Relative Dose Intensity Research Articles

Real-World Data Validation of NAPOLI-1 Nomogram for the Prediction of Overall Survival in Metastatic Pancreatic Cancer

The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram.

The impact of relative dose intensity on overall and progression-free survival during cabozantinib therapy for unresectable hepatocellular carcinoma.

569 Background: Cabozantinib (CAB) has been approved as 2nd or later-line worldwide in patients with unresectable hepatocellular carcinoma (u-HCC). There is no data about the relationship between the relative dose intensity (RDI) of CAB and clinical outcome. We investigated the impact of RDI on overall survival (OS) and progression-free survival (PFS) during CAB in real-world practice. Methods: A total of 38 u-HCC patients who received CAB between Jan 2021 and Sep 2022 at our institution were enrolled. Tumor assessments in accordance with RECIST ver1.1 were done using dynamic CT or MRI within 4-8 weeks and every 8-10 weeks thereafter. The RDI of CAB for the first month (1M-RDI) was calculated. Results: The median age was 74 years, and 30 patients were Child-Pugh A. BCLC stage A/B/C were 0/ 11/ 27 patients, and 34 patients were previously received atezolizumab plus bevacizumab. As 2nd or 3rd-line, 20 patients received CAB. The median follow-up duration was 7.2 months, and the median PFS was 4.4 months in all patients. The median overall survival (OS) was 16.2 months from the administration of CAB. The objective response rate (ORR) and disease control rate (DCR) was 13.8% and 89.7%. Adverse events (AEs) were observed in all patients, requiring dose reduction in 26 patients (68%) and interruption of CAB in 21 patients (55%). The median 1M-RDI was 35%, and there was no significant difference in PFS between 1M-RDI ≧40% (high 1M-RDI, n=13) and &lt;40% (n=16) (4.1 months vs. 4.7 months, p=0.89). There were no significant differences in age, pretreatment ALBI score, AFP, and major vascular invasion (MVI) between the patients with and without a high RDI. The induction rate of molecular targeted therapies after CAB was 60%. The only significant factor associated with PFS was MVI (HR 0.10, 95%CI 0.02-0.65, p=0.02). In a multivariate analysis, pretreatment ALBI score (HR 5.8, 95% CI 1.2-27.8, P=0.03) and hypertension as AE during CAB (HR 0.29, 95% CI 0.09-0.87, P=0.03) were the significant factors associated with OS. Conclusions: Maintaining a high 1M-RDI of CAB was not associated with OS and PFS in real-world practice. Dose modification is essential for CAB therapy in u-HCC patients.

Safety and efficacy of prophylactic pegfilgrastim on day 3 of neoadjuvant DCF chemotherapy in elderly patients with resectable esophageal cancer.

375 Background: Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (Neo DCF) is one of the standard treatment for resectable esophageal cancer (EC) based on the results of the JCOG1109 study, however, a high frequency (5-30%) of febrile neutropenia (FN) has been reported with NeoDCF and the elderly (patients) pts have higher risk for FN. A single arm phase II study indicated that use of primary prophylactic pegfilgrastim (PG) on day 3 of NeoDCF might prevent FN. We compared the frequency of neutropenia and FN with or without primary prophylactic administration of PG on day 3 of NeoDCF in elderly resectable EC pts. Methods: EC pts who had received NeoDCF between 2009 and 2022, were ≥70 years old, and had adequate organ functions and PS were selected for this retrospective study. Pts were divided into two groups with Day 3 PG-containing DCF (day3 prophylactic PG: D3PG) or No PG DCF (non-prophylactic PG: NPG). Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and prophylactic antibiotics was administered on days 5-15 in each group if possible. We retrospectively evaluated the relative dose intensity (RDI), histopathological and clinical benefit, and adverse events. Results: A total of 67 pts (D3PG, 32; NPG, 35) with a median age of 73 years were identified. The PS (0/1/2) and clinical stage (I-II/III/ IVA-B [only supraclavicular lymph node]) were 18 (56.3%)/12 (37.5%)/2 (6.2%) and 1 (3.1%)/18 (56.3%)/13 (40.6%) in the D3PG group and 20 (57.1%)/15 (42.9%)/0 and 7 (20.0%)/24 (68.6%)/4 (11.4%) in the NPG group, respectively. Six pts in the D3PG group and 3 pts in the NPG group discontinued NeoDCF because of toxicity and progression. All pts except 1 in the D3PG group underwent surgery. The RDIs (DTX/CDDP/5-FU) were 0.90/0.83/0.90 in the D3PG group and 0.83/0.83/0.83 in the NPG group. Pts who achieved a pCR (D3PG/NPG) were 7/3 (22.6%/28.6%). The common grade ≥3 adverse events (D3PG/NPG) were neutropenia (12.5%/71.4%) and FN (6.3%/20.0%). Three-year relapse-free survival rate (D3PG/NPG) was 70.8%/54.4% (hazard ratio [HR] 0.525 [95% confidence interval (CI) 0.189-1.457], p=0.216). Three-year survival rate (D3PG/NPG) was 91.8%/70.5% (HR 0.497 [95%CI 0.104-2.35], p=0.378), respectively. Conclusions: The use of primary prophylactic PG on day 3 of preoperative DCF improved the safety and maintained the RDI in the D3PG group. The efficacy was comparable between the D3PG and NPG groups despite the higher number of pts with more advanced disease in the D3PG group.

