic regression analysis, 3 variables were predictive of bpCR: pathological type, surgical methods and type of chemotherapy, with P values of .012, .001 and .021, respectively. Two variables were predictive of LNpCR: type of chemotherapy and Her-2 expression, with P values of .039 and .020, respectively. After a median follow-up of 54 months, there was no significant difference in survival for disease-free survival (DFS) (hazard ratio [HR], 0.788; 95% confidence interval [CI], 0.508 to 1.223; P = .288), distant disease-free survival (DDFS) (HR, 0. 709; 95% CI, 0.440 to 1.144; P = .159) or overall survival (OS) (HR, 0. 750; 95% CI, 0.420 to 1.338; P = .330) between the 2 groups. ConclusionOur study demonstrated that TNBC achieved a higher bpCR rate and LNpCR rate after dose-dense neoadjuvant chemotherapy than the conventional scheme. The survival benefit of the 2 groups did not reach statistical difference.

Efficacy and survival outcomes of dose-dense carboplatin plus paclitaxel as neoadjuvant chemotherapy for triple-negative breast cancer

Objective: To evaluate the efficacy and survival outcomes of dose-dense (biweekly) carboplatin plus paclitaxel (PC) as neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), and to explore an optimal neoadjuvant chemotherapy regimen for TNBC. Methods: Patients diagnosed as TNBC(cT1-4N0-3M0) in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Between January 2008 and September 2018 who received dose-dense PC and standard 3-weekly PC as NAC were 1∶1 matched using propensity score matching (PSM) to compare the efficacy, safety and survival outcomes. Results: One hundred of TNBC patients were enrolled (50 patients were divided in dose-dense group, 50 patients in standard group). The objective response rate (ORR) of dose-dense group and standard group were both 90.0% (45/50). The grade 3-4 neutropenia in dose-dense group was less than that of standard group (32.7% vs. 68.0%, P=0.001), while the rate of ALT/AST elevation in dose-dense group was higher than that of standard group (57.1% vs. 32.0%, P=0.012). The pathological complete response (pCR) rates were 34.0% (17/50) in dose-dense group and 38.0% (19/50) in standard group, without statistically significance (P=0.677). The median follow-up time was 55 months (3-150 months). The 5-year recurrence-free survival (RFS) in dose-dense group and standard group were 83.5% and 75.2%, respectively the 5-year overall survival (OS) in dose-dense and standard group were 87.9% and 84.5% the difference were not statistically significant (P=0.322 and 0.647, respectively). Patients with residual disease (tumor size≥1 cm or lymph node positive) had poor prognosis, the 5-year RFS and OS were 59.3% and 68.5%, respectively. Conclusions: Dose-dense PC has similar efficacy with standard 3-weekly PC and has a good safety profile. Since dose-dense regimen can shorten the duration of therapy, it can be an alternative in TNBC.

Impact of dose-dense neoadjuvant chemotherapy on pathologic response and survival for HER2-positive breast cancer patients who receive trastuzumab

To compare outcomes in patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer who received either dose-dense neoadjuvant chemotherapy (NAC) with trastuzumab or standard-interval chemotherapy with trastuzumab. Patients with HER2-positive breast cancer who received NAC, including epirubicin and cyclophosphamide followed by paclitaxel with trastuzumab were included. Patients were divided into either the dose-dense or standard-interval group. We compared pathologic complete remission (pCR), distant disease-free survival (DDFS), event-free survival (EFS), and breast cancer-specific survival (BCSS) between the two groups. Two hundred (49.6%) patients received dose-dense NAC, and 203 (50.4%) received standard-interval NAC. The pCR rate was 38.4% in the dose-dense group and 29.2% in the standard-interval group (P = 0.052). In patients with lymph node (LN) metastases, the LN pCR rate was 70.9% in the dose-dense group and 56.5% in the standard-interval group (P = 0.037). After a median follow-up of 54.6 months, dose-dense chemotherapy presented an improvement on DDFS (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.19–1.28, EFS (HR = 0.54, 95% CI: 0.24–1.21), and BCSS (HR = 0.41, 95% CI: 0.11–1.51), but the difference was not significant. Compared with standard-interval chemotherapy, dose-dense chemotherapy resulted in a superior 5-year DDFS (100% vs. 75.3%, P = 0.017) and 5-year EFS (96.9% vs. 78.3%, P = 0.022) in patients younger than 40 years. HER2-positive patients can achieve a higher LN pCR rate with dose-dense NAC than with standard-interval NAC with trastuzumab. Better survival may also be achieved with dose-dense chemotherapy with trastuzumab than with standard-interval chemotherapy with trastuzumab among young patients (age ≤ 40 years).

Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis.

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages.Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes.Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P<0.05). Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups (RR of ORR in metastatic vs early or locally advanced patients: 1.46 [1.09-1.96] vs 1.01 [0.94-1.08]; conventional vs dose dense group: 1.59 [1.23-2.06] vs 1.01 [0.91-1.12]).Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients.

Carboplatin plus paclitaxel weekly dose-dense chemotherapy for high-grade ovarian cancer: A re-evaluation.

We compared oncologic and clinical outcomes in patients with advanced ovarian cancer who received dose-dense weekly paclitaxel with 3-weekly carboplatin with those who received standard 3-weekly chemotherapy. Comparison of all consecutive patients with advanced (International Federation of Gynecology and Obstetrics stages III-IV) ovarian cancer who received a dose-dense protocol between 2010 and 2016 with an immediate historical cohort of consecutive patients who received standard chemotherapy. Patients who received less than three cycles of treatment were excluded. In all, 246 patients were included in the study, of whom 128 received the dose-dense protocol and 118 were treated with the standard Q3-week protocol. Patients in the dose-dense group had significantly better progression-free survival than those receiving the standard protocol (median progression-free survival 22 vs 15months; log rank=0.026). The overall survival of patients in the dose-dense group was also better than that of the patients in the standard protocol group; however, this difference was not statistically significant (median overall survival 66 vs 54months; log rank=0.185). The dose-dense protocol remained significantly associated with favorable survival outcome in multivariable analysis adjusted for stage, histologic type, cytoreductive results and neoadjuvant chemotherapy. The use of the dose-dense protocol was associated with higher rates of gastrointestinal, dermatologic, neurologic and hematologic side effects. Despite the limitations associated with the comparison to a historical cohort, a dose-dense chemotherapy protocol resulted in a significantly improved progression-free survival and the overall survival tended to be better, but this difference did not reach statistical significance compared with the standard chemotherapy protocol, and may be considered as a treatment alternative, albeit with some increased side effects.

Comparisons of Clinical Outcomes in Women with Advanced Ovarian Cancer Treated with Frontline Intraperitoneal versus Dose-Dense Platinum/Paclitaxel Chemotherapy without Bevacizumab.

Background: We aimed to compare the clinical outcomes between intraperitoneal chemotherapy and dose-dense chemotherapy for the frontline treatment of advanced ovarian, fallopian tube and primary peritoneal cancer in women not receiving bevacizumab. Methods: All consecutive women with stage II~IV cancer treated with either frontline intraperitoneal or dose-dense platinum/paclitaxel chemotherapy and not receiving bevacizumab between March 2006 and June 2019 were reviewed. Results: A total of 50 women (intraperitoneal group, n = 22; dose-dense group, n = 28) were reviewed. Median progression-free survival (32.6 months versus 14.2 months; adjusted hazard ratio = 0.38; 95% CI = 0.16 to 0.90, p = 0.03) and overall survival (not reached versus 30.7 months; adjusted hazard ratio = 0.23, 95% CI = 0.07 to 0.79, p = 0.02) were significantly higher in the intraperitoneal group than in the dose-dense group. A multivariable Cox proportional-hazards model also indicated that the number of frontline chemotherapy cycles (adjusted hazard ratio = 0.66, 95% CI 0.47 to 0.94, p = 0.02) was a predictor of better overall survival. Nausea/vomiting and nephrotoxicity occurred more frequently in the intraperitoneal group (p = 0.02 and <0.0001, respectively). Conclusions: Intraperitoneal chemotherapy seems to be superior in progression free survival and overall survival to dose-dense chemotherapy in the frontline treatment of women with optimally resected advanced ovarian, fallopian tube or primary peritoneal cancer and not receiving bevacizumab.

