Efficacy of adjuvant chemotherapy schedules for breast cancer according to body mass index: results from the phase III GIM2 trial.

BACKGROUND: The phase III GIM2 trial showed improved disease-free survival (DFS) and overall survival (OS) with adjuvant dose-dense (DD) as compared with standard-interval (SI) chemotherapy in women with node-positive early-stage breast cancer (BC). This exploratory analysis aimed to investigate the benefit of different schedules according to body mass index (BMI) in this trial. PATIENTS AND METHODS: This analysis explored the efficacy, in terms of DFS and OS, of different chemotherapy schedules according to BMI. Univariate and multivariable Cox proportional hazard models, adjusted for relevant prognostic factors, were used. RESULTS: Out of 2091 patients enrolled, 1925 with known baseline BMI were randomized in the DD versus SI comparison and therefore included in this analysis: 31.6% were overweight and 19.3% obese. Overweight and obesity were significantly associated with postmenopausal status, pT >2, and pN >2 tumors. After a median follow-up of 15.0 years (interquartile range 8.4-16.3 years), multivariable Cox survival models demonstrated no association of different BMI categories on DFS [adjusted hazard ratio (adjHR) 0.96, 95% confidence interval (CI) 0.80-1.15 and adjHR 1.11, 95% CI 0.91-1.35 for overweight and obese patients, respectively, compared to patients with normal BMI] or OS (adjHR 0.90, 95% CI 0.71-1.14 and adjHR 1.18, 95% CI 0.92-1.52 for overweight and obese patients, respectively). No significant interaction was found between BMI and treatment schedule in terms of DFS (Pfor interaction = 0.56) or OS (Pfor interaction = 0.19). The survival benefit of DD chemotherapy was observed irrespective of different BMI categories, with a more pronounced benefit for overweight and obese patients. CONCLUSION: In node-positive BC patients, DD schedule should be considered the preferred schedule irrespective of BMI.

A single institutional clinical outcome for stages III and IV ovarian cancer patients treated with dose-dense TC therapy in the frontline or first platinum-sensitive relapse setting.

AIM: Dose-dense paclitaxel /carboplatin (ddTC) therapy was shown to be more effective against ovarian cancer than conventional tri-weekly TC in the JGOG3016 study. However, two phase III studies performed after JGOG3016 did not show the same positive results. Because we have been using ddTC in the frontline or first platinum-sensitive relapse of ovarian cancer, we investigated the clinical outcome of the patients treated with ddTC. METHODS: We retrospectively examined the response rate (RR), progression free survival (PFS) and adverse events of the patients who were treated with ddTC for stage III and IV epithelial ovarian, tubal and peritoneal cancer from January 2012 to December 2018. RESULTS: We analyzed 50 patients for frontline treatment and 11 patients for first platinum-sensitive relapse treatment, excluding those receiving maintenance therapy. Among the patients that received frontline ddTC treatment, RR was 82.9% for those in a neo-adjuvant chemotherapy (NACT) setting and 85.0% for those in an adjuvant setting. The median progression-free survival (PFS) was 20 months after initial therapy. Among 31 cases that achieved remission by frontline surgery and the following ddTC, 22 had a platinum-sensitive relapse. RR of 11 patients treated with ddTC therapy alone for the first platinum-sensitive relapse was 81.8%, and the median PFS of these patients was 22 months after the first recurrence. CONCLUSIONS: ddTC therapy for advanced ovarian cancer achieved high response rates in all settings (NACT, adjuvant or platinum-sensitive relapse). ddTC therapy was effective for improving the prognosis of patients with stages III and IV of ovarian cancer.

Low-dose pegylated recombinant human granulocyte-colony stimulating factor as hematopoietic support for adjuvant chemotherapy in Chinese patients with breast cancer: An open-label, randomized, non-inferiority trial.

