Handle with care – effektives Toxizitätsmanagement während Chemotherapie eines serösen high-grade Ovarialkarzinoms

ZusammenfassungHier wird der komplikationsreiche Behandlungsverlauf einer heute 50-jährigen Patientin dargestellt. Operativ konnte bei schon weit fortgeschrittener Peritonealkarzinose keine Tumorfreiheit erreicht werden. Wegen des sehr reduzierten Allgemeinzustands war initial nur eine Monochemotherapie mit Carboplatin AUC 5 möglich. Unter dieser deeskalierten Monotherapie kam es schon nach dem ersten Zyklus zu einer ausgeprägten Hämatotoxizität mit behandlungsbedürftiger Anämie, Thrombopenie sowie Leukopenie, sodass mehrmalige Transfusionen von Erythrozyten- und Thrombozytenkonzentraten und G-CSF-Gaben notwendig wurden. Die weiteren Zyklen mussten mit erheblich reduzierter Dosierung angepasst werden. Unter dieser suboptimalen Dosierung war die maligne Erkrankung progredient, die Patientin musste einen Sigmastent bei symptomatischer Sigmastenose erhalten.Ab diesem Zeitpunkt wurde die weitere Behandlung der Patientin in einem intensiven komplementär/supportiven Konzept und mit einer individualisierten Chemotherapiekombination fortgeführt. Darunter kam es zu einer rückläufigen Hämatotoxizität, die Chemotherapie konnte nach 6 Zyklen mit einer weitgehenden Remission aller Tumormanifestationen beendet werden. Die genetische Testung ergab eine BRCA2-Mutation. Daraufhin erhielt die Patientin eine orale Erhaltungstherapie mit dem PARP-Inhibitor Niraparib 4.

413 Toripalimab in combination with concurrent chemoradiation in patients with advanced/metastatic esophageal carcinoma: protocol for a single-arm, prospective, open-label, phase II clinical trial

BackgroundEsophageal carcinoma is a disease with high morbidity and mortality in China and, recently, Immune checkpoint inhibitors(ICIs) combined with chemotherapy have shown good efficacy and safety for treatment; however, some patients still suffer from tumor progression or metastasis after treatment. Clinical studies have confirmed that immunotherapy combined with chemoradiotherapy can significantly improve the prognosis of patients with advanced esophageal cancer, but the efficacy and safety of adding radiotherapy to immunotherapy and chemotherapy have been less reported.MethodsThis is an open-label, single-arm, and single-center phase ll trial.Patients with unresectable stage IV esophageal squamous cell carcinoma(ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3W) combined with induction chemotherapy (paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30–50 Gy in 15–25 fractions, paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy;and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1- and 2-year overall survival(OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. Furthermore, we aimed to identify predictive biomarkers (such as the expression of PD-L1 ctDNA and cytokines) and to explore the relationship between these biomarkers and tumor response to the study treatment.AcknowledgementsWe thank all the participants and their advisors involving in this study. We owe thanks to the patients in our study and their family members.Trial RegistrationChiCTR(ChiCTR2100046715). Registered on the 27th of May 2021.Ethics ApprovalThe study protocol is approved by Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2021-021).Changes to the protocol will be communicated via protocol amendment by the study principal investigators. Written informed consent will be obtained from all participants.