Intraperitoneal paclitaxel and cisplatin compared with dose-dense paclitaxel and carboplatin for patients with stage III ovarian cancer

Patients diagnosed with stage III ovarian cancer are at high risk of recurrence and optimal adjuvant therapy is often debated. There is limited literature that directly compares intraperitoneal paclitaxel and cisplatin with dose-dense paclitaxel and carboplatin. The primary objective was to compare progression-free survival, overall survival, and tolerability of adjuvant intraperitoneal paclitaxel and cisplatin to dose-dense paclitaxel and carboplatin in stage III ovarian cancer patients. A retrospective, IRB-approved, single center chart review was conducted reviewing adult patients with stage III ovarian cancer undergoing adjuvant intraperitoneal therapy or dose-dense therapy between 2010 and 2018. Eighty-two patients were included in the final analysis; 44 in the intraperitoneal group and 38 in the dose-dense group. Intraperitoneal therapy was not associated with a longer progression-free survival (35.4 vs. 31.1 months; P = 0.97). The duration of overall survival did not differ between intraperitoneal and dose-dense (56.3 vs. 54.5 months; P = 0.55). Dose reductions were less frequent with intraperitoneal than dose-dense (11.36% vs. 31.58%; P = 0.02). No difference in treatment delays (45.5% vs. 65.8%; P = 0.07), dose cancellations (59.1% vs. 57.9%; P = 0.91), supportive care additions (95.5% vs. 84.2%; P = 0.09), or therapy discontinuation (59.1% vs. 39.5%; P = 0.07) between groups was noted. Intraperitoneal therapy with paclitaxel and cisplatin, as compared with dose-dense paclitaxel and carboplatin, did not prolong progression-free or overall survival in the adjuvant setting among stage III ovarian cancer patients. A trend towards decreased tolerability was noted with intraperitoneal therapy.

A retrospective study comparing the efficacy of dose-dense chemotherapy, intraperitoneal chemotherapy and dose-dense chemotherapy with hyperthermic intraperitoneal chemotherapy in the treatment of advanced stage ovarian carcinoma

ObjectivesHyperthermic intraperitoneal chemotherapy (HIPEC), intraperitoneal chemotherapy (IP) and dose-dense (DD) chemotherapy have been employed with varying success in the treatment of advanced stage ovarian carcinoma. Despite the clinical benefits associated with these specific forms of chemotherapy administration, they have not been comparatively analyzed, vis-à-vis their efficacy. Study designAdvanced stage ovarian cancer patients who were treated with platinum/taxane chemotherapy via a DD regimen (n = 100), IP approach (n = 81) or a DD regimen in conjunction with HIPEC (n = 64) were retrospectively evaluated. The clinical variables of interest were patient age, body mass index, surgery and pathology data, chemotherapy regimen, inclusion of maintenance therapy, and progression free/overall survival. ResultsProgression free survival (PFS) was significantly more pronounced in the HIPEC (34.9 months) and IP (34.0 months) patients, compared to the DD group (27.6 months) (P = 0.005). A cox-proportional hazards regression model indicated that there was a decreased risk of disease progression accorded to the patients who were treated with IP chemo or HIPEC and DD chemotherapy (HR, 0.43; 95 % CI: 0.21–0.88; P = 0.022) and the subjects who underwent optimal cytoreductive surgery (HR, 2.42; 95 % CI: 1.22–4.80; P = 0.011). Positive BRCA status (HR, 0.434; 95 % CI: 1.59–3.44; P = 0.001) and number of chemotherapy regimens (HR, 1.36; 95 % CI: 1.159–1.61; P = 0.001) were significantly correlated with improved OS although we did not discern a survival benefit associated with any of the chemotherapy treatments (P = 0.136). ConclusionWe observed PFS advantages conferred to the ovarian cancer patients treated with HIPEC and IP chemotherapy compared to DD chemotherapy. However, an overall survival advantage related to the chemotherapy regimens was not borne out, possibly due to the retrospective nature of the study or differing time periods wherein the specific patient cohorts underwent treatment.

Efficacy and safety of TC dose-dense chemotherapy as first-line treatment of epithelial ovarian cancer: a single-institution retrospective cohort study.