AIMS: The recommended dosage of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) for Western chemotherapy patients is 6 mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. METHODS: This open-label, randomized, non-inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6 mg of PEG-rhG-CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. RESULTS: A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3 mg arm was 89.8%, compared to 93.0% in the 6 mg arm (one-sided 95% confidence interval [CI] lower limit for difference: -11.7%), meeting the prespecified non-inferiority margin of 15%. The rate was 93.3% with PEG-rhG-CSF 3 mg and 96.6% with 6 mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6 mg arm. No grade ≥3 adverse events related to PEG-rhG-CSF occurred. CONCLUSION: Three milligrams of PEG-rhG-CSF per cycle provided non-inferior neutrophil protection and attenuated neutrophil overshoot compared to 6 mg doses. This low-dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

Therapeutic effect of dose-dense paclitaxel plus carboplatin with or without bevacizumab for Japanese patients with epithelial ovarian cancer.

BACKGROUND: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients. METHODS: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV. RESULTS: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively). CONCLUSION: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC.

Prediction of response to promising first-line chemotherapy in ovarian cancer patients with residual peritoneal tumors: practical biomarkers and robust multiplex models.

BACKGROUND: Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome. METHODS: Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm. RESULTS: The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes. CONCLUSION: Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer.

PURPOSE: This study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6 weeks, allowing for concomitant dose-dense (14 day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis. METHODS: This was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3 weeks for 12 weeks (4 cycles). The group then received either ddAC with pembrolizumab 400 mg every 6 weeks, or AC with pembrolizumab 200 mg every 3 weeks. The primary objective was pCR rate at time of surgery. RESULTS: This study assessed outcomes in 25 patients over 34 months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3-4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3-4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions. CONCLUSION: This study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices.

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer (TNBC), a highly aggressive disease with a poor prognosis. This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals, allowing for promising clinical outcomes with intensive treatment. However, the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance, limiting therapeutic efficacy and clinical benefit. Here, we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with time-programmed pulsatile release profiles. The implantable device can control the time between drug releases based on its internal microstructure design, which can be used to control dose density. The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar. Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo. Under the same dose density conditions, device-based chemotherapy shows a higher anti-cancer effect and less toxic response than intratumoral injection. We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose, number of releases, and treatment duration of the dose-dense AC (doxorubicin and cyclophosphamide) regimen preferred for TNBC treatment. Dose density modulation inhibits tumor growth, metastasis, and the expression of drug resistance-related proteins, including p-glycoprotein and breast cancer resistance protein. To the best of our knowledge, local dose-dense chemotherapy has not been reported, and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

Dose-Dense Chemotherapy Regimen for Breast Cancer Associated with Significant Decline in Ovarian Reserve.

Purpose: To determine the impact of dose-dense chemotherapy administration on ovarian reserve in women undergoing treatment for breast cancer. Patients and Methods: We conducted a retrospective cohort study of reproductive age women who underwent dose-dense chemotherapy regimens with doxorubicin hydrochloride and cyclophosphamide with or without paclitaxel for a new diagnosis of breast cancer. We compared pre- and post-treatment serum antimullerian hormone (AMH) levels and assessed changes in AMH over time. Results: Fifty-seven patients met inclusion criteria. Median pre-treatment AMH was 2.9 ng/mL, whereas post-treatment AMH was 0.1 ng/mL, demonstrating a dramatic reduction in AMH levels after treatment with a dose-dense regimen. This change was independent of age and was sustained over 12 months from treatment completion. Conclusions: Dose-dense chemotherapy regimens for breast cancer lead to marked and sustained decreases in AMH irrespective of patient age.

Phase 1/2 Study of the Timing and Efficacy of 3 mg Peg-GCSF in Neo/Adjuvant Dose Dense Breast Cancer Treatment Protocols.

