Chemotherapy Dose Reductions Research Articles

A contrast-enhanced CT-based whole-spleen radiomics signature for early prediction of oxaliplatin-related thrombocytopenia in patients with gastrointestinal malignancies: a retrospective study.

Thrombocytopenia is a common adverse event of oxaliplatin-based chemotherapy. Grade 2 or higher oxaliplatin-related thrombocytopenia may result in dose reduction, discontinuation or delay initiation of chemotherapy and may adversely affect the therapeutic efficacy and even overall survival of patients. Early recognition of patients at risk of developing grade 2 or higher thrombocytopenia is critical. However, to date there is no well-established method to early identify patients at high risk. The aims of this study were to develop and validate a contrast-enhanced CT-based whole-spleen radiomics signature for early prediction of grade 2 or higher thrombocytopenia in patients with gastrointestinal malignancies treated with oxaliplatin-based chemotherapy and to explore the incremental value of combining the radiomics signature and conventional clinical factors for risk prediction. A total of 119 patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy from March 2017 to December 2020 were retrospectively included and randomly divided into a training cohort (n=85) and a validation cohort (n=34). Grade 2 or higher thrombocytopenia occurred in 26.1% of patients (22 and nine patients in the training and validation cohort, respectively) with a median time interval of 101 days from the start of chemotherapy. The whole-spleen radiomics features were extracted on the portal venous phase of the first follow-up CT images. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to select radiomics features and to build the radiomics signature for the prediction of grade 2 or higher thrombocytopenia. A clinical model that included clinical factors only and a clinical-radiomics model that incorporated clinical factors and radiomics signature were constructed. The performances of both models were evaluated and compared in the training, validation and the whole cohorts. The radiomics signature yielded favorable performance in predicting grade 2 or higher thrombocytopenia, with the area under the curve (AUC), sensitivity and specificity being 0.865, 81.8% and 84.1% in the training cohort and 0.747, 77.8% and 80.0% in the validation cohort. The AUCs of the clinical-radiomics model in the training and validation cohorts reached 0.913 (95% CI [0.720-0.935]) and 0.867 (95% CI [0.727-1.000]), greater than the AUCs of the clinical model. Integrated discrimination improvement (IDI) index showed that incorporating radiomic signature into conventional clinical factors significantly improved the predictive accuracy by 17.0% (95% CI [4.9%-29.1%], p = 0.006) in the whole cohort. Contrast-enhanced CT-based whole-spleen radiomics signature might serve as an early predictor for grade 2 or higher thrombocytopenia during oxaliplatin-based chemotherapy in patients with gastrointestinal malignancies and provide incremental value over conventional clinical factors.

Relationship of Sarcopenia to Tolerance of Chemotherapy During Definitive Treatment of Primary Anal Squamous Cell Carcinoma

Primary therapy for anal squamous cell carcinoma consists of definitive radiation with concurrent chemotherapy, most commonly 5-fluorouracil and mitomycin-C. This regimen is associated with significant cutaneous, hematologic, and gastrointestinal toxicity. Sarcopenia, or low skeletal muscle mass, has been described as an adverse prognostic factor and predictor of poor tolerance to therapy across a range of malignancies, including breast, gynecologic and head and neck cancers. Here, we sought to determine if the presence of sarcopenia at the initiation of therapy is associated with increased rates of toxicity and poorer tolerance of definitive treatment for primary anal squamous cell carcinoma. This was a review of patients treated with curative intent for anal squamous cell carcinoma at a single academic medical center between 2007 and 2017, median follow up was 38 months. Analysis was limited to patients receiving definitive radiation with concurrent chemotherapy. Sarcopenia was objectively defined, using previously validated methods, as a skeletal muscle index (SMI) <41 cm2/m2 for female patients regardless of body mass index (BMI); for male patients sarcopenia was defined as SMI<43cm2/m2 for BMI<25 and <53 cm2/m2 for BMI >25. SMI calculations were performed using the average skeletal muscle cross sectional areas of two sequential axial CT slices at the L3 vertebral level obtained from radiation planning computed tomography scans. The image analysis was performed by a single trained observer using Sliceomatic software with a Hounsfield unit threshold of -29 to 150 to define skeletal muscle. Sarcopenia as a predictor for treatment toxicity was analyzed using Chi-Square testing. Overall survival and progression free survival were compared with 2-sample t tests. Sixty-one patients were included in the analysis with 49% meeting criteria for sarcopenia. Stage did not differ although sarcopenic patients were significantly more elderly than those without sarcopenia (mean 72 vs 58 years, p<0.001). Patients with sarcopenia were significantly more likely to have chemotherapy breaks, chemotherapy dose reductions, and incomplete chemotherapy courses compared to non-sarcopenic patients (33.3% vs 9.7%; p = 0.02). Sarcopenia was not predictive of more radiation treatment breaks, hematologic toxicity, progression free survival or overall survival. Sarcopenia is predictive of reduced tolerance to chemotherapy among patients receiving definitive combined modality therapy for primary anal carcinoma. We found no association between sarcopenia and tolerance of radiation therapy or survival outcomes.

