Impact Of Relative Dose Intensity Research Articles

106P Retrospective analysis of the impact of relative dose intensity on outcomes of colorectal cancer patients treated with 5-FU-based chemotherapy

106P Retrospective analysis of the impact of relative dose intensity on outcomes of colorectal cancer patients treated with 5-FU-based chemotherapy

Impact of Relative Dose Intensity (RDI) on Survival in Non-Metastatic Breast Cancer: Nigerian Experience

Impact of Relative Dose Intensity (RDI) on Survival in Non-Metastatic Breast Cancer: Nigerian Experience

The Prognostic Impact of Relative Dose Intensity of Vincristine in R-CHOP for Untreated Patients with Diffuse Large B-Cell Lymphoma: A Supplementary Analysis of JCOG0601

Introduction R-CHOP (rituximab, cyclophosphamide [CY], doxorubicin [DXR], vincristine [VCR], and prednisolone) is the standard of care for diffuse large B-cell lymphoma (DLBCL) and cures around 60% of patients. However, some DLBCL survivors suffer from long-lasting peripheral neuropathy (PN) caused by VCR, and the dose of VCR is usually decreased to prevent severe PN. Though, there is a lack of information regarding the effect of VCR dose reduction on DLBCL prognosis, especially based on data from prospective clinical trials. Recently, VCR dose reduction was not associated with poor prognosis in patients with aggressive B-cell lymphomas, based on the results of the RICOVER-60 trial (NCT00052936) (Bewarder et al., Haematologica 2023). In this trial, R-CHOP was administered in 14-day cycles. To evaluate the clinical impact of relative dose intensity (RDI) of VCR (RDI O) in patients with DLBCL treated with tri-weekly R-CHOP (R-CHOP21), we conducted a supplemental analysis of the JCOG0601: randomized phase II/III trial of the Japan Clinical Oncology Group (jRCTs031180139). In the JCOG0601 trial, RW-CHOP21 (CHOP21 with eight doses of weekly rituximab) and R-CHOP21 were compared for progression-free survival (PFS) (Ohmachi et al., Blood Adv. 2021). Methods Between 2007 and 2014, 422 patients were enrolled in the JCOG0601 trial. Among them, 401 patients who received at least six courses of R-CHOP21 (n=206) or RW-CHOP21 (n=195) were eligible for this supplemental analysis. Those who could not complete six courses of chemotherapy were excluded because their treatment outcomes might be impaired mainly due to their disease aggressiveness and not the dose intensity of chemotherapy. As PFS was not significantly different between the two treatment arms, these 401 patients were analyzed together (Figure A). The impact of decreased RDI O on PFS was assessed using the Cox proportional hazard model and two-sided log-rank p-values with several cutoff values of RDI O (95, 90, 85, 80, 70, 60, or 50%). The VCR dose was reduced according to the protocol. As a subgroup analysis, the impact of RDI O was evaluated in patients whose RDI of CY and DXR (RDI C+H) were retained, defined as RDI C+H were both ≥85% (high RDI C+H), or not retained, defined as either or both of RDI C+H were <85% (low RDI C+H). Clinical factors, including the cell of origin (COO), as defined by the Hans algorithm, were evaluated for their association with poor PFS. Result The baseline clinical characteristics of the 401 patients were as follows: median age, 62 years (range, 20-79), male sex (54.6%); performance status of 0 or 1 (97.5%); Ann Arbor stage Ⅰ or Ⅱ (53.4%); and International Prognostic Index (IPI) of low or low-intermediate (82.6%). The median RDI O of the 401 patients was 97% (interquartile range [IQR], 89-100). The median RDI of CY and DXR were as high (96% each). At the data cut-off date (Dec 2017), the median follow-up time was 59.4 months, and the 3-year PFS was 81.5% (95% confidence interval [CI], 77.3-85.0). Among the cutoff values investigated, 95% of RDI O (<95% [n=161], ≥95% [n=240]) showed the smallest p value (log-rank test, p = 0.0679), and the hazard ratio (HR) of low RDI O against high RDI O was 1.452 (95% CI, 0.971-2.171) (Figure B); RDI O <95% clinically means VCR dose was reduced in one or more times. A cutoff value of 95% was used for further analyses. Patients with RDI O <95% tended to have low RDI C+H. According to RDI O of <95% vs. ≥95%, there was a similar difference in the subgroup of patients with high RDI C+H as in the whole population (n=324, HR 1.508, 95% CI 0.934-2.434), but no remarkable difference in low RDI C+H (n=77, HR 0.932, 95% CI 0.432-2.009). Multivariable analysis revealed that the presence of B symptoms (HR 1.859, 95% CI 1.078-3.207) and high-intermediate or high IPI scores (HR 1.721, 95% CI 1.031-2.873) were risk factors for PFS. However, neither RDI O <95%, low RDI C+H, nor COO subtypes showed no remarkable impact on poor PFS in this patient population. Conclusion Our study demonstrated that among patients with DLBCL who completed six or more courses of R-CHOP21, VCR dose reduction was not associated with poor PFS as much as the presence of B symptoms and high IPI risk. VCR dose reduction driven by toxicity might not impair its efficacy if patients can complete R-CHOP21 therapy.