Amol PatelBackground Peg-GCSF has similar efficacy at a dose of 60 µg/kg and 100 µg/kg. The conventional 6 mg SC dose was based on the maximum tolerable dose. In Japan, 3.6 mg dose was approved on the basis of dose finding studies. Peg-GCSF is an integral part of dose-dense chemotherapy protocols. Dose finding and scheduling study of peg-GCSF have not been conducted in Indian patients. Materials and Methods We conducted two-center phase 1/2 clinical study addressing the timing and efficacy of peg-GCSF in Indian breast cancer patients (CTRI no: 2021/07/034751). Three groups of timing administration were studied, namely 1, 6, and 24 hours post chemotherapy. The phase 2 part was the expansion of the best timing group. The primary objective was dose density, which was defined as receiving chemotherapy on < 3 days of scheduled date. Adriamycin/epirubicin cyclophosphamide (AC/EC) was administered q2 weeks. The total leucocyte (TLC) and absolute neutrophil (ANC) kinetics were studied. Other outcomes were incidence of grade 4 neutropenia, febrile neutropenia (FN), and requirement of additional doses of G-CSF. Bone pain, fever, and myalgia were studied for adverse effects. Results From November 20 to December 21, 36 patients were enrolled. Patient characteristics are depicted in Table 1. Initially, three patients received the peg-GCSF in each timing group. One patient in each 1-hour and 6 hours needed G-CSF support for maintaining the dose density. The 24-hour group was carried to phase 2 part. Dose density was maintained in 97% of patients. None of the patient in 24-hour group had FN. Also, 4/30 patients had grade 4 neutropenia and required an additional dose of GCSF. Grade 3 or 4 bone pain was not noticed by any of the patients. During the first cycle, the mean ANC (cells/µL) was 5284, 20704, 3010, 6954 on D0, D + 3, D + 7, and D + 13, respectively (Fig. 1A-TLC and 1B-ANC). The mean ANC (cells/µL) rise on D + 3 in cycles 1, 2, 3, 4 was 23810, 29209, 32428,22455, respectively. Conclusion Dose density of AC/EC breast cancer protocol is maintained with peg-GCSF 3 mg. Post chemotherapy 24-hour timing of peg-GCSF administration remains as the standard. A phase 3 trial of 6 mg versus 3 mg is warranted.

[Dose-dense paclitaxel plus carboplatin in combination with trastuzumab neoadjuvant versus standard adjuvant therapy in human epidermal growth factor receptor-2 positive and hormone receptor negative breast cancer: a prospective cohort study].

Objective: To provide survival evidence of anthracycline-free neoadjuvant chemotherapy for patients with stages Ⅱ-Ⅲ human epidermal growth factor receptor-2 (HER-2) positive and hormone receptor (HR) negative breast cancer. Methods: The prospective cohort study was conducted at the Department of Medical Oncology of Cancer Hospital, Chinese Academy of Medical Sciences. Patients with HER-2 positive and HR negative breast cancer in stages Ⅱ-Ⅲ were enrolled to receive neoadjuvant therapy (NAT) of dose-dense paclitaxel (175 mg/m(2)) plus carboplatin (AUC=4.0) biweekly for 6 cycles in combination with trastuzumab (PCbH), and matched patients who received standard adjuvant therapy of physicians' choice were recruited for survival and safety comparison. Results: From July 2013 to November 2019, 166 patients were included (neoadjuvant 51, adjuvant 115). Compared with those who received adjuvant therapy, patients receiving NAT were younger (<35 years: 19.6% vs 5.2%, P=0.014), had larger tumors (T3: 62.7% vs 7.8%, P<0.001) and more advanced diseases (stage ⅡA: 2.0% vs 41.7%, P<0.001). Patients in the neoadjuvant group all received surgery, and 96 (83.5%) in the adjuvant group received anthracycline-and-taxane-containing regimens. A total of 98 patients (49 pairs) were matched, and the covariates between the two groups were acceptably balanced. Within a median follow-up of 46.5 (range, 14-87) months, the 4-year recurrence-free survival (RFS) rate among patients who received NAT was 73.3% (95% CI: 59.0%-87.6%), versus 80.6% (95% CI: 67.9%-93.3%) among those in the adjuvant group without statistical difference (P=0.418). A similar result was observed for the 4-year overall survival (OS) [neoadjuvant versus adjuvant: 91.5% (95% CI: 81.7%-100.0%) vs 97.8% (95% CI: 93.5%-100.0%), P=0.314]. Compared with standard adjuvant therapy, PCbH was related to less neutropenia and better cardiac safety. Conclusions: These results support the consideration of anthracycline-free neoadjuvant chemotherapy combined with anti-HER-2 therapy for patients with stages Ⅱ-Ⅲ HER-2-positive and HR-negative breast cancer. Optimized regimens with both efficacy and safety are needed and to be further investigated.

Dose-dense regimen versus conventional three-weekly paclitaxel combination with carboplatin chemotherapy in first-line ovarian cancer treatment: a systematic review and meta-analysis.