Multicenter observational study of nanoliposomal irinotecan and fluorouracil/leucovorin in patients with unresectable or recurrent pancreatic cancer (NAPOLEON-2): Final retrospective results.

706 Background: Nanoliposomal irinotecan (NAL-IRI) and fluorouracil with folinic acid (NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). We conducted this NAPOLEON-2 study to investigate the efficacy and safety of NFF and explore the predictive or prognostic factors, retrospectively and prospectively, in the real world. We previously reported the interim analysis of the retrospective data 6 months after the end of data collection ( Ann Oncol. 2022;33(suppl 4): S289-S290). Here, we report the final data 1 year after data collection. Methods: We retrospectively collected data from urPC patients treated with NFF who received at least one previous chemotherapy in 21 hospitals in Japan from June 2020 to May 2021. Patient characteristics, treatment efficacy, and adverse events were analyzed. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier analysis. OS and PFS among the therapeutic lines of NFF were also analyzed. Results: NFF was administered to 161 patients. The median follow-up period was 7.3 months (95% confidence interval [CI], 5.6–8.9); median age, 67 years (range, 38–85), with 73 female patients (45%). The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 74/76/10/1 patients, respectively. Nineteen patients (12%) had locally advanced disease; 142 (88%) had metastatic disease; 89 (55%) had liver metastasis; and 44 (27%) had peritoneal metastasis. All patients previously received gemcitabine-based therapy. NFF was administered as 2nd/3rd/4th-or-later-line therapy to 104/41/16 patients, respectively. The median OS was 8.1 months (95% CI, 7.1–9.7); median PFS, 3.4 months (95% CI, 2.8–4.4); overall response rate, 5%; and disease control rate, 52%. The relative dose intensity was 81.6% with NAL-IRI and 90.7% with fluorouracil. The initial dose of NAL-IRI was reduced in 57 patients (35%), mainly owing to UGT1A1 examination status (8%), followed by decreased organ function or worsened performance status (6%). Dosage reduction during treatment (independent of the initial dose reduction) was performed in 67 patients (42%), mainly owing to neutropenia (16%) and anorexia (11%). Frequent Grade 3/4 adverse events were neutropenia (24%), anorexia (12%), and leukopenia (12%). No Grade 5 adverse events were observed. The median OS and PFS for NFF in the 2nd-line group, compared with the 3rd-or-later-line group, were 7.6 vs 9.1 months (hazard ratio [HR], 0.92; 95% CI, 0.64–1.35; p = 0.68) and 2.9 vs 3.8 months (HR, 0.89; 95% CI, 0.64–1.24; p = 0.49), respectively. Conclusions: NFF had appropriate efficacy and manageable toxicity profiles, consistent with our previous report. NFF could be a candidate for 2nd-or-later-line regimens in the real world.

Phase 2 multi-institutional prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged 80 years or more after curative resection of colorectal cancer: The HiSCO-03 study.

101 Background: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective phase II feasibility study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. Methods: This study involved 15 institutions of the Hiroshima Surgical Oncology Study Group (HiSCO). Patients with stage III CRC aged ≥80 years who underwent curative resection with an Eastern Cooperative Oncology Group performance status of 0–1 were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1–28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. Results: Sixty-nine patients were enrolled in the study between December 2013 and June 2021. Of the 69 patients, 65 were included in the analysis, excluding two ineligible patients and two who discontinued before treatment commenced. There were 32 males and 33 females with a median age of 82 years (range, 80–88 years). There were four patients with stage IIIA CRC, 49 with stage IIIB, and 12 with stage IIIC. In the primary endpoint, administration completion rate was 67.3% (95% confidence interval: 54.9The median relative dose intensities were 84% (range, 4–100%) for UFT, and 100% (range, 4–100%) for LV. Incidence of grade three or higher adverse events were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). No treatment-related deaths occurred. An independent risk factor was not identified in the background risk factor analysis for treatment discontinuation. Conclusions: Uracil-tegafur and leucovorin are not recommended as standard adjuvant therapy for patients with stage III CRC ≥80 years of age because of the possibility of lower completion rates. The frequency of serious adverse events was acceptable, and safety was confirmed in the treated patients. It is necessary to clarify the background of patients in which administration is discontinued and to investigate the impact on long-term prognosis. Clinical trial information: R000013902 .

Benefits of measuring urinary protein/creatinine ratio in lenvatinib treatment for unresectable hepatocellular carcinoma.

529 Background: Proteinuria is a well-known lenvatinib (LEN)-associated adverse event. The standard management of proteinuria includes measurement of the urinary protein/creatinine ratio (UPCR) in patients with a qualitative result for proteinuria of ≥1+. Although several studies have shown a good correlation of the UPCR with the qualitative result, it remains unclear how the management of proteinuria by measuring the UPCR might affect the clinical outcomes. This study was aimed at revealing the effect of measuring UPCR on the treatment efficacy and safety in unresectable hepatocellular carcinoma (uHCC) patients receiving LEN. Methods: We retrospectively analyzed the data of uHCC patients who received LEN between March 2018 and February 2022 at National Cancer Center Hospital East. Patients in the UPCR group were monitored by measurement of the UPCR when the qualitative result was ≥2+, while those in the non-UPCR group were not. LEN was withdrawn when the UPCR was ≥3.5 in the UPCR group, and the qualitative result for proteinuria was ≥3+ in the non-UPCR group. Results: A total of 89 patients were included in this study, of which 39 had a qualitative result for proteinuria of ≥2+. Of these 39 patients with proteinuria, 22 were classified into the UPCR group and the remaining into the non-UPCR group. Of the 209 qualitative results of ≥2+ in the UPCR group, 10 (4.8%) corresponded to a UPCR of ≥3.5. The relative dose intensity of LEN during the first 8 weeks was significantly higher in the UPCR group (64.4%) than in the non-UPCR group (52.8 %, p = 0.047). The time to treatment failure was 12.6 months (95% CI, 6.3-16.9) in the UPCR group and 5.5 months (95% CI, 2.1-11.0) in the non-UPCR group (p = 0.125). The rate of change in eGFR from the baseline to the end of treatment was not significantly different between two groups. Conclusions: Measurement of UPCR might contribute to avoiding unnecessary interruption of LEN, because the UPCR values in most patients were below 3.5.