Impact of relative dose intensity on pathologic complete response in human epidermal growth factor receptor 2 positive breast cancer patients receiving neoadjuvant TCHP.

The standard of care for locally advanced, human epidermal growth factor receptor 2 positive (HER2+) breast cancer includes neoadjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). Many patients do not receive the full course of therapy due to various complications, possibly affecting the potential to achieve a pathologic complete response (pCR). The amount of therapy received is typically measured by relative dose intensity (RDI). This study aimed to evaluate pCR rates in patients receiving optimal and suboptimal RDI TCHP. This study was a retrospective chart review of patients treated between 2014 and 2021 at UK HealthCare. Patients included were 18 years of age or older with HER2+ breast cancer and received at least one cycle of neoadjuvant TCHP. The primary objective compared pCR rates in patients receiving ≥ 85% RDI or <85% RDI. Secondary objectives included pCR rates based on clinical stage, age, body mass index, or hormone receptor status; factors leading to discontinuation or delay in treatment; and impact of dose reductions and delays on pCR. A total of 101 patients were included and divided into two cohorts: 54 patients received ≥ 85% RDI and 47 patients received <85% RDI. Patients who received ≥ 85% total RDI had an approximate increase of 17% in pCR rates (59.3% vs 42.6%, p = 0.11). Additionally, 82% of patients experienced a dose delay or adjustment. Patients who received ≥ 85% RDI had increased pCR rates compared to patients receiving <85% RDI. A larger patient population is needed to formulate definitive conclusions on the impact of RDI and pCR rates.

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

THU-155 - Clinical impact of relative dose intensity over the first four weeks in cabozantinib therapy for unresectable hepatocellular carcinoma

THU-155 - Clinical impact of relative dose intensity over the first four weeks in cabozantinib therapy for unresectable hepatocellular carcinoma

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.

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.

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.

Impact of relative dose intensity of R-CCOP regimen in elderly patients with diffuse large B-cell lymphoma in China

BackgroundThe actual relative dose intensity (RDI) of the attenuated R-CCOP regimen (rituximab, cytoxan, pegylated liposomal doxorubicin [PLD], vincristine, and prednisone) has not been fully investigated in Chinese geriatric patients with diffuse large B-cell lymphoma (DLBCL). In particular, the optimum dose for PLD remains unclear. MethodsWe retrospectively collected clinical data from patients with untreated DLBCL aged 65–80 years subsequently treated with the R-CCOP. The restricted cubic spline model (RCS) was used to test the non-linear relationship between the predictors and outcomes. ResultsEighty-four patients were enrolled, with a median age of 73.5 years. More than half of the patients (54.8%) received at least 6 cycles. The median dose per cycle of cytoxan and PLD were 605.5 and 19.9 mg/m2. The 5-year progression-free survival (PFS), overall survival rate, and disease-specific survival rates were 38.7%, 44.8%, and 57.2%, respectively. The RDI of PLD (PLD-RDI, <70% vs ≥ 70%) was only significant in the univariate analysis (P = 0.002) but not in the multivariate analysis. The RCS model showed a decreasing trend of hazards with an increasing PLD dose per cycle after adjustment. No significant difference was observed between the low- and high-risk groups with PLD-RDI ≥ 70% (P = 0.548). However, patients in the high-risk group had unfavorable PFS with PLD-RDI < 70% (P = 0.006). ConclusionThe optimal dose of PLD for elderly patients with DLBCL in China remains to be determined. Evaluating the tolerance and identifying risk categories are critical for clinical decision-making in this population.