BACKGROUND: Paclitaxel dose-dense regimen has been controversial in clinical trials in recent years. This systematic review and meta-analysis tried to evaluate the efficacy and safety of paclitaxel dose-dense chemotherapy in primary epithelial ovarian cancer. METHODS: An electronic search following PRISMA guidelines was conducted (Prospero registration number: CRD42020187622), and then a systematic review and meta-analysis of included literature were initiated to determine which regimen was better. RESULTS: Four randomized controlled trials were included in the qualitative evaluation, and 3699 ovarian cancer patients were included in the meta-analysis. The meta-analysis revealed that the dose-dense regimen could prolong PFS (HR0.88, 95%CI 0.81-0.96; p = 0.002) and OS (HR0.90, 95%CI 0.81-1.02; p = 0.09), but it also increased the overall toxicity (OR = 1.102, 95%CI 0.864-1.405; p = 0.433), especially toxicity of anemia (OR = 1.924, 95%CI 1.548-2.391; p < 0.001), neutropenia (OR = 2.372, 95%CI 1.674-3.361; p < 0.001). Subgroup analysis indicated that the dose-dense regimen could significantly prolong not only PFS (HR0.76, 95%CI 0.63-0.92; p = 0.005 VS HR0.91, 95%CI 0.83-1.00; p = 0.046) but also OS (HR0.75, 95%CI 0.557-0.98; p = 0.037 VS HR0.94, 95%CI 0.83-1.07; p = 0.371) in Asian, and overall toxicity was significantly increased in Asians (OR = 1.28, 95%CI: 0.877-1.858, p = 0.202) compared to non-Asians (OR = 1.02, 95%CI 0.737-1.396, p = 0.929). CONCLUSION: Paclitaxel dose-dense regimen could prolong PFS and OS, but it also increased the overall toxicity. Therapeutic benefits and toxicity of dose-dense are more obvious in Asians compared to non-Asians, which need to be further confirmed in clinical trials.

[Preoperative chemotherapy for patients with upper tract urothelial carcinoma: Impact on renal function]. / Chimiothérapie préopératoire des tumeurs des voies excrétrices supérieures : impact sur la fonction rénale.

PURPOSE: Upper tract urothelial carcinoma (UTUC) are rare tumors with a poor prognosis. The standard treatment for localized disease is based on total nephroureterectomy (NUT) followed by platinum-based adjuvant chemotherapy for eligible patients at risk of recurrence. However, many patients have renal failure after surgery preventing chemotherapy. Thus, the place of preoperative chemotherapy (POC) is questioned with little information available about renal toxicity and efficacity. METHODS: A single center retrospective study was performed on patients with UTUC who received POC. RESULTS: In all, 24 patients with localized UTUC were treated with POC between 2013 and 2022. Twenty-one (91%) had secondarily NUT. In this cohort, POC did not result in degradation of median renal function (pre-POC median GFR: 70mL/min, post-POC median GFR: 77mL/min, P=0.79), unlike NUT (post-NUT median GFR: 51.5mL/min, P<0.001). In addition, the rate of complete pathological response to pathological examination was 29%. After a median follow-up of 27.4 months, the overall survival rate was 74% and the recurrence-free survival rate was 46%. CONCLUSION: POC for UTUC shows a very reassuring renal toxicity profile and encouraging histological results. These data encourage prospective studies assessing its place for UTUC management.

Phase II study of neoadjuvant chemotherapy with four cycles of dose-dense MVAC followed by radical cystectomy in Korean patients with muscle-invasive or locally advanced urothelial carcinoma of bladder.