Retrospective analysis of the impact of dose delay and reduction on outcomes of colorectal cancer patients treated with FOLFIRI‑based treatment.

To determine the relationship between chemotherapy dose delay/reduction with progression-free survival (PFS) and overall survival (OS) in colorectal cancer patients treated with FOLFIRI based first-line chemotherapy in real-world retrospectively study. We identified 144 eligible patients with advanced CRC who received FOLFIRI as first-line based treatment. The study protocol was submitted to the institutional review board and was exempted. Dose delay was defined as an average delay of more than 3 days (>3 days vs. ≤3 days) from the intended date. Dose reduction (actual dose/standard dose * 100%) ≤85% was considered as chemotherapy reduction in the chemotherapy dose relative to the standard (mg/m2) regimen for all cycles. Relative dose intensity (RDI) ≤80% was described as chemotherapy reduction. OS and PFS were measured using Kaplan-Meier and Cox proportional hazard models. There were 114 patients with chemotherapy dose delay (dose delay >3 days). PFS of patients without dose delay had better survival than patients with dose delay (p = 0.002). There were 28.47% patients treated with dose reduction of 5-Fu. PFS and OS were better in patients without 5-Fu dose reduction than in patients with 5-Fu dose reduction with p values of 0.024 and <0.001, respectively. Patients with high 5-FU RDI had better PFS than patients with low 5-FU RDI (p < 0.001). While, there was no statistical difference in OS between the two groups. Then we stratified the analysis by age. In <65 years cohort, both PFS and OS were better in patients with high 5-Fu RDI than in those with low 5-Fu RDI (p < 0.001, p = 0.005, respectively). But, in ≥65 years cohort, OS were better in patients with low 5-Fu RDI than in those with high 5-Fu RDI (p = 0.025). Moreover, both dose reduction and RDI of irinotecan had no statistically significant difference in both PFS and OS. In the advanced colorectal cancer patients who received FOLFIRI based treatment as first-line regimen, chemotherapy dose delay and reduction dose of 5-Fu were associated with worse survival, especially among patients younger than 65 years.

Evaluation of factors predicting the benefit from systemic oncological treatment for severely ill hospitalized patients: a retrospective study

BackgroundPatients with cancer in the disease’s end-stage with poor performance represent a challenging clinical scenario, as they have high chance of a fatal outcome due to clinical conditions, oncological emergencies, and/or metastatic disease. This study examines the factors predicting the potential benefit of “urgent” chemotherapy during hospitalization in this setting, thus addressing a research gap.MethodsThis retrospective observational study was conducted in the largest cancer center in the outskirts of São Paulo. It identified factors predicting the benefit from antineoplastic treatment in severe in-hospital patients admitted during 2019–2020, considering post-chemotherapy survival time as the main dependent variable. Data were retrieved from medical records. All patients aged ≥ 18 years, with an ECOG-PS score ≥ 2, and undergoing non-elective systemic cancer treatment were included.ResultsThis study evaluated 204 records, of which 89 were included in the final analysis. A statistically significant association with the worse outcome (death within 30 days of chemotherapy) was found with higher ECOG performance status; chemotherapy dose reduction; lower values of serum albumin, hemoglobin, and creatinine clearance; and higher values of leukocytes, neutrophils, direct bilirubin, urea, and C-reactive protein. In the multivariate analysis, only albumin remained statistically associated with the outcome (hazard ratio = 0.35; confidence interval: 0.14, 0.90; p = 0.034).ConclusionsSerum albumin and other clinical and laboratory variables might be associated with early post-treatment deaths in patients with cancer. The study data might help guide the decision to administer systemic treatment in this scenario and manage critically ill patients. This study adds to our knowledge of the factors predicting the objective benefits from “heroic” or “urgent” chemotherapy for hospitalized and severely ill patients with cancer.

Efficacy and safety of reduced-dose chemotherapy plus immunotherapy in patients with lung squamous cell carcinoma: A real-world observational study.