P-243 Impact of relative dose intensity of bevacizumab in first-line treatment of hepatocellular cancer

Atezolizumab-Bevacizumab (AB) is the current standard of care for treatment of unresectable hepatocellular cancer (HCC), with the recommended dosage of bevacizumab at 15mg/kg. Notable adverse events with an incidence of >20% in the AB group include hypertension and proteinuria, consistent with bevacizumab’s distinctive toxicity profile. In the real-world, many physicians choose to use a lower dose of bevacizumab upfront based on patients' comorbidities, anticipated toxicities, and cost considerations. Early phase II data comparing 5mg/kg versus 10mg/kg of bevacizumab in advanced HCC suggested no difference in outcomes, though they were not powered to examine this. In other tumour types like colon cancer, the standard dose of bevacizumab is lower, though there is some data describing higher dose intensity of bevacizumab and improved survival on progression. A relative dose intensity (RDI) of ≥70% is correlated with better overall survival (OS) and radiological responses for other first-line therapies for HCC like Lenvatinib. We sought to examine the dose effect of bevacizumab in the use of AB for HCC treatment. We retrospectively analysed data on patients treated at a single-centre in Singapore who received at least one dose of AB for unresectable HCC between September 2020 and December 2021. RDI over the 1st two doses was calculated as the cumulative dose for those two cycles divided by the weight-based standard dose of bevacizumab. We evaluated the association of RDI ≥70% compared to RDI < 70%, with OS, progression free survival (PFS), and response rate (by RECIST v1.1). 57 patients were included, with a mean age of 65 years. All were ECOG 0 and majority were male (96.49%), Chinese (85.69%), had underlying viral hepatitis (56.14%) and were Child’s-Pugh A (98%) on treatment initiation. 65.91% had BCLC C disease, while the rest had BCLC B disease. Majority used AB as 1st line of systemic therapy (82.46%), and 42.11% achieved a relative dose intensity ≥70%. Patients who had RDI ≥70% were not significantly different from those with RDI < 70% in terms of baseline characteristics such as age, gender, race, cirrhosis etiology, BCLC status, or line of usage of AB (1st or later). Response rates (25.0% vs 18.2%, p = 0.742) and disease control rates (43.8% vs 54.6%, p = 0.435) did not differ between those with RDI ≥70% or < 70%. Median OS was 10.99 months (95% CI, 5.83-NR) in the RDI ≥70% group and did not differ significantly from 10.76 months (95% CI, 8.45-NR) in the RDI < 70% group (HR 0.94; 95% CI, 0.404-2.215). Median PFS was likewise similar in both groups, at 4.04 months (95% CI, 1.01-7.76) in RDI ≥70% and 3.09 months (95% CI, 1.55-NR) in RDI < 70% (HR 0.83; 95% CI, 0.45-1.70). Both OS and PFS remained not significantly different on adjustment for age, gender, BCLC status, viral/non-viral etiologies, and line of usage of AB. Frequency of common adverse events were similar between both groups. We demonstrated that a lower dose of bevacizumab at < 70% RDI achieved similar radiological and survival outcomes as ≥70% when given in combination with atezolizumab for advanced HCC. Use of reduced dose bevacizumab can be considered to reduce cost and toxicity without significantly affecting treatment outcomes. This should be explored further in a prospective setting.

Prognostic Impact of Relative Dose Intensity of Adjuvant Chemotherapy With S-1 on Pancreatic Ductal Adenocarcinoma.