ĐÁNH GIÁ HIỆU QUẢ HOÁ XẠ TRỊ ĐỒNG THỜI TRIỆT CĂN UNG THƯ THỰC QUẢN GIAI ĐOẠN III SỬ DỤNG PHÁC ĐỒ PC HÀNG TUẦN

Mục tiêu: Đánh giá hiệu quả hoá xạ trịđồng thời triệt căn (HXTĐTTC) trong điều trị (ĐT) ung thư thực quản (UTTQ) giai đoạn III đồng thời nhận xét một số tác dụng không mong muốn (TDKMM) của phương pháp ĐT này. Đối tượng và phương pháp: Nghiên cứu mô tả hồi cứu kết hợp tiến cứutrên 42 bệnh nhân (BN) được xạ trị IMRT hoặc 3D – CRT (liều 50,4 Gy cho vùng thể tích dự phòng, 60 – 66 Gy cho vùng u và hạch nguyên phát) kết hợp hóa chất Paclitaxel – Carboplatin (PC) hàng tuần (liều Paclitaxel 50mg/m2, Carboplatin AUC 2pha truyền tĩnh mạch ngày 1, chu kỳ 7 ngày trong quá trình xạ trị), đánh giá kết quả điều trị trên lâm sàng, trên cắt lớp vi tính (CLVT) theo RECIST và tác dụng không mong muốn sau 4 tuần kể từ khi kết thúc điều trị. Kết quả: Tỷ lệ đáp ứng sau điều trị trên lâm sàng đạt 90,5%. Tỷ lệ đáp ứng khách quan đạt 85,7%, trong đó đáp ứng hoàn toàn đạt tỷ lệ 33,3% và không có BN tiến triển sau điều trị trong thời gian theo dõi, đánh giá. Qua phân tích một số yếu tố liên quan đến đáp ứng điều trị bao gồm: giai đoạn T (T2 đáp ứng tốt hơn T3, p = 0,023), giai đoạn N (N1 đáp ứng tốt hơn N2, p = 0,001), kích thước u (kích thước u nhỏ đáp ứng tốt hơn kích thước u lớn, p = 0,033), kỹ thuật xạ trị (xạ trị bằng kỹ thuật IMRT cho hiệu quả tốt hơn kỹ thuật 3D – CRT, p = 0,006). TDKMM sớm hay gặp liên quan đến xạ trị bao gồm viêm da (61,9%), viêm thực quản (38,1%) và viêm phổi (11,9%) độ 1, độ 2. Hầu hết các TDKMM trên hệ huyết học, tiêu hoá, gan thận ở độ 1 và 2; chỉ gặp 2,4% bệnh nhân giảm bạch cầu độ 3. Kết luận: HXTĐTTC với phác đồ PC hàng tuần điều trị BN UTTQ giai đoạn III đảm bảo tốt kế hoạch điều trị, TDKMM chấp nhận được và hiệu quả điều trị tương đương với phác đồ CF.

Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: Exploratory analyses of ICON-8 trial.

5530 Background: ICON8 phase III trial did not show improvement in PFS or OS with first-line weekly dose-dense chemotherapy in EOC. This analysis evaluated the impact of tumor intrinsic primary chemosensitivity (assessed with modeled CA-125 ELIMination rate constant K (KELIM) based on the CA-125 kinetics during the first 100 days of chemo), on survival by treatment arms. Methods: Retrospective analysis of ICON8 where EOC patients were treated with chemo (Arm 1, standard (std) carboplatin AUC5-6 & paclitaxel 175mg/m2 q3weeks; Arm 2, carboplatin AUC 5-6 q3weeks and weekly paclitaxel 80 mg/m2; or Arm 3, weekly carboplatin AUC 2 & paclitaxel 80 mg/m2; ratio1:1:1) and debulking primary surgery (immediate (IPS), or delayed (DPS)). The association between standardized KELIM (dichotomized as favorable ≥ 1, or unfavorable < 1) and efficacy of treatment arms and surgery completeness was assessed univariate & multivariate analyses. Results: Of 1,566 enrolled patients, KELIM was calculated in 1,004 with ≥ 3 CA-125 available values. KELIM did not differ by treatment arm. Irrespective of surgical strategy, both KELIM and surgery completeness were significant prognostic factors, but treatment arms were not. In 354 IPS patients, 225 had unfavorable KELIM (63%). Weekly dose-dense carboplatin-paclitaxel (Arm 3) (compared to std chemo-Arm 1) was associated with improved survival in unfavorable KELIM patients (PFS:19.6 vs 11.0 months, HR 0.80 [0.54-1.17]; OS : 53.7 vs 40.1 months, HR 0.75 [0.50-1.14]), and worse survival in those with favorable KELIM (PFS: 26.7 vs 48.2 months, HR 1.27 [0.72-2.22]; OS: NR vs 69.2 months, HR 1.05 [0.53-2.06]). Maximum benefit was seen in highest-risk diseases (unfavorable KELIM + incomplete IPS; n = 116; PFS: 17.0 vs 7.4 months, HR 0.49 [0.29-0.82]; OS: 42.6 vs 27.0 months, HR 0.56 [0.33-0.96]). In 611 patients treated with neo-adjuvant chemo +/- DPS (279 unfavorable KELIM, 46%), the same trend for higher survival benefit from dose-dense carboplatin-paclitaxel was found in those with unfavorable KELIM (PFS: 10.8 vs 7.4 months, HR 0.84 [0.63-1.13]; OS: 26.4 vs 23.5 months, HR 0.80 [0.60-1.08]), and reversely. The higher KELIM, the higher the likelihood of complete surgery (OR 4.82 [3.21-7.37]). The prognostic impact of the surgery completeness was greater in unfavorable KELIM patients. Conclusions: In ICON8 trial, both the tumor primary chemosensitivity (by KELIM) and completeness of debulking surgery were major drivers of the prognosis & survival. Dose-dense fractionated chemotherapy in 1st-line setting may be beneficial for patients with lower tumor chemosensitivity, whilst it might be detrimental in those with highly chemosensitive disease. The greatest OS benefit (HR 0.56) from dose-dense chemotherapy was seen in highest-risk diseases (unfavorable KELIM and incomplete IPS).