Recently, chemotherapy plus immunotherapy has achieved remarkable efficacy in lung squamous cell carcinoma (LUSC). However, some patients, especially frail people, cannot tolerate full-dose chemotherapy in the real world. To reduce toxicity, appropriate dose reduction in chemotherapy is necessary. Therefore, this study aimed to demonstrate the efficacy and safety of reduced-dose chemotherapy plus immunotherapy in LUSC patients in the real world. A real-world observational study was conducted concerning patients who received chemotherapy plus immunotherapy in our situation. The primary endpoints were objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Between December 2018 and January 2022, 110 patients were enrolled, of whom 54 patients were chemotherapy reduced-dose group and 56 patients were chemotherapy standard-dose group. The ORR in the reduced-dose group is similar to standard-dose group (85.19% vs. 71.43%, p = 0.082). Similar DCR were observed (100% vs. 94.64%, p = 0.086). Median PFS was 12 months in the reduced-dose group and standard-dose group, respectively. Median OS was 15 months and 16 months in the reduced-dose group and standard-dose group, respectively. We reported a lower incidence of grade 3-4 toxicity in the reduced-dose group compared with standard-dose group (27.78% vs. 42.86%, p = 0.100). The major toxic reactions were better alleviated in the reduced-dose group than in the standard-dose group, especially in the thrombocytopenia (p = 0.044), peripheral nerve damage (p = 0.001), gastrointestinal reactions (p < 0.0001), and fatigue (p = 0.001). The modified regimen with attenuated doses of chemotherapy in combination with immunotherapy was effective and well tolerated in patients with LUSC. The efficacy of this modified regimen is similar to that of the full-dose regimen.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5days, P = 0.042) than in the MF group. The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Ataxia-telangiectasia and combined hepatocellular-cholangiocarcinoma: A case report

ABSTRACT Ataxia-telangiectasia (A-T) is a rare autosomal recessive disease characterized by ataxia, cutaneous and ocular telangiectasia, impaired immunity with susceptibility to sino-pulmonary infections, radiation sensitivity, and cancers particularly of hemato-lymphoid origin. Liver function tests abnormalities and elevated alfa feto-protein have been reported in A-T; however, there is no reported case of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in literature. These tumors should be treated in similar fashion as in general population; however, reduction of chemotherapy dose might be helpful in decreasing chemo-toxicity.

Integrated Analysis of the RASH Study with the Use of the "Burden of Therapy" (BOTh®TM) Methodology-A Novel Tool for Assessing Adverse Events in Metastatic Pancreatic Cancer.

This analysis of the RASH trial (NCT01729481) aimed at gaining a better understanding of the "Burden of Therapy" (BOTh®TM) in pancreatic ductal adenocarcinoma (PDAC). In the RASH study, 150 patients with newly diagnosed metastatic PDAC were treated with gemcitabine plus erlotinib (gem/erlotinib) for four weeks. Patients who developed a skin rash during this four-week run-in phase continued with the gem/erlotinib treatment, while rash-negative patients were switched to FOLFIRINOX. The study demonstrated a 1-year survival rate of rash-positive patients who received gem/erlotinib as first-line treatment that was comparable to previous reports of patients receiving FOLFIRINOX. To understand whether these comparable survival rates may be accompanied by better tolerability of the gem/erlotinib treatment compared to FOLFIRINOX, the BOTh®TM methodology was used to continuously quantify and depict the burden of therapy generated by treatment emergent events (TEAEs). Sensory neuropathy was significantly more common in the FOLFIRINOX arm, and prevalence as well as severity increased over time. In both arms, the BOTh®TM associated with diarrhea decreased over the course of treatment. The BOTh®TM caused by neutropenia was comparable in both arms but decreased in the FOLFIRINOX arm over time, possibly due to chemotherapy dose reductions. Overall, gem/erlotinib was associated with a slightly higher overall BOTh®TM, but the difference was not statistically significant (p = 0.6735). In summary, the BOTh®TM analysis facilitates the evaluation of TEAEs. In patients fit for intense chemotherapeutic regimens, FOLFIRINOX is associated with a lower BOTh®TM than gem/erlotinib.

Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients &gt; 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .

A pragmatic, single-arm clinical trial of a dose-adjustment algorithm for preventing cytopenia-related delays during FOLFOX chemotherapy.