Although adjuvant chemotherapy (AC) with S-1 is currently the standard treatment for pancreatic ductal adenocarcinoma (PDAC) in Japan, the associations between its relative dose intensity (RDI) and survival outcomes remain unclear. We reviewed 310 patients with PDAC who had undergone pancreatectomy from January 2014 to June 2020 at three institutions. Of these, patients who had received adjuvant S-1 monotherapy were analyzed. Patients who had died or developed recurrences within 6 months, or received neoadjuvant chemotherapy, were excluded from the analyses. Possible predictors of overall survival (OS), including RDI, were analyzed using Cox regression. The cutoff value for RDI was determined by receiver operating characteristic analysis. Ninety-four patients with a median age of 69 years (range=39-84 years) were analyzed. In the high-RDI group (RDI≥72.3%, n=74), the OS rates were 98.5% and 80.8% at 1 and 3 years, respectively, whereas in the low-RDI group (RDI <72.3%, n=20) they were 88.9% and 51.6%, respectively (p=0.001). By multivariate analysis, lymph node metastasis [hazard ratio (HR)=3.06; p=0.020], low RDI (HR=2.95; p=0.020), and time interval from surgery to initiation of AC > 51 days (HR=2.50; p=0.046) were independently associated with inferior OS. The combination of the latter two factors clearly stratified both OS and recurrence-free survival (p<0.001 and p=0.017, respectively). Early initiation and maintenance of RDI of S-1 monotherapy after pancreatectomy may improve the OS of PDAC patients.

Impact of Relative Dose Intensity of FOLFOX Adjuvant Chemotherapy on Risk of Death Among Stage III Colon Cancer Patients

BackgroundThe National Comprehensive Cancer Network (NCCN) guidelines have recommended tailored chemotherapy for stage III high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) colon cancer since 2018. Studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on stage III colon cancer survival, however, none has performed a stratified analysis by risk profiles. This study aims to identify the FOLFOX optimal RDI for high-risk and low-risk stage III colon cancer patients. MethodsData on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by 8 population-based cancer registries. Multivariable Cox model and Fine-Gray competing risks model were employed to explore Optimal RDI defined as the lowest RDI administered without significant differences in either overall or cause-specific death. ResultsAmong the 168 high-risk patients, the optimal RDI cut-off was 70% (HR = 1.59 with 95% CI: 0.69-3.66 in overall mortality; HR = 1.24 with 95% CI: 0.42-3.64 in cause-specific mortality when RDI < 70% vs. RDI ≥ 70%). Among the 239 low-risk patients, none of the evaluated cut-offs were associated with significant differences in risk of death between comparison groups. The lowest assessed RDI was 45%, HR = 0.80; 95% CI: 0.24 to 2.73 for overall mortality and HR = 0.53; 95% CI: 0.06 to 4.95 for cause-specific mortality, when RDI <45% versus RDI ≥45%. ConclusionsThere is no significant harm on the risk of death when reducing RDI by <30% for high-risk patients. For the low-risk patients, we found that RDI as low as 45% did not significantly affect the risk of death.

Prognostic impact of six versus eight cycles of standard regimen in patients with diffuse large B-cell lymphoma: propensity score-matching analysis

BackgroundR-CHOP-21 has been the standard treatment for diffuse large B-cell lymphoma (DLBCL), but there is a paucity of evidence focusing on the number of cycles of regimens.Patients and methodsWe conducted a retrospective study to compare the effectiveness of six cycles of standard regimens versus eight cycles for overall survival (OS) in DLBCL patients using propensity score matching, in consideration of relative dose intensity (RDI).ResultsA total of 685 patients with newly diagnosed DLBCL were identified in three institutions from 2007 to 2017. Patients treated using six cycles of standard regimens were matched by propensity scores with those treated using eight cycles. A 1 : 1 propensity score matching yielded 138 patient pairs. Eight cycles did not significantly improve OS in the conventional Cox proportional hazards model (hazard ratio 0.849, 95% confidence interval 0.453-1.588, P = 0.608). Restricted cubic spline Cox models for OS confirmed that the effect of the number of cycles was not modified by total average RDI, the International Prognostic Index, and age. Occurrence of adverse events did not differ between six and eight cycles.ConclusionEven considering the impact of RDI, six cycles of the initial standard regimen for DLBCL is not inferior to eight cycles.

Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis.

