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 timeprogrammed 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 anticancer 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.

Dose-dense paclitaxel plus carboplatin vs.epirubicin and cyclophosphamide with paclitaxel as adjuvant chemotherapy for high-risk triple-negative breast cancer

Objective:The objective of this open-label,randomized study was to compare dose-dense paclitaxel plus carboplatin(PCdd)with dose-dense epirubicin and cyclophosphamide followed by paclitaxel(ECdd-P)as an adjuvant chemotherapy for early triple-negative breast cancer(TNBC).Methods:We included Chinese patients with high recurrence risk TNBC who underwent primary breast cancer surgery.They were randomly assigned to receive PCdd[paclitaxel 150 mg/m2 on d 1 and carboplatin,the area under the curve,(AUC)=3 on d 2]or ECdd-P(epirubicin 80 mg/m2 divided in 2 d and cyclophosphamide 600 mg/m2 on d 1 for 4 cycles followed by paclitaxel 175 mg/m2 on d 1 for 4 cycles)every 2 weeks with granulocyte colony-stimulating factor(G-CSF)support.The primary endpoint was 3-year disease-free survival(DFS);the secondary endpoints were overall survival(OS)and safety.Results:The intent-to-treat population included 143 patients(70 in the PCdd arm and 73 in the ECdd-P arm).Compared with the ECdd-P arm,the PCdd arm had significantly higher 3-year DFS[93.9%vs.79.1%;hazard ratio(HR)=0.310;95%confidence interval(95%CI),0.137-0.704;log-rank,P=0.005]and OS(98.5%vs.92.9%;HR=0.142;95%CI,0.060-0.825;log-rank,P=0.028).Worse neutropenia(grade 3/4)was found in the ECdd-P than the PCdd arm(47.9%V5.21.4%,P=0.001).Conclusions:PCdd was superior to ECdd-P as an adjuvant chemotherapy for early TNBC with respect to improving the 3-year DFS and OS.PCdd also yielded lower hematological toxicity.Thus,PCdd might be a preferred regimen for early TNBC patients with a high recurrence risk.

Comparison of Dose-dense ABVD and Standard ABVD in the Treatment of Early Unfavorable and Advanced Hodgkin's Lymphoma: A Retrospective Analysis

This retrospective analysis compared standard regimen of doxorubicin, bleomycin, vin- blastine, and dacarbazine （ABVD） with the dose-dense ABVD regimen （ABVD-21） in terms of effi- cacy and toxicity. Patients who had early-stage unfavorable or advanced Hodgkin＇s lymphoma （HL） according to German Hodgkin Study Group criteria from March 1999 to February 2011 were ana- lyzed for treatment response, long-term survival and hematological toxicity. There were 85 patients in the ABVD-21 group and 118 patients in the ABVD group respectively. The complete remission rates aider completion of treatment were 92.9% and 90.7% for ABVD-21 and ABVD, respectively. During a median follow-up period of 62 months, no significant difference was found in projected 10-year progression-free survival （PFS） and overall survival （OS） rates （84.7% and 94.1% respectively for ABVD-21; 81.4% and 91.5% for ABVD）. Subgroup analyses showed that ABVD-21 was signifi- cantly better than ABVD for patients with IPS〉3 in terms of PFS and OS rates. Grade 3 to 4 leuko- penia （51.8% vs. 28.8%, P=0.001） and neutropenia （57.6% vs. 39.0%, P=0.009） were more common with ABVD-21. We were led to conclude that dose-dense ABVD did not result in better tumor con- trol and overall survival than did ABVD for early-stage unfavorable HL. However, patients at high risk, for example, with IPS〉3, may benefit from dose-dense ABVD.

Dose-Dense Regimen of Cisplatin and Infusional Fluorouracil in Advanced Gastric Cancer—A Single Institution Experience

Chemotherapy with continuous infusion of 5-fluorouracil and cisplatin in a monthly schedule is one of the most common regimens in the treatment of advanced gastric cancer. In this study, we evaluated the efficacy and safety of a dosedense administration of this regimen in this patient population. Sixty-six consecutive patients with previously untreated histologically confirmed unresectable or metastatic gastric adenocarcinoma were treated with a 2-hour infusion of cisplatin 100 mg/m2 followed by continuous infusion of 5-fluorouracil 1000 mg/m2/day for 5 days, every 21 days. The most common grade ≥3 toxicities were fatigue (42%), nausea/vomiting (30%) and leucopenia (12%). Four patients (6%) died from treatment-related toxicity. The response rate was 35%, the median progression-free survival was 4.3 months and the median survival was 5.9 months. In light of these results, the dose-dense approach seems to offer little, if any, benefit compared with the standard regimens.