6608 Background: Unplanned delays are common during FOLFOX chemotherapy, and cytopenias (neutropenia and/or thrombocytopenia) are the most common cause of delays. We evaluated a novel, provider-driven FOLFOX dose-adjustment algorithm designed to reduce unplanned delays while maintaining chemotherapy dose intensity. Methods: We conducted a pragmatic, single-arm clinical trial to evaluate the FOLFOX dose adjustment algorithm (NCT04526886). The algorithm prescribed graded chemotherapy dose reductions without delay on day 1 of cycles 2-6 for patients with an absolute neutrophil count (ANC) of 750 to 1499/microL and/or a platelet count of 50 to 99 K/microL. The algorithm prescribed a delay when ANC was less than 750 or platelet count was less than 50 on day 1 of cycles 2-6. Chemotherapy dose adjustments and delays for reasons other than cytopenias were at the discretion of the treating provider. Patients receiving initial treatment with FOLFOX chemotherapy (with or without concomitant monoclonal antibodies) were eligible. Subjects received standard chemotherapy doses in cycle 1 (bolus 5-FU 400 mg/m2, oxaliplatin 85 mg/m2, and infusional 5-FU 2400 mg/m2/46 hours). Use of granulocyte colony stimulating factor (GCSF) was not permitted, except for patients who had already experienced an unplanned delay. The primary outcome was any unplanned delay prior to completion of day 1 of cycle 6 of chemotherapy (with an interval of &gt;18 days between cycles.) We tested whether the incidence of any unplanned delay was less than the historical rate of 43%, using a one-sample test of proportions. Chemotherapy relative dose intensity (RDI) over cycles 1-6 was a key secondary outcome. Results: 48 of 54 enrolled subjects were evaluable. The median age was 66, and 50% were female. The most common primary cancer sites were colorectal (n = 31) and gastroesophageal (n = 12). Metastatic cancer was present in 67%, and 35% received a concurrent monoclonal antibody. Sixteen of 48 subjects had any unplanned delay before completing cycle 6 (33%, 95% CI 0.22-0.47, p = 0.08 for comparison with historical proportion of 43%), and 7 subjects had any cytopenia-related delay (15%, CI 0.07-0.27). Twenty-one subjects (44%) had one or more algorithm-driven chemotherapy dose reductions without a delay, and 8 cycles were delivered without delay with an ANC of 750-999 (without GCSF). The mean (median) chemotherapy RDIs were: bolus 5-FU, 65% (67%); oxaliplatin, 85% (90%); and infusional 5-FU, 92% (97%). Conclusions: The 33% observed incidence of any unplanned chemotherapy delay was nominally but not significantly lower than the historical rate of 43%. The incidence of any cytopenia-related delay was 15%, lower than the historical rate of &gt;30%. Further refinement and evaluation of the FOLFOX dose adjustment algorithm may help to reduce unplanned delays and their attendant disruptions and costs for patients and providers. Clinical trial information: NCT04526886 .

A pilot study of intraneural facilitation versus standard physical therapy for prevention of chemotherapy-induced peripheral neuropathy.

12068 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect necessitating chemotherapy (CT) dose adjustments or early termination. Intraneural Facilitation (INF) is a novel form of manual physical therapy (PT) developed to mitigate CIPN-related symptoms and improve patients’ functional outcome. We conducted a randomized pilot study evaluating the efficacy of INF vs. standard PT in the prevention of CIPN (NCT 03272919). Methods: Eligible participants were patients with newly diagnosed breast cancer (stages I-III) and gynecologic cancer without preexisting peripheral neuropathy planning to receive platinum-based and/or taxane-based CT. Participants were randomly assigned to either INF or PT arm and received two 45-minute treatments twice a week for six weeks during their CT course. Outcomes reported here are a) assessment of pain between the 2 arms using the Pain Quality Assessment Scale (PQAS), and b) measurement of vascular patterns using ultrasound (US), evaluating pulsatility index, volume flow and peak systolic velocity between the 2 arms. Participants were evaluated at baseline, week 3 (W3), week 6 (W6), and month 3 (M3). PQAS scores ranged from 0 to 10 with subscale evaluations of paroxysmal, surface, and deep pain. Pain scores on a scale from 0 to 10 were grouped into none (0), mild (1-3), moderate (4-6) and severe (7-10). The use of neuropathy medications, CT dose reductions, premature CT discontinuation and participant satisfaction surveys between the two groups were previously reported at SABCS 2022. Results: Of 104 screened participants, 44 met the eligibility criteria, with 38 eligible for analysis (n=20 INF arm and n=18 PT arm). Participants reporting moderate or severe pain in either arm were combined (Table). Pain symptoms peaked at W6 coinciding with cumulative CT effects. At M3, none in the INF arm reported moderate or severe paroxysmal pain compared to two participants in the PT arm. One participant in each arm reported moderate or severe surface or deep pain at M3. The US results showed physiologic impact in both arms at W3 and W6, suggesting their role in preserving neural tissue blood flow and reducing vascular damage. Conclusions: Our study shows fewer number of participants on both intervention arms reporting pain, with numerically lower scores on PQAS in INF arm compared to PT arm, especially during ongoing CT. The US results suggest that INF has a unique pathophysiological impact on the microvasculature compared to standard PT; further studies are needed to validate these findings and potentially address their clinical significance as a combined modality. Clinical trial information: NCT03272919 . [Table: see text]

Phase II trial of rifaximin in patients with early-stage HER2 positive breast cancer with gastrointestinal toxicities related to pertuzumab-based therapy.