BackgroundChemotherapy‐induced toxicities lead to therapy dose reduction or delay, affecting patient outcomes. This systematic review and meta‐analysis evaluated the impact of relative dose intensity (RDI) on survival in adult patients with solid tumor cancer on nonadjuvant‐based chemotherapy regimens.MethodsPubMed, Embase, and Web of Science databases were searched for peer‐reviewed English journal articles or congress abstracts evaluating association between RDI and survival; observational studies, case series of ≥20 patients, and clinical trials published between 2013 and 2020 were eligible. Meta‐analyses were conducted to quantify the association between RDI levels and overall survival (OS) among studies reporting a hazard ratio (HR) for OS by similar tumor types, regimens, and RDI. Forest plots represented summary HR and 95% confidence interval (CI); Cochran's Q and I2 tests evaluated study heterogeneity.ResultsOverall, 919 articles were reviewed and 22 included; seven were eligible for meta‐analysis. Significantly shorter OS at RDI <80% versus ≥80% and <85% versus ≥85% was observed upon meta‐analysis of four carboplatin‐based studies for breast, non‐small cell lung, or ovarian cancer (HR 1.17; 95% CI: 1.07–1.27) and three FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based studies for colorectal or pancreatic cancer (HR 1.39; 95% CI: 1.03–1.89). Grade 3 or higher hematologic toxicities were higher for carboplatin‐based regimens (thrombocytopenia: 14%–22%; anemia: 15%–19%; neutropenia: 24%–58%) than FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based regimens (thrombocytopenia: 1%–4%; anemia: 5%–19%; neutropenia: 19%–47%).ConclusionThe results suggested longer OS with RDI ≥80% or ≥85% for both regimens, indicating that management of toxicities across treatment modalities may contribute to maintenance of higher RDI and benefit survival for patients with advanced solid tumors.Implications for PracticeChemotherapy‐induced toxicities lead to dose reduction and/or treatment delay, thus affecting patient outcomes. Results of this systematic review and meta‐analysis, evaluating the impact of relative dose intensity (RDI) on survival of patients with solid tumors on nonadjuvant‐based chemotherapy regimens, demonstrate a longer overall survival with RDI levels of at least 80% for patients with solid tumors on carboplatin‐based and FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based chemotherapy regimens, suggesting a protective effect of maintaining RDI ≥80% or ≥ ‐85%. Although grade 3 or higher hematologic toxicities occurred more in carboplatin‐based studies, managing toxicities across treatment regimens may contribute to maintenance of higher RDI and ultimately benefit overall survival.

Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study

BackgroundOxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients.MethodsThe study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed.ResultsThe median follow-up was 51.8 months (range 8.2–115.1). Early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt < 60% of RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18–3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96–2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25–4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55–4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29–0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06–3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9–37.6; p < 0.001).ConclusionsRDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

Prognostic Impact of Six Versus Eight Cycles of Standard Regimen in Patients With Diffuse Large B-Cell Lymphoma

Background: R-CHOP-21 has been the standard treatment for diffuse large B-cell lymphoma (DLBCL), but no randomized trials have focused on the number of cycles of regimens. This study was designed to assess the effectiveness of six cycles of standard regimens for DLBCL compared with eight cycles in terms of prognostic impact, considering confounding by relative dose intensity (RDI). Methods: A total of 685 patients newly diagnosed with DLBCL were identified within the database of three participating institutions from 2007 to 2017. Patients treated using six cycles of standard regimens were matched by propensity scores with those treated using eight cycles. Overall survival (OS) was compared using Cox hazard modeling with restricted cubic spline (RCS). Findings: After matching, 138 patients treated using six cycles were compared with 138 patients treated using eight cycles. Eight cycles did not significantly improve OS in the Cox hazard proportional model (P = 0·608, 95% confidence interval 0·453–1·588, hazard ratio 0·849). RCS-Cox models confirmed that the number of cycles interacted with neither effect of RDI on OS, nor effect of age on OS. Eight cycles of regimens had little impact on OS compared with six cycles in any category divided by International Prognostic Index. Sensitivity analyses strengthened the robustness of no evidence of any difference in outcome for six cycles compared with eight cycles. Interpretation: Even considering the impact of RDI, six cycles of the standard regimen for DLBCL is not inferior to eight cycles. Funding Statement: None. Declaration of Interests: TY has received research funds and honoraria from Stargen, Boehringer Ingelheim, Mundipharma, Solasia, Pfizer, and Chugai Pharmaceutical. All other authors declare no competing interests. Ethics Approval Statement: This study was conducted in accordance with the principles of the Declaration of Helsinki, and all protocols were approved by the appropriate institutional review boards. The need to obtain written, informed consent was waived, since this study used retrospective data obtained only from hospital medical records.