The optimal first-line therapy of advanced ovarian cancer still remains questionable: standard paclitaxel-carboplatin (TC), dose-dense TC, intraperitoneal chemotherapy or TC plus bevacizumab. In this study, we present the real-life results of dose-dense treatment of the single-institution on Caucasian population. A retrospective cohort study was used on consecutive samples of 74 patients treated with the conventional 3-weekly TC protocol (2008-11) and on 70 treated with TC dose-dense protocol (2012-16). The primary endpoint of this study was overall survival (OS). Secondary endpoints were progression free-survival (PFS) and toxicity. We made adjustments for age, pathohistological type, tumor grade, stage and postoperative residual disease by Cox regression. After adjustment for pre-planned clinical and sociodemographic factors, patients treated with dose-dense protocol showed a significantly lower hazard for dying from any cause, than patients treated with conventional protocol (HR = 0.50; 95% CI 0.26-0.98; P = 0.042). Median OS, at 60 months follow-up had not been reached in the dose-dense group, while in the standard treatment group was 48 months (95% CI 33-62). Unadjusted PFS was significantly longer in the dose-dense group (HR = 0.58; 95% CI 0.38-0.88; P = 0.011), but not after the adjustment (P = 0.096). Generally, the level of toxicity was similar in both groups of patients. The need for blood transfusions and usage of filgrastim was significantly higher in the TC dd group. The incidence of neutropenia and thrombocytopenia Grade 3 or 4 were not significantly different in both regimens. Our retrospective study has shown the superior efficacy and comparable toxicity of dose-dense chemotherapy regimen over the conventional regimen in treatment of ovarian cancer on Caucasian population at a single-institution.

Comparing clinical outcomes between patients with urothelial carcinoma who treated neoadjuvant chemotherapy by gemcitabine-cisplatin and dose-dense MVAC.

376 Background: Prospective randomized trials demonstrated efficacy of MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC). In metastatic setting urothelial cell carcinoma (UCC), clinical trials showed no difference in oncologic outcomes between Gemcitabine-Cisplatin (GC) and MVAC, and another prospective trial proved dose-dense (dd) MVAC had significantly better overall survival (OS) and response rate then MVAC. Comparative data between GC and ddMVAC are limited in neoadjuvant setting. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received NAC from January 2011 and December 2017 in Asan Medical Center was conducted. Patients who received GC were compared to patients received ddMVAC in terms of outcomes including downstaging ( &lt; ypT2 and no N upstaging), pathologic complete response (pCR, ypT0N0), disease-free survival (DFS), and overall survival (OS) and tolerability. Results: In a total of 277 patients, 176 patients received NAC with GC and 41 patients with dose-dense MVAC. The median chemotherapy cycle is 4 (IQR 3-4) cycles for GC group, 4 (IQR 3-5.5) cycles for dose-dense MVAC group. With an exception of age; GC group is associated with younger age (p = 0.002), other baseline characteristics are well balanced between groups. Downstaging rate are 50.8% in GC group, 58.1% in dose-dense MVAC group (p = 0.47). The rates of achieving ypT0 (28.7% vs 22.6%, p = 0.68), ypN0 (78.3% vs 81.5%, p = 0.39). There were no differences in overall survival (OS) at 3 year (72.2% vs 73.2%, p = 0.58), disease-free survival (DFS) at 3 years (54.9% vs 63.3%, p = 0.21) according to chemotherapy regimens. ddMVAC with prophylactic G-CSF are associated with higher incidence of febrile neutropenia (p = 0.004) than GC. NAC regimen is not independent prognostic factor for OS on multivariable analysis. Conclusions: GC regimen had no significant difference in oncologic outcomes compare to ddMVAC as NAC in UCC.

Response and prognosis of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B breast cancer

Objective: To evaluate the efficacy and safety of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer. Methods: From January 2010 to December 2014, 168 Luminal B (HER2-) breast cancer patients with stageⅡA-ⅢC confirmed by pathology were randomly assigned to receive one of the following regimens: (group A) concurrent TEC× 4 every 3 weeks, ( group B ) sequential EC× 4-T × 4 every 3 weeks, (group C ) dose-dense TEC× 4 every 2 weeks with G-CSF, (group D) sequential EC× 4(dose-dense)-T × 4 with dose-dense every 2 weeks . Results: A total of 168 patients completed the neoadjuvant chemotherapy as planned. The pathologic complete response (pCR) was 16.8% in the 4 groups.The pCR were 30.9% and 26.1% in the group C and group D respectively, significantly higher than patients with group A and group B(9.5%and 7.1%) ( P<0.05). Median follow-up was 43 months (IQR 3-63). The 3-year disease free survival (DFS) rate was 64.7%, 55.5%, 87.8% and 92.1% and the 3-year overall survival(OS)rate was 79.4%, 77.7%, 95.1%, 97.3% in the 4 groups respectively. Patients in the dose-dense group had better 3-year DFS and 3-year OS than those with the regular group.The side-effects could be evaluated in 154 patients.The incidence of neutropenia was 29.2% and 21.9% in the group C and group D versus 65.7%and 51.3% in the regular group(P<0.05), the incidence of nervous toxicity was 54.2%, 18.9%, 60.0%, 26.8% in the 4 groups respectively. The incidence of nervous toxicity in the dose-dense group was lower than that in the regular regimen group(P<0.05). Conclusion: Neoadjuvant dose-dense chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer was effective and can improve the pCR, DFS and OS.Comparing the two dose dense regimens, sequentially with anthracyclines and taxanes, the incidence of nervous toxicity were lower.