e24161 Background: Pertuzumab-induced gastrointestinal toxicities (PIGT), particularly diarrhea, is the most common adverse event reported in over 70% of patients receiving pertuzumab in combination with chemotherapy. PIGT can result in dose reduction, treatment delay, and discontinuation of chemotherapy. Rifaximin is a minimally absorbed oral antibiotic approved for gastrointestinal tract infections and bacterial overgrowth. Our aim was to evaluate the efficacy of rifaximin in reducing PIGT. Methods: Patients with stage I-III HER2-positive (HER2+) breast cancer who received pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCHP) were enrolled. PIGT included diarrhea, abdominal distention, abdominal pain, dyspepsia, stomach pain, and typhlitis. Patients with any PIGT ≥ grade 2 after the first cycle of TCHP received rifaximin 550 mg orally twice daily on days 1-5 in all subsequent cycles of chemotherapy. Patients with PIGT grade &lt; 2 were observed without rifaximin. Simon's Two-Stage design was used. Results: Between 2018-2022, a total of 21 patients were enrolled. One patient was excluded due to significant anemia not meeting the eligibility criteria to proceed with rifaximin after the first cycle of TCHP. Of 20 patients, the median age was 52.5 (39-69) years. 18/20 (90.0%) patients had PIGT ≥ grade 2 after 1 cycle of TCHP with PIGT grade 2 in 15 (83.3%) and grade 3 in 3 (16.7%). PIGT ≥ grade 2 included diarrhea in 14 (70.0%) with grade 2 in 12 (60.0%) and grade 3 in 2 (10.0%), abdominal pain in 9 (45.0%) with grade 2 in 8 (40.0%) and grade 3 in 1 (5.0%), abdominal distension in 3 (15.0%), dyspepsia in 5 (25.0%), and stomach pain in 4 (20.0%) patients. Among 18 patients who received rifaximin, 15 (83.3%; 95% CI 0.586-0.964) had at least 1 cycle with a maximum PIGT grade &lt; 2. This result surpassed the threshold of the Two-Stage analysis. Reduction of individual PIGT symptoms for patients who experienced &gt; grade 2 at baseline after the first cycle of rifaximin was reported in 2/3 (66.7%) for abdominal distention, 8/9 (88.9%) for abdominal pain, 6/14 (42.9%) for diarrhea, 3/4 (75.0%) for stomach pain, and 4/5 (80.0%) for dyspepsia. No patients experienced &gt; grade 2 typhilitis at baseline and during treatment. Treatment is well tolerated, with no significant grade 3+ adverse event related to rifaximin observed. Among patients who received rifaximin, there was no treatment delay or discontinuation of pertuzumab related to PIGT. Conclusions: PIGT is a debilitating side effect observed in most patients receiving pertuzumab. A short course of rifaximin after each cycle of treatment is a well-tolerated treatment option that significantly reduces PIGT in patients receiving pertuzumab in combination with chemotherapy. Clinical trial information: NCT04249622 .

Chemotherapy dose density and effect on prognosis for patients with resectable pancreas cancer: A secondary analysis of SWOG S1505.

4158 Background: Chemotherapy is an integral part of multimodality treatment for resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose reductions or missed cycles on survival is difficult as few trials prospectively address the prognostic value of this important metric. Methods: SWOG S1505 (NCT02562716) was a randomized, phase II study of perioperative (12 weeks neoadjuvant and 12 weeks adjuvant) chemotherapy with mFOLFIRINOX or gemcitabine/nab-paclitaxel for resectable PDAC. Dose density (DD) was defined as the estimated percent of chemotherapy dose received of the total planned per protocol. Thresholds were based on published analyses and balance in sample size across treatment arms. Cox regression analysis of overall survival (OS) according to DD was performed in patients alive at two landmark time points: after surgery (among those who completed surgery) and at 40 weeks (when protocol therapy was to be completed). Results: Of the 103 eligible patients enrolled, median age was 64 years, 81% underwent pancreaticoduodenectomy, 15% distal pancreatectomy, and 3% a total pancreatectomy. In the 73 patients who underwent surgery, median neoadjuvant chemotherapy DD was 89%. Patients with ≥ 85% DD had higher median OS from surgery (38.1 v. 17.2 months, p = 0.039) compared to patients with &lt; 85% DD. Of the 82 patients who survived to 40 weeks post randomization, 67 underwent surgery and 58 started adjuvant chemotherapy. The median DD for all perioperative chemotherapy was 67%; DD was significantly higher for neoadjuvant compared to adjuvant therapy (83% vs. 58%, p &lt; 0.001). In this cohort, DD ≥ 70% was associated with better median OS from 40 weeks post randomization (32.2 v. 14.0 months, p = 0.017). DD was not significantly associated with pathologic response, margin status, or lymph node negativity. There were no significant differences in DD between the mFOLFIRINOX and gemcitabine/nab-paclitaxel arms. Conclusions: This is the first study to identify a prognostic role for chemotherapy DD in patients undergoing perioperative chemotherapy for resectable PDAC. Patients who received ≥ 85% DD preoperatively and/or ≥70% DD perioperatively had significantly higher mOS than those receiving a smaller proportion of protocol therapy. With greater survival benefit in patients who received higher chemotherapy DD, and higher DD being likelier in preoperative vs. postoperative treatment, these data support use of neoadjuvant chemotherapy for resectable PDAC. Moreover, these findings suggest that DD should be considered in prospective studies for localized PDAC to optimize therapy to be received.