Efficacy and safety of nanoliposomal irinotecan plus fluorouracil and folinic acid after irinotecan-based chemotherapy in patients with advanced pancreatic cancer: Results of the retrospective part of the NAPOLEON-2 study.

705 Background: Nanoliposomal irinotecan plus fluorouracil and folinic acid (nal-IRI/FU/LV; NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). However, the efficacy and safety of NFF in patients who previously received irinotecan-based chemotherapy remain unclear. Methods: This retrospective study collected data from patients with urPC who received at least one previous chemotherapy before receiving NFF therapy at 21 hospitals in Japan between June 2020 and May 2021 (NAPOLEON-2 study). We analyzed antitumor efficacy, progression-free survival (PFS), and overall survival (OS) after the initiation of NFF and compared adverse events (AEs) between previous irinotecan users and non-users. Results: NFF was administered to 161 patients. The median follow-up period was 7.3 months (95% confidence interval [CI] = 5.6–8.9). All patients received prior gemcitabine-based therapy, and NFF was administered as the second-, third-, and fourth-or-later-line chemotherapy in 104, 41, and 16 patients, respectively. Eighteen patients (11%) previously received irinotecan. Patients’ characteristics did not significantly differ between irinotecan users (n = 18) and non-users (n = 143), excluding age (mean [range], 64 [38–78] vs. 68 [47–85] years; p = 0.01), the lung metastasis rate (44% vs. 14%; p &lt; 0.01), the treatment line (2nd/3rd/4th-or-later, 0%/56%/44% vs. 73%/22%/6%; p &lt; 0.01), and the pretreatment period (15.3 [6.8–45.0] vs. 9.1 [1.4–36.2] months; p &lt; 0.01). The median relative dose intensities of nal-IRI were 87.1% and 81.1% in irinotecan users and non-users, respectively (p = 0.28), and those of FU were 93.5% and 89.2%, respectively (p = 0.54). The objective response rate (6% vs. 5%; p = 0.90), disease control rate (44% vs. 53%; p = 0.49), PFS (2.8 months vs. 3.6 months; hazard ratio [HR] = 1.23; 95% CI = 0.74–2.05; p = 0.42), and OS (9.2 months vs. 8.0 months; HR = 0.88; 95% CI = 0.49–1.57; p = 0.66) did not differ between irinotecan users and non-users, nor did the rates of Grade 3/4 hematological (p = 0.68) and non-hematological (p = 0.13) AEs. Among irinotecan users, the duration of irinotecan-based therapy and the irinotecan-free interval before NFF did not affect the efficacy of NFF. Conclusions: NFF might be effective and safe even in patients with urPC who received irinotecan-based chemotherapy irrespective of its duration or the interval to NFF. Therefore, NFF is a possible treatment option after irinotecan-based chemotherapy. Further studies with a sufficient number of patients and a prospective design are warranted to examine the efficacy of NFF after irinotecan-based chemotherapy.

Adjuvant nab-paclitaxel plus S-1 versus oxaliplatin plus capecitabine after curative D2 gastrectomy in patients with stage III gastric adenocarcinoma: a phase 3 open-label, randomized controlled trial