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.

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.

Impact of dosing schedule of doxorubicin and cyclophosphamide (AC) chemotherapy on rates of hospitalization and resource utilization.

78 Background: 4 cycles ofAC chemotherapy are given as a component of several important and widely used chemotherapy regimens in the adjuvant treatment of breast cancer. We queried whether the use of dose-dense (every 2 week) AC chemotherapy is associated with a lower rate of hospitalization and resource utilization in clinical practice. Methods: We identified patients with early stage breast cancer treated with 3-weekly AC chemotherapy in a single institution. Cases were matched to controls by year of diagnosis and age. Rates of hospitalization during AC chemotherapy as well as duration of hospitalization, associated costs and use of pegfilgrastim were compared between the two groups. Fisher's exact test was used to compare categorical variables, and paired t-test was used to compare continuous variables. Results: 26 patients were included in the analysis. The mean age was 56 in both groups. As expected, rates of growth factor support with pegfilgrastim were higher in the dose dense versus 3-weekly group (52 versus 23 cycles, 2-tailed p = 0.0003). There was no difference in the likelihood of hospitalization among patients treated with dose dense versus 3-weekly AC (Fisher's exact test, p-value = 1.00). There was no difference in the mean duration of hospitalization between groups (mean 2.31 versus 1.23 days, 2-tailed p = 0.3352).Costs pertaining to pegfilgrastim use and hospitalization will be compared. Conclusions: In this clinical setting, dose dense administration of AC was not associated with lower rates or mean duration of hospitalization.

Clinic study of dose-dense cisplatin and 5-fluorouracil in patients with distant metastatic nasopharyngeal carcinoma

Objective To investigate the efficacy and tolerability of dose-dense chemotherapy with cisplatin plus 5-fluorouracil (PF regimen) in distant metastatic nasopharyngeal carcinoma (NPC) patients. Methods From April 1, 2008 to April 30, 2014, 168 patients were assigned to traditional group (n=83) and dose-dense group (n=85) using digital random table in 1∶1 ratio. All patients received PF regimen, and once every 28 days in traditional group and once every 14 days in dose-dense group. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS), toxicity and response rate. Results The median PFS, median OS, 1, 2, 3-year survival rate, complete response rate and objective response rate were significantly improved in dose-dense group which were 13.3 months, 20.2 months, 80.2%, 36.0%, 16.1%, 16.5%, 84.7%, and those in control group were 10.0 months, 16.1 months, 59.6%, 10.1%, 0, 3.6%, 54.2% respectively (χ2=24.47, P=0.000; χ2=16.65, P=0.000; χ2=8.41, P=0.004; χ2=16.96, P=0.000; χ2=14.91, P=0.000; χ2=7.63, P=0.006; χ2=18.47, P=0.000). The rates of grade 3-4 adverse events in dose-dense and traditional group were 38.8% and 6.0% (χ2=25.81, P= 0.000). Conclusion Dose-dense chemotherapy of PF is more efficient and acceptable toxic than the traditional one. It can be a new treatment option for patients with distant metastases of NPC. Key words: Nasopharyngeal neoplasms; Drug therapy; Dose-dense

Abstract S5-06: Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil, epirubicin and cyclophosphamide (FEC) followed by T, all given every 3 weeks or 2 weeks, in node-positive early breast cancer (BC) patients (pts). Final results of the gruppo Italiano mammella (GIM)-2 randomized phase III study