PURPOSE: While previous retrospective or phase II studies in Western populations showed that dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as neoadjuvant chemotherapy (NAC) was beneficial, no studies have been reported in Asian populations. This prospective phase II study aimed to evaluate efficacy and safety of ddMVAC in Korean patients with muscle-invasive bladder cancer (MIBC) or locally advanced urothelial cancer (UC). MATERIALS AND METHODS: Patients with MIBC (cT2-4aN0M0) or locally advanced UC (cTanyN1-3M0) eligible for radical cystectomy (RC) were enrolled prospectively. The participants were treated with four cycles of ddMVAC with pegfilgrastim every 2 weeks. The primary endpoint was pathologic response rate (≤ypT1N0). Secondary endpoints were pathologic complete response (pCR, ypT0N0), relapse-free survival (RFS), overall survival (OS), and safety. RESULTS: Among 24 patients enrolled between December 2019 and August 2021, 23 were evaluable (52%, cT2-4aN0; 48%, cTanyN1-3). Eighteen patients (78%) completed four cycles of ddMVAC, while remaining five patients experienced early discontinuation. Dose modification (91%) and dose delay (70%) occurred, and the dose intensity of ddMVAC was 79%. Nineteen patients underwent RC and four patients declined. Of 19 patients who underwent RC, eight patients (42%) achieved ≤ypT1N0. With a median follow-up of 22.8 months, the median RFS was 13.5 months (95% CI, not yet evaluable) and the median OS was 28.9 months (95% confidence interval, 19.9-37.9). CONCLUSION: Our study showed substantial efficacy and safety of ddMVAC, even in patients with locally advanced UC. The ddMVAC still should be a promising option as NAC in Asian patients with UC.

Adjuvant Dose Dense Chemotherapy in Patients With Obesity: Short-Term Toxicities and Breast Cancer Outcome.

BACKGROUND: Dose dense adjuvant chemotherapy is associated with improved outcomes in breast cancer compared to standard dosing. Despite current guidelines recommending that chemotherapy is dosed according to actual body weight, reviews have shown patients with obesity often receive a capped chemotherapy dose. The latter is commonly undertaken as clinicians have concerns that adverse events are more frequent if full doses are administered. This study assessed surgical, radiotherapy and chemotherapy related adverse events between patients with and without obesity receiving dose dense adjuvant chemotherapy for breast cancer. MATERIALS AND METHODS: A retrospective review of prospective collected data for patients receiving adjuvant chemotherapy from 30 April 2018 from a single institution was analyzed. Data collected included demographic data, height, weight, pathological information, comorbidities, surgical, radiotherapy chemotherapy treatment, and toxicity. Primary outcomes were surgical complications at 30 days, radiotherapy skin toxicity at 30 days and chemotherapy side-effects. Secondary outcomes were rates of recurrence and time to recurrence. RESULTS: A total of 280 patients were included in the analysis: 55 obese and 225 nonobese. Obese status was associated with higher rates of grade >2 skin toxicity and this difference was significant after adjusting for age, comorbidity and radiotherapy field (P = .017). Obese status was not associated with higher rates of surgical or chemotherapy related adverse events. All patients regardless of obese status received adequate dose intensity with similar rates of recurrence and time to recurrence. CONCLUSION: Patients with obesity who receive dose dense adjuvant chemotherapy do not experience higher rates of surgical or chemotherapy related adverse events although they do experience higher rates of grade >2 radiotherapy related skin toxicity. This supports the use of dose dense chemotherapy being based on actual body weight in patients with obesity.

Prognostic and predictive impact of gene expression in node-positive early breast cancer patients receiving dose-dense versus standard-dose adjuvant chemotherapy.

The utility of multigene expression assays in advanced (≥ 4 positive lymph nodes) early breast cancer (EBC) is limited. We conducted exploratory transcriptomic analysis of 758 genes (Breast Cancer 360 panel, nCounter® platform; NanoString) in primary tumor samples collected during a phase 3 trial comparing adjuvant taxane-containing dose-dense chemotherapy (ddCTX) versus standard-dosed chemotherapy (stCTX) in resected EBC with ≥ 4 positive lymph nodes. Prognostic and predictive associations with disease-free survival (DFS) and overall survival (OS) were evaluated by Cox regression with false discovery rate (FDR) adjustment. Data were available from tumor samples of 141/226 patients (median follow-up: 14 years). Several genes/signatures, including immune markers, showed prognostic relevance in unadjusted analyses. Of these, two remained significant after multiplicity adjustment: a positive effect on DFS of programmed cell death 1 ligand-2 (PD-L2) in the ddCTX arm (univariate HR: 0.53, FDR-adjusted P = 0.036) and a negative effect on OS of HER2-enriched (HER2-E) signature in the stCTX arm (univariate HR: 5.40, FDR-adjusted P = 0.036). Predictive analyses showed greater DFS benefit of ddCTX in tumors with high antigen processing machinery (APM) expression (multivariate interaction P = 0.024). Multigene expression assays have a prognostic and predictive potential in advanced EBC, and further investigation is warranted in order to identify candidates for de-escalated treatment. In addition, intrinsic subtype and immune gene expression have predictive potential.