Effect of proprioceptive neuromuscular facilitation technique and TENS on improving lower limb sensorimotor function, balance and quality of life in chemotherapy induced peripheral neuropathy in gynecological cancer: A randomized controlled trial protocol

Gynecological cancers are the most prevalent cancers in women, making it a significant public health concern. Chemotherapy drugs are an extremely effective approach for reducing cancer progression since they have various targets and mechanism of action focused at killing quickly multiplying cancer cells. Unfortunately, these drugs also affect normal cells and structures of the body, resulting in a variety of deleterious effects. Most common among them is chemotherapy induced peripheral neuropathy (CIPN). Taxanes, platinum medicines, vinca alkaloids and thalidomide are examples of popular pharmaceuticals that are prone to cause CIPN. When CIPN develops during active chemotherapy phase, it may result in the discontinuation or reduction of chemotherapy dose, which may render the dosage ineffective in cancer management. As a result, it is essential that physiotherapists investigate novel approaches to successfully manage the side effects that survivors must deal with. Here’s the idea we suggest by conducting a study which aim to assess the effectiveness of Proprioceptive Neuromuscular Facilitation Technique (PNF) with Transcutaneous Electrical Nerve Stimulation (TENS) and closed kinetic chain exercises with TENS on subjects with CIPN in Gynecological Cancer in two arm parallel superiority randomized control trial (RCT) on improving lower limb sensorimotor function, balance &amp; quality of life. The total participants in the study will be divided into two equal groups and then the intervention will be given for 8 weeks to both the groups with 5 days in a week with 50 minute session each day. The results will be evaluated after 8 weeks of treatment and 3 weeks after completion of intervention for follow up. If the hypothesis of our study proves to be effective, this physiotherapy intervention could be included in management of CIPN. Along with it, it will help in reducing the rate of discontinuation of chemotherapy dose due to neuropathy.

Outcomes in Patients With Curative Malignancies Receiving Filgrastim as Primary Prophylaxis.

Granulocyte colony-stimulating factor prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and febrile neutropenia and is recommended for at-risk patients receiving chemotherapy. Within the South Texas Veterans Health Care System, daily filgrastim injections remain the preferred formulation of granulocyte colony-stimulating factor for primary prophylaxis of febrile neutropenia. This retrospective, single-center cohort study included 59 patients who received daily filgrastim as primary prophylaxis with a curative cancer diagnosis and a chemotherapy regimen at the South Texas Veterans Health Care System from September 1, 2015 to September 24, 2020. Patients had either a high risk for febrile neutropenia or a chemotherapy regimen with an intermediate risk for febrile neutropenia and additional risk factors. The primary outcome was the incidence of neutropenia/febrile neutropenia leading to treatment delays. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia/febrile neutropenia. Patients received a median (IQR) of 7 (5-10) doses of filgrastim for primary prophylaxis. Overall, 10 patients (17%) experienced treatment delays due to neutropenia/febrile neutropenia. Fifteen patients (25%) were hospitalized with a median (IQR) length of stay of 5 (4-7) days, 9 patients (15%) had documented infections, and 2 patients (3%) required a chemotherapy dose reduction. Additionally, 9 patients (15%) required an additional median (IQR) of 2 (2-5) doses of filgrastim, and 9 (15%) patients were transitioned to pegfilgrastim. These results suggest that additional measures such as tracking postnadir absolute neutrophil counts should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia/febrile neutropenia.

Peripheral myeloid cells control resolution of painful Chemotherapy-Induced Peripheral Neuropathy (CIPN) (S23.001)