KEYNOTE-799: Phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC.

8512 Background: KEYNOTE-799 (NCT03631784) is an ongoing study of the anti‒PD-1 antibody pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in patients (pts) with unresectable, locally advanced stage III NSCLC. Prior results from this study in a subset of pts (primary efficacy population) showed an ORR of 69.6% in cohort A (squamous and nonsquamous, n = 112) and 70.5% in cohort B (nonsquamous, n = 61), and grade ≥3 pneumonitis in 8.0% and 7.9% of pts, respectively. Here, we present results for all pts enrolled in KEYNOTE-799. Methods: This nonrandomized, multisite, open-label phase 2 trial enrolled pts aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA‒C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received 1 cycle of carboplatin AUC 6 and paclitaxel 200 mg/m2 and pembro 200 mg. After 3 wks, pts received carboplatin AUC 2 and paclitaxel 45 mg/m2 QW for 6 wks and 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous only) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2,and pembro 200 mg Q3W, and TRT in cycles 2 and 3. All pts received an additional 14 cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Efficacy and safety were assessed in all pts as-treated. Results: Of 216 pts enrolled in KEYNOTE-799 (cohort A, n = 112; cohort B, n = 104), 112 in cohort A and 102 in cohort B received treatment. As of October 28, 2020, the median (range) time from first dose to database cutoff was 18.5 (13.6–23.8) mo in cohort A and 13.7 (2.9–23.5) mo in cohort B. ORR (95% CI) was 70.5% (61.2%‒78.8%) in cohort A and 70.6% (60.7%‒79.2%) in cohort B. Median DOR was not reached in either cohort (Table). ORR was similar regardless of PD-L1 status ([TPS <1% and TPS ≥1%]; Cohort A, 66.7% and 75.8%; Cohort B, 71.4% and 72.5%) and tumor histology (Cohort A, squamous, 71.2% and nonsquamous, 69.2%). Grade ≥3 pneumonitis occurred in 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Grade 3‒5 treatment-related AEs occurred in 72 pts (64.3%) in cohort A and 51 (50.0%) in cohort B. Conclusions: Pembro plus cCRT continues to demonstrate promising antitumor activity, regardless of PD-L1 TPS and tumor histology, and manageable safety in pts with previously untreated, locally advanced, stage III NSCLC with longer follow-up. Clinical trial information: NCT03631784. [Table: see text]

Clinical and pathological response to neoadjuvant chemotherapy (NCT) in patients with triple-negative breast cancer (TNBC).

e12616 Background: Neoadjuvant chemotherapy (NCT), Triple-negative breast cancer (TNBC) including anthracyclines and taxanes for early stages of TNBC, allows to achieve pathological complete response (pCR) in 25-36% of patients. Pathological complete response (pCR) significantly correlates with an increase in disease-free survival (DFS) and overall survival (OS). Methods: Randomized, monocentric trial was conducted in NN Petrov National Medical Research Center of Oncology from 2016 to 2019. 99 patients aged from 28 to 68 years with confirmed TNBC were included in trial: 96 had invasive ductal carcinoma G3, 3 - metaplastic cancer, negative BRCA mutations (a test for Founder mutations was performed).Patients were randomized in 3 groups, depending on the NCT regimen:1st subgroup (24 patients) - Eribulin in combination with Carboplatin AUC 5 x 4 cycles 2nd subgroup (37 patients) - Paclitaxel in combination with Carboplatin AUC 5 x 4 cycles 3rd subgroup (38 patients) –Carboplatin AUC5 + Doxorubicin + Paclitaxel x 6 cycles. Patients 1 and 2 subgroups in an adjuvant mode received 4 cycles of AC. Results: Clinical complete response (cCR) by physical examination (palpation) was achieved in 44 out of 99 patients (44.4%). Clinical complete response (cCR) by ultrasound and MG - in 27 (27.2%) patients. Miller-Payne V regression stage was achieved in 55 out of 99 cases (55.6%). In clinical cT1-T2 stage (n = 70), ypCR was achieved in 49 cases (70%), cT3-T4 (n = 29) ypCR in 6 patients (20.68%). Before NCT, 71 patients had status cN0-N1. Conversion to ypN0 occurred in 57 patients (80.2%). In 28 patients with cN2-N3 status, conversion to ypN0 occurred in 7 patients (25%). The median follow-up was 58 months. Progression was observed in 15.1% of patients, mortality – 6%. Local recurrence - 6 patients (6%), all patients were with residual tumor after NCT. Distant recurrence – 8 patients (8.1 %). Local recurrence rate and distant recurrence rate did not correlate with type of surgery (BCS or ME), but correlated with ypCR. Conclusions: NCT for TNBC is advisable both for locally advanced breast cancer and early breast cancer BC. De-escalation of BC surgery is possible in the future, especially in cT1-T2 stage patients (n = 70) where ypCR rate reaches 70%. It is planned to continue the trial with the vacuum aspiration biopsy of the tumor bed and SLNB after NCT.SLNB after NCT is advisable only in cN0-N1 group of patients (n = 71), since conversion to ypN0 was achieved in 57 patients - 80.2%.