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

INTRODUCTION/BACKGROUND: To 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 METHODS: Patients 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. RESULTS: The 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. CONCLUSION: Our 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.

Neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation for locally advanced cervical cancer.

BACKGROUND: Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). Forty percent of patients present with disease recurrence. This study aims to investigate the feasibility, safety and efficacy of neoadjuvant chemotherapy (NACT) with weekly cisplatin and paclitaxel (TP) followed by CCRT. METHODS: We are conducting a phase III trial comparing the efficacy and side effects of patients with cervical cancer (FIGO 2018 stage IIB to IVA) who were assigned to four cycles of NACT with cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly followed by CCRT or CCRT alone. In this report, we studied the medium-term effect of 50 patients enrolled in the NACT + CCRT arm. The primary endpoints were the response rate post-NACT and 12 weeks post-CCRT evaluated by MR/CT based on RECIST v 1.1. The secondary endpoints were 3-year OS (overall survival) and PFS (progression-free survival) measured by the Kaplan-Meier method. RESULTS: Among 50 patients enrolled in the NACT + CCRT arm, the complete and partial response rates were 10.4% and 68.8%, post-NACT. Twelve weeks after treatment completion, the complete response rate was 72.0%, whereas the total response rate (complete and partial response) was 90.0%. After a median follow-up of 28 months, the 3-year OS rate was 83.9%, and the 3-year PFS rate was 73.6%. NACT response was related to superior PFS and OS compared with NACT nonresponse (P < 0.01). Late AEs were exiguous, while early AEs mainly included myelosuppression and gastrointestinal AEs. CONCLUSIONS: This study showed a good response rate achieved by dose-dense weekly cisplatin and paclitaxel followed by standard CCRT. The treatment regimen is feasible, as evidenced by the acceptable toxicity of NACT and by the high compliance with radiotherapy. TRIAL REGISTRATION: Protocol version number and date. Chinese clinical trial registry, ChiCTR1900025327; http://www.chictr.org.cn . Registered 24 August 2019. Retrospectively registered, medresman.org.cn/ChiCTR1900025326. The date recruitment began 01-01-2019.

Survival Outcomes of Epithelial Ovarian Cancer Patients Following Dose-dense Versus 3-Weekly Platinum-Paclitaxel Chemotherapy: A Meta-Analysis.

AIMS: Dose-dense chemotherapy has proven its value in several cancer fields. The purpose of the present systematic review is to evaluate the impact of dose-dense chemotherapy on survival outcomes of epithelial ovarian cancer patients. MATERIALS AND METHODS: Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta and metafor functions. A sensitivity analysis was carried out to evaluate the possibility of small study effects and P-hacking. The methodological quality of the included studies was assessed using Risk of Bias 2 (RoB2) and Risk of Bias in non-Randomized Trials (RoBINS) tools. RESULTS: Overall, 12 studies were included in the present systematic review, involving 4979 epithelial ovarian cancer patients. The risk of recurrence was substantially improved in patients receiving dose-dense chemotherapy (hazard ratio 0.82, 95% confidence interval 0.70, 0.96); however, the result of the meta-analysis may be attributed to the effect size of smaller studies as following adjustment for small study effects the outcome becomes non-significant (hazard ratio 0.91, 95% confidence interval 0.81, 1.02, P = 0.123). Overall survival rates were not improved by dose-dense chemotherapy (hazard ratio 0.79, 95% confidence interval 0.60, 1.04). Thirty-five types of adverse effect were identified following retrieval of data from the original studies. Dose-dense chemotherapy did not increase significantly the rates of severe adverse effects, although thrombosis, severe diarrhoea and severe nausea were more prevalent in this group of patients. CONCLUSION: Dose-dense chemotherapy is associated with comparable side-effects to those of standard chemotherapy; however, data related to survival outcomes are not positive; hence, its use outside the setting of clinical trials should be discouraged.