386 Background: Although adjuvant chemotherapy improvs the survival rate of stage III gastric cancer after curative D2 gastrectomy, the overall benefit is unsatisfactory. Therefore, the study was designed to evaluate the efficacy and safety of adjuvant nab-paclitaxel plus S-1 (AS) versus oxaliplatin plus capecitabine (CAPOX) in the treatment of stage III gastric adenocarcinoma (GAC) after curative D2 gastrectomy. Methods: This phase 3, open-label, randomized study was conducted in patients with stage III GAC after curative D2 gastrectomy. Patients were randomized (1:1) to receive adjuvant AS (100 mg/m2 nab-paclitaxel on days 1 and 8; 40-60 mg oral S-1 twice daily on days 1-14) or CAPOX (130 mg/m2 oxaliplatin on day 1; 1000 mg/m2 oral capecitabine twice daily on days 1-14), repeat every 3 weeks for 8 cycles. The primary endpoint was the 3-year disease-free survival (DFS) rate by intention-to-treat analysis. Secondary endpoints included overall survival (OS) and safety. Results: Between March 2020 and August 2022, 280 patients were screened and 233 were randomly assigned to study treatment (AS, 115; CAPOX, 118). The median age was 62 years (range, 27-77) in AS and 63 years (range, 35-75) in CAPOX. The pathological stages were 42.61% stage IIIA, 34.78% stage IIIB, and 22.61% stage IIIC in AS, while those of CAPOX were 47.46% stage IIIA, 30.51% stage IIIB, and 22.03% stage IIIC. The 1-year DFS rate was 89.0% in AS versus 76.9% in CAPOX. The 1-year OS rate was higher in AS versus CAPOX (100% vs. 95.5%). Seven (6.09%) in AS and 11 (9.32%) in CAPOX experienced recurrence during follow-up; thereinto, one in CAPOX confirmed recurrence with tumor markers and clinical manifestations. Recurrence sites in AS and CAPOX involved the peritoneum (1 vs. 4), locoregional (1 vs. 2), and distant (5 vs. 6), of which, certain patients had 2 simultaneously. Among 6 deaths in CAPOX, 3 died from GAC, 1 died from other diseases and 2 died from unknown. The median relative dose intensity was 96.91% for nab-paclitaxel and 88.00% for S-1 in AS, 82.77% for oxaliplatin and 79.36% for capecitabine in CAPOX. Certain patients in AS (38.26%) and CAPOX (22.03%) experienced grade 3/4 adverse events (AEs). The most common AEs in AS and CAPOX included anemia (20.96% vs. 19.63%), neutropenia (30.70% vs. 21.02%), and thrombocytopenia (1.10% vs. 15.47%). Conclusions: In this study, AS showed longer trends in the DFS rate, OS rate, and manageable safety profile in patients with stage III GAC after curative D2 gastrectomy compared with CAPOX, suggesting a potential therapeutic option for this population. Clinical trial information: NCT04135781 .

Real-Life Effectivity of Dose Intensity Reduction of First-Line mFOLFIRI-Based Treatment of Metastatic Colorectal Cancers: Sometimes Less Is More.

Aim: The key purposes of the treatment of metastatic malignancies are to extend survival and maintain the quality of life. Recently it has been emphasized in the scientific literature that the maintenance of maximal dose intensity is not always beneficial. Method: We examined the effectiveness of first-line mFOLFIRI-based treatments used in mCRC indication in 515 patients, treated between 1 January 2013 and 31 December 2018 at the Department of Oncotherapy of the University of Pécs, on a basis of real-world retrospective data analysis. We studied the effect of decreased dose intensity treatment modifications on patient survival. Results: 45% of all patients achieved the optimal relative dose intensity (RDI) of 85%, and the median progression-free and overall survival (mPFS, mOS) were 199 and 578 days, compared to 322 and 743 days, (mPFS p < 0.0002, 1 y (year) PFS OR (odds ratio) 0.39 (95% CI: 0.26−0.56) and mOS p = 0.0781, 2 yrs OS OR 0.58 (95% CI: 0.39−0.85), respectively) in the group of patients not achieving the RDI of 85%. Conclusions: Decreased dose intensity did not reduce the effectiveness of treatment; in fact, there was a significant improvement in most of the analyzed parameters. The option of reduced dose intensity, which shows the same or even better results with less toxicity, should definitely be considered in the future palliative treatment of mCRC patients.

Impact of Relative Dose Intensity of Docetaxel, Cisplatin, and 5-Fluorouracil Neoadjuvant Chemotherapy on Survival of Esophageal Squamous Cell Cancer Patients

Introduction: This study aimed to clarify the impact of the average relative dose intensity (RDI) of neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-NAC) for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Materials and Methods: To identify the optimal RDI, recurrence-free survival (RFS) and cumulative incidence function (CIF) for recurrence were calculated in low and high RDI groups with any cut-off points. The optimal RDI was defined as the highest RDI administered with a significant increase in either RFS or CIF. The clinicopathological characteristics of the two groups divided by optimal RDI were investigated. The preoperative prognostic factors associated with RFS were confirmed by multivariable Cox proportional hazards model. Results: Among the 150 eligible patients treated with DCF-NAC from 2010 to 2020, 3-year RFS and CIF were 56.3% and 37.8% in 90 patients in the less than 80% RDI group (<80% RDI) and 73.3% and 26.7% in 60 patients in the more than or equal to 80% RDI group (≥80% RDI), respectively. The optimal cut-off RDI was identified as 80%. The <80% RDI group included older individuals, a lower value of creatinine clearance, a higher Charlson Comorbidity Index, reduced RDI at first course, and grade 1–0 in the histopathological tumor response than the ≥80% RDI group. R0 resection and postoperative complication rates were equal in both groups. Cox proportional hazards model identified the response rate and RDI as predictors of RFS. Conclusion: An average RDI of more than or equal to 80% improved prognosis in patients receiving DCF-NAC for ESCC.

Dose Delays, Dose Reductions, and Relative Total Dose Intensity in Patients With Advanced Cancer Who Exercised During Neoadjuvant Chemotherapy Treatment.