<h3>Objective:</h3> The objective of this study is to identify endogenous mediators controlling CIPN pain resolution. <h3>Background:</h3> Chemotherapies contribute to decreased cancer mortality but are associated with severe side effects including Chemotherapy-Induced Peripheral Neuropathy (CIPN). CIPN presents as a distal symmetric polyneuropathy causing numbness, tingling, and in a subset of patients, pain. Painful CIPN is a main cause for chemotherapy dose reduction, treatment cessation and reduced quality of life. A subset of painful CIPN patients will have pain resolution while others maintain pain persistency, however the mechanisms that mediate pain resolution are unknown and constitute a large gap of knowledge. <h3>Design/Methods:</h3> We developed painful CIPN models in mice using the chemotherapeutic paclitaxel, where mice treated with specific injection protocols develop resolving or persistent mechanical hypersensitivity measured via von Frey. Using these models, we performed bulk RNA sequencing on hind paw, whole dorsal root ganglion (DRG), DRG sensory neurons and spinal cord at initiation, pre-resolution, post-resolution, and persistency time points. DEGs were selected (P-adj &lt;0.05, FC &gt; 2, RPKM &gt; 1) and PANTHER analysis was performed to identify biological processes. To investigate the contribution of particular cell types in these tissues, we used the inducible diphtheria toxin receptor ablation model. <h3>Results:</h3> PANTHER analysis identified upregulation of immune system related genes in the hind paw during resolution of Model-1 not seen in Model-2. As myeloid cells are known to contribute to immune system related genes in the periphery, we ablated myeloid cells. We identified that CD11b+ peripheral, but not IBA1+ central, myeloid cells are critical for painful CIPN resolution. Further RNA sequencing analysis identified pro-inflammatory pathways correlated with painful CIPN resolution. <h3>Conclusions:</h3> These studies provide mechanistic insights for CIPN pain resolution and identify a unique therapeutic strategy for permanent treatment of painful CIPN. Future studies will delineate the myeloid cell sub-type and factors required for CIPN pain resolution. <b>Disclosure:</b> Mr. Naratadam has nothing to disclose. Prof. Akopian has nothing to disclose.

An evaluation of the effect of lithium on taxane-induced neuropathy.

No medications are known to protect against chemotherapy-induced peripheral neuropathy (CIPN). Pre-clinical models suggest that lithium may lessen taxane-induced neuropathy. Our aim was to use clinical data to assess whether concurrent lithium usage decreased the frequency or severity of CIPN in patients receiving taxane chemotherapy. A retrospective analysis was performed using the electronic health record at Mayo Clinic to identify all patients prescribed concurrent lithium and paclitaxel. Four controls were matched to each case based on clinical variables. Neuropathy severity was graded from available patient and clinician reports. Rates of any neuropathy, dose reduction for CIPN, and treatment discontinuation for CIPN were compared. Conditional regression analysis was performed with propensity score matching. Six patients, receiving concurrent lithium and paclitaxel, were included in the analysis, and compared to 24 control cases. A similar number of paclitaxel cycles were administered to both groups. Any neuropathy was experienced by 33% (2/6) of patients receiving lithium and 38% (9/24) patients who did not receive lithium (p = 1.000). There was no difference in neuropathy severity (p = 0.8565), rate of chemotherapy dose reduction (17% vs. 17%, p = 1.000), or treatment discontinuation (17% vs 4%, p = 0.3655) for CIPN. In the propensity score analysis, the odds ratio for developing any neuropathy was 0.63 (95% confidence interval, 0.06 to 6.96, p = 0.7079). Lithium does not appear to significantly lessen the risk of neuropathy for patients receiving paclitaxel. Targeted approaches for preventing CIPN are desperately needed. Despite sound scientific rationale, the current study did not identify neuroprotective properties of lithium.

Abstract 2186: An exploratory analysis of the intestinal microbiome in neoadjuvant chemotherapy for pancreatic cancer

Abstract Background: Pancreatic cancer portends a very poor prognosis. It is the third leading cause of cancer deaths in the United States. African Americans have a 50- 90% increased incidence of pancreatic cancer in comparison to other racial groups. 20% of patients with pancreatic cancer present with early-stage disease and will have a median overall survival of 2.5 years if able to undergo surgical resection. There is a desperate need to discover novel ways of treating pancreatic cancer. Understanding of the microbiome may be informative to overcoming chemotherapy resistance, toxicity and improving outcomes and disparities. The aim of this study is to (1) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment response and (2) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment toxicity in a diverse patient population. Methods: Patients with resectable or borderline resectable pancreatic cancer who are enrolled in a multi-site clinical trial (NCT03483038) receiving neoadjuvant NEO-Nali-IRI (oxaliplatin, liposomal irinotecan and 5- FU) followed by surgical resection were asked to provide stool samples and a dietary log during the following four (or five) time points: baseline, mid-therapy (after C4), at completion of chemotherapy (after C8), after radiation if applicable, and at 4-6 weeks post-operative. Participants will be given stool collection kits at clinic visits for home sample acquisition. All samples will be mailed to the University of Florida Health Cancer Center Microbiome Biorepository. Data will be collected regarding demographics, stage, medical history and concurrent medications including antimicrobics and probiotics, chemotherapy dose-reductions, delays, discontinuations, adverse events, safety adverse events, attribution of causality, and hospitalizations. Outcomes will include imaging response using RECIST criteria, CA 19-9 trend, development of metastatic disease, and the ability to proceed to definitive surgical resection. DNA will be extracted from stool and analyzed using 16S rRNA sequencing methods to determine signatures and biodiversity. Descriptive statistics and correlative analysis will be reported. Continuous and categorical variables will be compared with Student’s t-test and Chi-squared test. Multiple groups will be compared by ANOVA. Kaplan-Meier logistic regression will be performed to compare outcomes between the different microbiota groupings. Conclusion: Stool collection from a multi-site clinical trial is feasible during neoadjuvant chemotherapy for pancreatic cancer and can increase diversity of the sample population. Citation Format: Sherise Rogers, Ryan Thomas, Brain Ramnaraign, Ilyas Sahin, Jesus Fabregas, Karen Russell, Steven Hughes, Ibrahim Nassour, Kathyrn Hitchcock, Omar Kayaleh, Anita Turk, Ji-Hyun Lee, David DeRemer, Carmen Allegra, Thomas George. An exploratory analysis of the intestinal microbiome in neoadjuvant chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2186.