Pyrotinib as neoadjuvant therapy for HER2+ breast cancer: A multicenter, randomized, controlled, phase II trial.

574 Background: Pyrotinib is a new irreversible tyrosine kinase inhibitor (TKI) which significantly improved the progression-free survival (PFS) of patients with HER2+ metastatic breast cancer (MBC). In this study we aim to investigate the efficacy and safety of pyrotinib in neoadjuvant therapy. Methods: This is an open-label, multicenter, randomized controlled trial. Eligible patients (pts) aged 18–70 years with invasive carcinoma, cT2-3N0-3M0 stage, HER2-positive breast cancer were included. We randomized 34 pts into the treatment group and 33 into the controlled group from 2019-2021. Pts in the treatment group received 6 cycles of pyrotinib 400mg + trastuzumab 6mg/kg (LD 8mg/kg) + docetaxel 75mg/m2 + carboplatin (AUC = 6mg/ml·min) (TCbH+Py) treatment while the controlled group received 6 cycles of trastuzumab 6mg/kg (LD 8mg/kg) + docetaxel 75mg/m2 + carboplatin (AUC = 6mg/ml·min) (TCbH). Total pathologic complete response (tpCR) was defined as no invasive or in situ disease in the breast or axilla (ypT0/Tis, ypN0) and was assigned to be the primary outcome (NCT03756064). Results: 51 cases had completed 6 cycles of neoadjuvant therapy and successfully underwent operation (21 in the treatment group and 30 in the controlled group). In the treatment group, 6 cases have not complete neoadjuvant therapy, 6 cases quitted because of poor compliance and 1 patient has not receive operation yet. For controlled group, 3 patients have not complete neoadjuvant therapy. The tpCR rate in the treatment group is 71.4% (15/21) versus 36.7% (11/30) in the controlled group. A significant difference was determined between the two groups (p < 0.05). All pts achieved an objective response in the treatment group while in the controlled group for about 83.3% (25/30). 4 cases showed stable disease (SD) and 1 case was evaluated as progressive disease (PD) in the controlled group. The most common AE in the treatment group is diarrhoea with grade 3 occurred in 6 cases (28.6%), most of this event limited in the first treatment cycle. In the controlled group 3 pts (10%) occurred grade 3 diarrhoea. Conclusions: In this study TCbH+Py neoadjuvant therapy significantly improved the tpCR rate of HER2+ breast cancer pts for about twice higher than TCbH with a manageable safety. Clinical trial information: NCT03756064.

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Before the approval of first-line immune checkpoint inhibitors, platinum doublets were the standard of care in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Pemetrexed-platinum combinations are preferred in non-squamous NSCLC. However, there has been no direct comparison to paclitaxel-carboplatin. Methods: This open-label randomized trial was designed to compare pemetrexed-carboplatin with (weekly) paclitaxel-carboplatin in treatment-naïve advanced/metastatic non-squamous NSCLC without driver mutations. Patients received either pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks, or paclitaxel 80 mg/m2 on day 1, day 8, and day 15 with carboplatin AUC 5 every 4 weeks for 4 cycles. Patients in both arms were allowed to receive pemetrexed maintenance. Results: A total of 180 patients were enrolled. The study was terminated early; however, at the time of analysis 75.8% of the required events had occurred. Finally, 164 patients were evaluable, 83 in the pemetrexed arm and 81 in the paclitaxel arm. After a median follow-up of 17 months, progression-free survival (PFS) rates at 6 months were not different in the two treatment arms (47.45 vs. 48.64%, p = 0.88). The median PFS values were 5.67 months (95% CI 3.73–7.3) and 5.03 months (95% CI 2.63–7.43) in each arm, respectively (HR 1.13, 95% CI 0.81–1.59, p = 0.44). The median overall survival was also not different: 14.83 months (95% CI 9.5–18.73) and 11.3 (95% CI 8.3–19.7; HR 1.19, 95% CI 0.8–1.78, p = 0.37). All grade toxicities were similar except for alopecia and peripheral neuropathy, which were higher in the paclitaxel arm. Conclusion: Pemetrexed-carboplatin is not superior to (weekly) paclitaxel-carboplatin as the first-line regimen in advanced non-squamous NSCLC in terms of PFS.