When it comes to chemotherapy, maintaining the dose and schedule of treatment are of vital importance, as clinical evidence suggests that dose intensity is associated with optimal treatment outcomes for various tumors. Yet, reduced dose intensity is a common method of mitigating the chemotherapy-induced side effects. Exercise has been shown to attenuate chemotherapy-related symptoms that frequently cluster together. Understanding this, we conducted a retrospective analysis in patients with advanced disease treated with adjuvant or neoadjuvant chemotherapy regimens and who completed exercise training during treatment. Data were collected retrospectively in a chart review of 184 patients, aged 18 years or older and treated for Stage IIIA-IV cancer. Data collection included baseline patient demographics and clinical characteristics, including age at diagnosis, cancer stage at initial diagnosis, chemotherapy regimen, and planned dose and schedule. Cancer types included brain (6.5%), breast (35.9%), colorectal (8.7%), non-Hodgkin's lymphoma (7.6%), Hodgkin's lymphoma (11.4%), non-small cell lung (16.8%), ovarian (10.9%), and pancreatic (2.2%). All patients completed at least 12 weeks of prescribed, individualized exercise. Each program included cardiovascular, resistance training, and flexibility components, under the supervision of a certified exercise oncology trainer once a week. RDI was measured for each myelosuppressive agent in a regimen over the entire chemotherapy course and then averaged across the myelosuppressive agents in a regimen. An RDI of less than 85% was designated as the clinically meaningful threshold for reduction in RDI based on previously published studies. A considerable proportion of patients across regimens had dose delays (18.3%-74.3%) and dose reductions (18.1%-84.6%). Between 12% and 83.9% of patients missed at least 1 dose of a myelosuppressive agent that was part of their standard regimen. Overall, 50.8% of patients received less than 85% of the RDI. In short, patients with advanced cancer and an exercise adherence above 84.3% saw fewer chemotherapy dose delays and dose reductions. These delays and reductions occurred significantly less frequently compared to the published norms in the sedentary population (P < .05).

G-CSF filgrastim biosimilar-Sandoz reduces the incidence of febrile neutropenia in patients receiving chemotherapy regimens with rest periods not exceeding 14 days: A French, multicenter, prospective, non-interventional study

PurposeThe objective of this study was to describe filgrastim biosimilar-Sandoz modalities of use in patients receiving cytotoxic chemotherapy regimens with a rest period of ≤14 days and to investigate the incidence of febrile neutropenia (FN) in routine clinical practice. MethodsThis was a French, multicenter, prospective and descriptive, non‐interventional study including patients with breast, lung, gastrointestinal cancer or a lymphoma initiating filgrastim biosimilar-Sandoz treatment and in the context of cytotoxic chemotherapy with a rest period not exceeding 14 days. Data were collected during two routine clinical visits on the modalities of use of filgrastim biosimilar-Sandoz, on the incidence of neutropenia events and on adverse events. ResultsBetween November 2015 and June 2018, 1080 patients were enrolled in the study in 129 centers. Overall, 941 patients were evaluable for efficacy and 937 for safety. Of the 941 patients, 84.8% had a solid tumor and 15.2% had a lymphoid hemopathy. Filgrastim biosimilar-Sandoz was prescribed as primary prophylaxis in 74.0% of the patients and as secondary prophylaxis in 22.4% of the patients. FN was reported in 1.5% of patients with a solid tumor and 12.6% of patients with a lymphoma. A chemotherapy relative dose intensity of over 85% with regard to the reference dose was achieved by more than 80% of the patients in all tumor localizations. ConclusionsThe study showed that filgrastim biosimilar-Sandoz is safe to use and effective in preventing FN and in allowing to maintain the dose intensity of chemotherapy.

Impact of relative dose intensity of trabectedin with pegfilgrastim support: a single-centre retrospective study

Relative dose intensity (RDI) has been associated with improved survival in patients with advanced solid tumours. However, there is no evidence regarding RDI in patients under long-term treatment with trabectedin for adult advanced soft tissue sarcoma (STS). Pegfilgrastim use was associated with chemotherapy dose intensity maintenance in patients with various cancers. We retrospectively evaluated the RDI in patients with STS receiving trabectedin. The patients were grouped based on whether trabectedin administration was supported by pegfilgrastim. RDI was obtained for 114 of the 140 included patients. Chemotherapy cycles that included filgrastim were excluded. Patients treated with and without pegfilgrastim had similar RDI rates (77.1% ± 17.6% vs 78.8% ± 16.4%; P = 0.485). Moreover, we found no association between patients receiving ≥4 trabectedin cycles and the use of pegfilgrastim. These results suggested that trabectedin dose delays or reductions should be considered before administering prophylactic pegfilgrastim.

Bendamustine in the treatment of patients with indolent non-Hodgkin lymphoma refractory or relapse to rituximab treatment: An open-label, single-agent, multicenter study in China.

The optimal treatment strategy for refractory or relapse (R/R) indolent non-Hodgkin lymphoma (iNHL) has not been fully identified. This study aims to investigate the efficacy and tolerance of bendamustine hydrochloride developed in native Chinese corporation in the treatment of patients with R/R iNHL. A total of 101 patients from 19 centers were enrolled in this study from July 2016 to February 2019. Bendamustine hydrochloride (120mg/m2 ) was given on days 1 and 2 of each 21-day treatment cycle for six planned cycles or up to eight cycles if tolerated. Parameters of efficacy and safety were analyzed. The median age of the patients was 53.44 (range, 24.4-74.6) years old. A total of 56 (55.44%) patients completed at least six treatment cycles, and the relative dose intensity was 93.78%. The overall response rate was 72.28%, and the median duration of response was 15.84months (95% confidence interval [CI], 13.77-27.48months). Median progression-free survival was 16.52months (95% CI, 14.72-23.41months), and the median overall survival was not reached. Grade 3 or 4 hematologic toxicities included neutropenia (77.22%), thrombocytopenia (29.70%), and anemia (15.84%). The most frequent nonhematologic adverse events (any grade) included nausea, vomiting, fatigue, fever, decreased appetite, and weight loss. Seven patients died during the trial, and four cases may be related to the investigational drug. This study reveals that bendamustine hydrochloride is a feasible treatment option for the indolent B-cell non-Hodgkin lymphoma patient who has not remitted or relapsed after treatment with rituximab. All adverse events were predictable and manageable.