Abstract Background. Using a 2 × 2 factorial design, we compared the efficacy of two different schedules of chemotherapy (CT), dose-dense (DD) every 2 weeks versus standard duration every 3 weeks and the role of Fluorouracil (F) in addition to EC, in the adjuvant treatment of node positive BC pts. Patients and Methods. Node positive early BC pts younger than 70 years were eligible and randomly assigned to one of the following treatment arms: ARM A (4 courses of EC [90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM B (4 courses of FEC [600/90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM C (4 courses of EC [90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]); ARM D (4 courses of FEC [600/90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]). Pts enrolled in the DD arms (ARM C and D) received subcutaneous pegfilgrastim (6 mg) 24 hours after CT. HER2-positive pts enrolled after April 2006 received trastuzumab for 1 year at the end of CT. The primary study endpoint was disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. All analyses were conducted according to the intention-to-treat principle. Results. From April 2003 to July 2006, 2091 pts were enrolled (545 in ARM A, 544 in ARM B, 502 in ARM C, 500 in ARM D). The planned number of CT cycles was completed in 89% of pts in the DD group and in 88.1% of pts in the standard duration group. Pts treated with DD CT (ARM C + ARM D) experienced more frequently anemia (all grades: 67.2% vs 49.5%, p &amp;lt; .0001; G3-G4: 0.2% vs 1.4%, p = .004) and bone pain (53.5% vs 39.2%, p &amp;lt; .0001). Neutropenia occurred more frequently in standard duration arms (ARM A + ARM B): 66.7% vs 28.0%, p = &amp;lt; .0001. At a median follow up of 7.0 years, multivariate analysis, showed that DD treatments (ARM C + ARM D vs ARM A + ARM B) improved the primary endpoint, DFS (hazard ratio [HR] = 0.78; 95% CI 0.66-0.94; p = .007), and OS (HR = 0.68; 95% CI 0.52-0.87; p = .002). Conversely, the addition of F to EC did not improve clinical outcomes: the HR for DFS and OS (ARM A + ARM C vs ARM B + ARM D) were respectively 0.98 (95% CI 0.83-1.17; p = .85) and 0.93 (95% CI 0.73-1.19; p = .578). Subgroup analyses revealed that the benefits associated with DD CT were independent of hormone receptor status: in hormone receptor positive the HRs for DFS and OS were 0.80 (0.65-0.98) and 0.69 (0.51-0.93) respectively; in hormone receptor negative the HRs for DFS and OS were 0.67 (0.47-0.95) and 0.57 (0.36-0.92) respectively (p for interaction for DFS: 0.339; p for interaction for OS: 0.495). Pathological tumor size, nodal status (1-3 vs ≥ 4 positive nodes), histological grade and hormone receptor status were independently associate with DFS and OS. Conclusions. DD CT as adjuvant treatment in node positive BC pts, improves DFS and OS significantly. Conversely, the addition of F to EC does not improve clinical outcomes. (ClinicalTrials.gov number, NCT00433420). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-06.

Feasibility and efficacy of neoadjuvant chemotherapy with dose-dense methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) in patients with high-grade urothelial cancer with muscle invasion.

e15189 Background: Dose dense M-VAC was compared to standard dose MVAC in EORTC study in patients with advanced metastatic baldder cancer which revealed significant improvement in complete and partial response than standard MVAC. The objective of our retrospective study was to evaluate response rate, the impact on disease-free survival, and toxicity adverse events of our patients who were treated with dose dense MVAC neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. Methods: We reviewed the clinical and pathological data of 12 patients who underwent neoadjuvant chemotherapy using dose dense MVAC q 14 days for 4-6 cycles followed by radical cystectomy and bilateral pelvic lymphadenectomy at two institution between 9/2007 and 12/2010. Dose dense MVAC therapy consisted of 30 mg/m2 methotrexate on days 1, and cisplatin 70 mg/m2, doxorubicin 30 mg/m2 and vinblastine 3 mg/m2 on day 2 and pegylated GCSF 6 mg sq on day 3. The primary endpoint was the objective response rate, and the secondary endpoints were overall survival, disease free survival, and toxicity. Results: 6 patients (50%) had a complete response rate and 6 patients (50%) had a partial response in the dose dense MVAC group. After radical cystectomy 50% of the patients had no evidence of residual cancer cells while the other 50% had stage I or II Urothelial carcinoma with no evidence of residual metastatic disease. The disease-free survival currently is 100%. Hematologic toxicities were the main adverse events. Grade 3/4 Neutropenia occurred in 5 patients (41%) and thrombocytopenia in 2 patients(16%). Conclusions: Although this is not a randomized study, the dose dense MVAC neoadjuvant therapy followed by radical cystectomy is very effective and well tolerated and may be associated with improved survival among patients with muscle-invasive bladder cancer. This data needs to be confirmed by randomized clinical trials.