Abstract 3218: Lifestyle intervention of food and exercise for lymphoma survivors (LIFE-L): a pilot intervention protocol for adults

Abstract Background: Lymphomas are among the top seven most frequent cancers in men and women in the United States. In 2022, more than 21,000 deaths related to this neoplasm are expected. The use of common treatment modalities (e.g., chemotherapy, radiation, stem cell transplant) may lead to negative physical and psychosocial symptoms. Furthermore, these adverse effects decrease treatment tolerance and adherence. Little is known about the potential of lifestyle factors (nutrition and physical activity) to mitigate these adverse events in lymphoma patients. To fill this gap, we propose a pilot feasibility study to assess the impact of healthy diet and exercise intervention on relative dose intensity (RDI), an integrated measure of chemotherapy dose delays and reductions; patient-reported outcomes, (e.g., quality of life (QoL), fatigue, and cognition);immune and metabolic markers; and body composition. Methods: 60 newly diagnosed lymphoma patients will be recruited in this two-arm stratified (by treatment type) randomized waitlist controlled pilot study. Eligibility criteria include adults fluent in English or Spanish, presenting with any type of lymphoma at any stage, receiving one of the following three chemotherapy regimens: R-CHOP, BR, B±ABVD. Participants must have clearance from their oncologist to participate. Participants must have access to the internet through an electronic device. They are randomized to either the intervention arm, that consists of telephone- or video call-delivered health coaching to achieve a Mediterranean diet and 150 minutes per week of moderate or vigorous exercise, or a waitlist control (n=15) arm which will receive the study materials and two telephone-based coaching sessions after study completion. Interventions will take place during active treatment. Data will be collected prior to randomization, the third and sixth cycle of chemotherapy, and four weeks post-treatment at standard of care visits through self-reported questionnaires, anthropometric measures, physical assessments, ActiGraph watches, blood samples, CT scans (if available), and clinical information from electronic medical records (EMR). Discussion: Results from this pilot will provide valuable information about the feasibility, acceptability, and preliminary efficacy of a lifestyle intervention in lymphoma patients undergoing active treatment. Lessons learned from this study seek to fill the gap in supportive oncology care programs among lymphoma patients to improve treatment outcomes, such as RDI, and patient reported outcomes, and overall QoL. Citation Format: Paola Rossi, Moira Pissinis, Melissa Lopez-Pentecost, Sarah Freylersythe, Hong Su An, Lashae Rolle, Craig Moskowitz, Tracy Crane. Lifestyle intervention of food and exercise for lymphoma survivors (LIFE-L): a pilot intervention protocol for adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3218.

Outpatient administration of paclitaxel, ifosfamide, and cisplatin (TIP) for germ cell tumor.

The combination of paclitaxel, ifosfamide, and cisplatin (TIP) is frequently used for the treatment of metastatic germ cell tumors. Due to complex supportive care and infusion requirements, TIP is typically given in the inpatient setting. This analysis describes the development and implementation of a protocol for complete outpatient administration of TIP chemotherapy. From July 2020 to June 2021, adults receiving TIP for germ cell tumor at University of Michigan Rogel Cancer Center were evaluated for outpatient administration. The primary outcome was number of inpatient bed days saved by giving outpatient TIP chemotherapy, with the goal of giving 75% of TIP cycles outpatient. Patients receiving outpatient TIP were also assessed for chemotherapy dose reduction or delays and acute toxicities of kidney injury, encephalopathy, and hemorrhagic cystitis. From July 2020 to July 2021, three patients received 13 cycles of TIP. Ten cycles (77%) were administered in the outpatient setting, resulting in a savings of 50 inpatient bed days in one year. No patients required a dose reduction or delay in chemotherapy or experienced acute kidney injury, encephalopathy, or hemorrhagic cystitis during outpatient TIP treatment. Despite logistic and supportive care challenges, TIP can be administered completely in the outpatient setting.