Impact of the COVID-19 Pandemic on the Management and End-of-life Care of Unresectable Pancreatic Cancer.

Objective The coronavirus disease (COVID-19) pandemic has altered the delivery of medical care. The present study evaluated the impact of COVID-19 on the outcomes of unresectable pancreatic cancer (PC) patients who received end-of-life care. Methods We retrospectively compared the management of PC patients during the COVID-19 pandemic (from April 2020 to March 2021) to the preceding year, which was unaffected by the pandemic (from April 2019 to March 2020), based on a prospectively maintained institutional database. Results A total of 178 patients were included in the COVID-19-exposed group and 201 patients were included in the COVID-19-unexposed group. The median overall survival was similar between the groups (exposed vs. unexposed: 12.6 vs. 11.9 months, p = 0.174). Treatment regimens and relative dose intensities and the progression-free survival of GnP (gemcitabine in combination with nab-paclitaxel) and mFOLFIRINOX as first- and second-line chemotherapy did not differ significantly between the two groups. Only 9.0% of patients died at home in the COVID-19-unexposed group, compared to 32.0% in the COVID-19-exposed group (p <0.001). A multivariate analysis revealed that death during the COVID-19 exposed period was independently associated with home death (odds ratio: 4.536, 95% confidence interval: 2.527-8.140, p <0.001). Conclusions While the COVID-19 pandemic did not seem to influence chemotherapeutic treatment for PC patients at our institution, it had a large impact on end-of-life care. These findings may promote discussion about end-of-life care in Japan.

Predictive Factors of Febrile Neutropenia After Primary Prophylactic Pegfilgrastim With DCF Chemotherapy for Esophageal Cancer.

We investigated the predictive factors of febrile neutropenia (FN) after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) to support the appropriate management of FN. We evaluated changes in neutrophil counts and relative dose intensity (RDI) after the incidence of FN. This retrospective study involved 122 patients with esophageal cancer who were treated with DCF and pegfilgrastim at Showa University Hospital, Japan, between April 2016 and August 2021. The primary outcome was FN incidence after cycle 1 of DCF chemotherapy. The significant independent factors associated with FN incidence were selected using the multivariate analysis. Changes in neutrophil counts and RDI were compared between the FN and non-FN groups. One-hundred patients were included in the analysis. The incidence of FN in cycle 1 was 21%. In the multivariate analysis, geriatric nutritional risk index (GNRI) <92 [odds ratio (OR)=13.162, p<0.001] and combination of platelet and neutrophil-to-lymphocyte ratio (COP-NLR) score of 0 (OR=4.619, p=0.012) were independent predictors of FN. The neutrophil count on day 7-10 and RDI in the FN group were lower than those in the non-FN group (all p<0.05). GNRI <92 and COP-NLR score of 0 are important indicators to predict patients at high risk of DCF chemotherapy-induced FN. Furthermore, FN incidence after pegfilgrastim administration had a strong effect on delayed neutrophil recovery and reduced RDI.

RWD9 Real-World Relative Dose Intensity in Patients With Advanced or Metastatic Breast Cancer Treated With Cyclin-Dependent Kinase 4/6 Inhibitors in Sweden

Evaluate real-world relative dose intensity (RDI) and drug holiday RDI in patients with locally advanced or metastatic breast cancer treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) (ribociclib, palbociclib or abemaciclib).

Efficacy and Safety of Oral Ixazomib (Ixa), Intravenous (IV) Daratumumab (Dara), and IV/Oral Dexamethasone (Dex; IDd) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and 1-3 Prior Therapies: Results of the Final Analysis of a Phase 2 Study