Abstract P5-14-08: Predictors of relative dose intensity and early dose reduction in patients with metastatic breast cancer treated with palbociclib and endocrine therapy

Abstract Background: The combination of endocrine therapy with the cyclin-dependent kinases 4/6 inhibitor palbociclib was proven to be effective for the treatment of hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC). Although generally well tolerated, treatment delays and dose reductions are frequently observed with palbociclib, mainly due to severe neutropenia. Predictors of palbociclib-related toxicities are still unknown, as well as the clinical relevance of its relative dose intensity (RDI). Henceforth, this study aimed to identify baseline clinicopathological features associated with a RDI &amp;lt;75% and early dose reduction (within the first 3 months of treatment). Secondarily, we explored the impact of RDI &amp;lt;75% and early dose reduction on progression-free survival. Methods: We reviewed data of 150 consecutive patients with HR-positive/HER2-negative MBC patients treated with palbociclib at two Italian cancer centers from 2017 to 2019. Eligible patients must have received at least 3 cycles of treatment. Those who experienced early suspension due to unacceptable toxicities were still eligible. RDI was calculated as the ratio of actual dose intensity (cumulative administered dose/treatment duration) and planned dose intensity (cumulative planned dose/planned treatment duration). The association of both RDI &amp;lt;75% and early dose reduction with baseline clinicopathological features was assessed using multivariate logistic regression. The following variables were investigated as predictors of dose reduction: de novo vs. recurrent MBC, prior chemotherapy, treatment line, associated endocrine therapy, performance status (PS), weight, renal clearance, hemoglobin level, absolute white blood cell (WBC) count, absolute neutrophils count and absolute platelet count. A ROC analysis was performed to identify the best cut-off for baseline weight in predicting a RDI &amp;lt;75%, while continuous laboratory variables were dichotomized according to clinically relevant cut-offs. Results: Overall, 142 patients were deemed eligible. Of these patients, 98 (69.0%) were treated with palbociclib plus fulvestrant, 44 (31.0%) with palbociclib plus aromatase inhibitors, and 73 (51.4%) in the first-line setting. The median number of administered palbociclib cycles was 8 (range: 1-24) and 61 patients (43.0%) required at least a first-level dose reduction (29 within 3 months). Furthermore, the median time to first dose reduction was 3.22 months, with neutropenia being responsible for 85.24% of first-level dose reductions. In the whole cohort, median RDI was 90.5% (95.1% for patients without dose reduction and 80% for those who had received a dose reduction). Notably, 28 patients (19.7%) experienced a RDI &amp;lt;75%. Through multivariate logistic regression, baseline weight ≤66 kg (OR 3.01, 95% CI: 1.08-8.35, p=0.03) and WBC ≤4.5 × 109/L (OR 3.15, 95% CI: 1.08-9.12, p=0.03) were independently associated with a RDI &amp;lt;75%. Moreover, baseline weight ≤66 kg was also significantly correlated with early dose reduction (OR 2.77, 95% CI: 1.09-7.01, p=0.03). After a median follow-up of 11.76 months, median PFS was 13.99 months. When exploring potential prognostic factors, neither a RDI &amp;lt;75% (HR 1.01, 95% CI: 0.52-1.95, p=0.97) nor a dose reduction within the first 3 months (HR 1.39, 95% CI: 0.67-2.91, p=0.31) did significantly impact PFS. Conclusions: In our analysis, baseline weight and WBC were statistically associated with a RDI &amp;lt;75% in patients with MBC treated with palbociclib. Furthermore, baseline weight was also able to predict an early dose reduction in the study population. Lastly, early dose reduction and RDI &amp;lt;75% did not impact PFS. Although the small sample size and the limited follow-up, our results warrant further investigation in specifically designed trials. Citation Format: Giacomo Pelizzari, Elisa Bertoli, Marco Giavarra, Carla Corvaja, Lorenzo Gerratana, Debora Basile, Michele Bartoletti, Camilla Lisanti, Lucia Bortot, Silvia Buriolla, Mattia Garutti, Debora Avoledo, Marta Bonotto, Lucia Da Ros, Silvia Bolzonello, Mauro Mansutti, Paola Di Nardo, Gianpiero Fasola, Simon Spazzapan, Alessandro M Minisini, Fabio Puglisi. Predictors of relative dose intensity and early dose reduction in patients with metastatic breast cancer treated with palbociclib and endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-08.

Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma.

Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.