Introduction The development of more effective therapies has improved the prognosis for pts with MM, however most will ultimately relapse. The oral proteasome inhibitor (PI) Ixa is approved with lenalidomide (len)-dex (IRd) for pts with ≥1 prior therapy, & the monoclonal antibody Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd; Palumbo NEJM 2016), Vd was limited to 8 cycles; however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. In this prospective, open-label, multicenter, phase 2 study (NCT03439293) we used a treat-to-progression approach to evaluate IDd in RRMM. Methods Ixa/Dara-naïve pts with RRMM (1-3 prior therapies) received oral Ixa (4 mg; days [d] 1, 8, 15), IV Dara (16 mg/kg; d 1, 8, 15, 22, cycles 1-2; d 1, 15, cycles 3-6; d 1, cycles 7+), & IV (required before first Dara dose only) or oral dex (20 mg; d 1, 2, 8, 9, 15, 16, 22, 23) in 28-d cycles. The primary endpoint was ≥very good partial response (VGPR) rate. Secondary endpoints included: overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. Health-related quality of life (HRQoL; exploratory endpoint) was assessed with EORTC QLQ-C30 & QLQ-MY20. We report data from the final analysis, conducted 1 year (y) after 50% of PFS events had occurred (data cut-off: 1/1/2022). Results Sixty-one pts were enrolled: median age was 69 y (≥75 y, 19.7%); 49.2/36.1/14.8% of pts had International Staging System stage I/II/III disease; 34.4% were len-refractory; 26.2% & 42.6% had high-risk [del(17p), t(4;14), t(14;16)] & expanded high-risk (high-risk &/or amp1q21) cytogenetics, respectively; 59.0/26.2/14.8% had received 1/2/3 prior lines. Pts had received a median of 16 IDd cycles; 24.6% were ongoing at data cut-off. Relative dose intensity was ≥80-<100% for Ixa/Dara/dex in 37.7/67.2/24.6% of pts. In 59 response-evaluable pts, the confirmed ≥VGPR rate was 32.2% compared with 23.7% & 30.5% at the first & second interim analyses (IA1, IA2), respectively; ORR was 66.1% (Figure). In 12 pts aged ≥75 y: ≥VGPR rate was 16.7%; ORR was 50.0%. In 21 len-refractory pts: ≥VGPR rate was 28.6%; ORR was 61.9%. In 16 pts with high-risk cytogenetics: ≥VGPR rate was 25.0%; ORR was 50.0%. In 25 pts with expanded high-risk cytogenetics: ≥VGPR rate was 28.0%; ORR was 56.0%. Minimal residual disease (MRD) was evaluated at time of complete response (CR) in 8 pts, of whom 6 were evaluable: 4/6 (66.7%) pts were MRD-negative (threshold level 10-5); 3/6 (50.0%) pts maintained MRD-negative status at 6 & 12 cycles post-CR achievement. After a median follow-up of 31.6 months (mos; 41 events), median PFS was 16.8 mos (95% confidence interval [CI]: 10.1-23.7). Median TTP was 21.1 mos (35 events; 95% CI: 10.2-27.9). With 18 deaths, 1-y OS rate was 91.4% (95% CI: 80.6-96.3). Median time to ≥VGPR & ORR was not estimable (NE; range: 1.0-40.8 mos) & 2.7 mos (range: 0.9-31.6), respectively. In 21 len-refractory pts, after a median follow-up of 35.9 mos (12 events), median PFS was 12.6 mos (95% CI: 5.6-NE). Pt-reported HRQoL was maintained during treatment with IDd. Ixa pharmacokinetics were comparable to those observed in the approved triplet (IRd) & single-agent maintenance studies. Any-grade (G) & G≥3 treatment-emergent adverse events (TEAEs) occurred in 96.7% & 54.1% of pts, respectively. Common (>25%) any-G TEAEs were diarrhea (42.6%), anemia (27.9%), & thrombocytopenia (26.2%); common (>10%) G≥3 TEAEs were thrombocytopenia (11.5%) & pneumonia (11.5%). 44.3% of pts had serious AEs, most frequently pneumonia (9.8%) & COVID-19 pneumonia (4.9%). 18.0% of pts had any-G peripheral neuropathy (PN, 1.6% G≥3). TEAEs led to dose modifications in 62.3% of pts (Ixa 39.3%, Dara 36.1%, dex 44.3%), dose reductions in 36.1%, & discontinuation of any study drug in 16.4%. There were 5 on-study deaths (all unrelated to study drug). Conclusions This final analysis of a phase 2 study in pts with RRMM showed a positive risk-benefit profile for IDd: ≥VGPR rate was 32.2% (increased from IA1 & 2), median PFS was 16.8 mos (comparable to that seen with DVd in CASTOR; Mateos CLML 2020), & HRQoL was maintained. The discontinuation rate due to TEAEs was low with no new safety signals identified & a low rate of any-G PN. Furthermore, IDd was also active in pts aged ≥75 y, len-refractory pts, & those with high-risk & expanded high-risk cytogenetics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim PET-Guided ABVD or ABVD/Escalated BEACOPP for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma (JCOG1305, INNOVATE-HL study)

Introduction Interim positron-emission tomography (PET) can predict clinical outcomes in patients with classic Hodgkin lymphoma (cHL). The objective of this single-arm confirmatory study (JCOG1305, INNOVATE-HL) is to establish interim PET-guided treatment strategy for newly diagnosed advanced-stage cHL. Methods Patients aged 16-60 years with cHL received 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as an induction chemotherapy, and then underwent an interim PET scan. Images were centrally reviewed with the use of a 5-point scale for PET findings for further response guided treatments. Patients with negative interim PET findings (defined as score 1 to 3) continued additional 4 cycles of ABVD, whereas those with positive interim PET findings (score 4 or 5) switched to 6 cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone). Involved site radiation therapy (ISRT) was set as a protocol treatment if patients with partial response had a single residual lesion after completion of chemotherapy. The primary endpoint were 2-year progression-free survival (PFS) among all eligible patients and among interim PET-positive patients (co-primary endpoints). We had the following hypotheses: 2-year PFS of eligible patients and interim-PET positive patients will exceed 75% and 35%, respectively, compared to a historical control with one-sided alpha of 0.1. Secondary endpoints included overall survival (OS), event-free survival (EFS), in which events were defined as death, progression or not achieving complete response at end of protocol treatment, and incidences of adverse events and secondary malignancy. This study was registered at jRCTs031180218. Results A total of 93 patients were enrolled from 35 institutions between January 2016 and December 2019. One patient was ineligible because of diagnostic error. Baseline characteristics of 92 eligible patients who underwent an interim PET scan were as follows: a median age of 35 years (interquartile range [IQR]: 28-48); 58% were male; most of patients (87 [95%]) had performance status of 0 or 1; Ann Arbor stage III and IV consisted of 40 (43%) and 43 (47%), respectively, the remaining 9 (10%) had stage IIB with bulky (10 cm or more) mediastinal lesion or nodal lesion involving directly to extranodal lesion; 51 (55%) and 15(16%) had B symptoms and bulky lesions, respectively. An interim PET scan showed 19 patients (21%) with positive findings; those patients received escalated BEACOPP; 18 completed 6 cycles of BEACOPP including one who underwent ISRT, the remaining one discontinued BEACOPP. On the other hand, 73 patients (79%) who had interim PET-negative findings continued ABVD; 70 completed additional 4 cycles of ABVD including two who underwent ISRT, the remaining 3 discontinued ABVD. Average relative dose intensity of induction ABVD, additional ABVD and escalated BEACOPP were 98.6% (±4.0), 96.7% (±5.7) and 82.2% (±9.3%), respectively. With a median follow-up of 41.1 months (IQR: 29.7-53.1), the 2-year PFS were 84.8% (80% confidence interval [CI]: 79.2-88.9) and 84.2% (80% CI: 69.7-92.1) among all 92 eligible patients and 19 interim PET-positive patients, respectively (Figure 1). The 2-year EFS were 76.1% and 68.4% among all eligible patients and interim-PET positive patients, respectively. Bleomycin lung toxicity (BLT) occurred in 9 patients, but no patients led to BLT-related death. Twelve and three patients underwent autologous and allogeneic hematopoietic stem cell transplantation (HSCT) as a salvage treatment, respectively, including one received allogeneic HSCT for relapse after autologous HSCT. The 2-year OS was 98.9%; two patients died due to interstitial pneumonia after autologous HSCT and brain hemorrhage without relapsing cHL among the interim PET-positive patients, whereas no patients died among interim PET-negative patients. Diffuse large B-cell lymphoma developed in one patient with interim PET-negative findings as a secondary malignancy 4.6 years after enrollment. Conclusions This INNOVATE-HL study demonstrated that interim PET-guided treatment strategy was useful for younger patients with newly diagnosed advanced-stage cHL. Of note, 6 cycles of escalated BEACOPP is a feasible and effective regimen for interim PET-positive cHL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Single Institutional Experience Using Romiplostim to Manage Treatment Related Thrombocytopenia in Pediatric Solid Tumor Patients

Background: Therapy related thrombocytopenia (TRT), particularly chemotherapy induced thrombocytopenia (CIT), is a common toxicity encountered by pediatric solid tumor patients. It is associated with both reduced relative dose intensity of chemotherapy treatment as well as increased platelet transfusion requirements. Given the utility of thrombopoietin receptor (TPO-R) agonists in adult CIT and the reassuring safety profile in pediatric immune thrombocytopenia (ITP), romiplostim has been widely used in our department for management of TRT. This study describes our single institution experience of the off-label use of romiplostim for TRT in pediatric solid tumor patients. Methods: This study retrospectively evaluated solid tumor patients (sarcomas, high-risk neuroblastoma, and CNS tumors) treated at Memorial Sloan Kettering Cancer Center between 2010-2022 who received romiplostim during their cancer therapy for TRT. TRT was defined as thrombocytopenia attributed to cancer-directed therapy that persisted despite adequate recovery time and/or resulted in treatment modifications. Baseline data (Table 1) was collected on patient demographics, tumor types, cancer therapy, and dosing and duration of romiplostim administration. The primary endpoint was impact of romiplostim on TRT measured through (1) the median platelet count throughout romiplostim treatment, (2) the time-to-platelet count recovery after initiation of romiplostim (defined by platelet count of ≥75 µ/L), (3) the median number of platelet transfusions while on romiplostim. Safety data was also collected on incidence of venous thromboembolism (VTE) development during romiplostim treatment. Results: A total of 62 patients were included with mean age 8.5 years (range: 1.0 to 30.0 years). The overall median time on romiplostim was 17 weeks (range 1-95). The median starting dose ranged from 1-5 mcg/kg, with the majority (81%) starting at 3 mcg/kg and a median maximum dose of 8mcg/kg. There was an upward trend of platelet counts over time with a sustained response measured 30 days post-romiplostim discontinuation (Figure 1). Disease subgroup was a predictor of platelet counts while on romiplostim as the patients with sarcomas had higher counts compared to the other histologic subgroups (p < 0.001). Within the neuroblastoma cohort, there appears to be a difference in platelet response depending on type of cancer-directed therapy, with chemo and immunotherapy groups exhibiting a higher response than the radionuclide group. Of the total 62 patients, 48 (77%) experienced a platelet recovery and the median measured time-to-recovery was 45 days; with the sarcoma patients experiencing the earliest time-to-recovery with a median time of 8 days (p < 0.001). In assessing incidence of adverse events, of the 62 studied patients, 2 (3%) were noted to be on anticoagulation for a documented VTE while on romiplostim. Conclusions: Given such paucity of available data in pediatrics, the purpose of this retrospective study was to provide insight into the off-label use of romiplostim in pediatric oncology patients. From the analysis of the 62 patients treated with romiplostim during their cancer treatment course, it appears that romiplostim was well tolerated and exhibited potential in providing clinical benefit. While the length of romiplostim treatment varied depending on the specifics of a patient's cancer-directed therapy, overall, the median time on romiplostim was approximately 4 to 5 months with some patients being notably treated for > 1 year. Future, prospective studies are warranted to study the efficacy of using TPO-R agonists in pediatric oncology patients for the indication of TRT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal