Poor Tolerance To Chemotherapy Research Articles

Dietary restriction rescues 5-fluorouracil-induced lethal intestinal toxicity in old mice by blocking translocation of opportunistic pathogens

ABSTRACT Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in ad libitum (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial Lactobacillus genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or Lactobacillus gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.

Clinical outcomes of patients who are frail and elderly with unresectable pancreatic ductal adenocarcinoma (PDAC) treated with chemotherapy.

e16281 Background: Gemcitabine plus nab-paclitaxel and fluorouracil (5-FU)-based chemotherapy, such as FOLFIRINOX and FOLFOX, are standard treatment for unresectable PDAC. While older age and poor performance status (PS) are established negative prognostic factors, most clinical trials exclude these vulnerable populations. We aimed to assess the impact of older age and reduced PS in a real-world cohort of patients with PDAC who received chemotherapy. Methods: We retrospectively reviewed patients with unresectable or metastatic PDAC treated with first line (1L) therapy at Mount Sinai Health System from 1/2012 to 12/2021. We evaluated the association between age (≥ 75 vs. < 75) and PS (ECOG PS ≥ 2 vs. < 2) on overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Chemotherapy tolerability was compared between these vulnerable and non-vulnerable populations using Chi-squared and Mann-Whitney tests. Results: 254 patients were evaluable. The median age of the full cohort was 66 years, and 130 (51.2%) patients were male. All patients had locally advanced (29.8%) or metastatic disease (70.2%). 47.6% of patients received gemcitabine-based and 49.6% received 5-FU-based 1L therapy. 41 patients (16.1%) had ECOG PS ≥ 2, and 60 (23.6%) were 75 or older. The type of 1L chemotherapy and rate of adverse events (AEs) requiring dose change or discontinuation did not differ significantly between patients with ECOG PS ≥ 2 and PS < 2. However, patients with ECOG PS ≥ 2 received a shorter duration of therapy (median 2.6 vs. 3.4 months, P = 0.018), and the reason for discontinuation was more often due to clinical deterioration (56.1% vs. 29.6%, P = 0.004). As a result, fewer continued on to second-line (2L) therapy (29.3% vs. 51.2%, P = 0.016). ECOG PS ≥ 2 was associated with worse OS (HR 1.6, 95% CI 1.1-2.4, P = 0.016) in univariate analysis but not in multivariate analysis. ECOG PS ≥ 2 correlated with worse PFS in both univariate and multivariate analyses (HR 1.6, 95% CI 1.1-2.3, P = 0.009; HR 1.5, 95% CI 1.1-2.2, P = 0.023). Patients older than 75 were more likely to receive gemcitabine-based therapy (83.3% vs. 40.2%, P < 0.001). While no significant differences in duration of therapy, rate of AEs, or reasons for discontinuation were observed based on age, older patients were less likely to receive 2L therapy (28.3% vs. 53.6%, P = 0.001). Age ≥ 75 was associated with worse OS (HR 1.6, 95% CI 1.19-2.25, P = 0.003) and worse PFS (HR 1.4, 95% CI 1.05-1.89, P = 0.024) in univariate but not multivariate analyses. Objective response rates did not differ based on PS or age. Conclusions: Reduced PS was associated with worse clinical outcomes and poor chemotherapy tolerance, but older patients appeared to tolerate gemcitabine-based regimens. Future studies should more specifically address the treatment needs of frail and elderly patients.

Combination Anti-PD1 Antibody and Rituximab Followed By R-CHOP for Elderly Patients with Newly Diagnosed DLBCL: Analysis of the Phase II TREND Trial

Background: Patients with diffuse large B-cell lymphoma (DLBCL) in the elderly face challenges in treatment due to comorbidities and poor tolerance of chemotherapy. Age >60 years is an unfavorable risk factor in DLBCL in the International Prognostic Index (IPI) system. Besides, increased proportion of ABC/non-GCB subgroups, complex molecular features also lead to unfavorable prognosis with distinct biological or immune microenvironment features in elderly patients. Although clinical benefit of single-agent anti-PD-1 antibody in DLBCL was not obvious, pre-use anti-PD-1 antibody as first-line may be an opportune for elderly DLBCL. Toripalimab, a recombinant, humanized programmed death receptor-1 (PD-1) monoclonal antibody has been approved by the NMPA for the treatment of various cancers. Methods: Patients aged 60-85 years, ECOG 0-2 with untreated DLBCL or grade 3b follicular lymphoma and at least one measurable or evaluable lesion were enrolled. This study consisted of a phase 1b (Toripalimab dose escalation) followed by a Phase 2 expansion portion. In the phase Ib, a standard "3+3" design was utilized to identify the MTD, DLT and recommended phase 2 dosage (RP2D) of Toripalimab.In phase 2, patients received 2 cycles of Toripalimab (RP2D) plus Rituximab (375mg/m2) every 3 weeks. They allowed to accept two additional cycles of Toripalimab plus Rituximab (To-Ri) if they obtained complete response (CR) after the first 2 cycles. To-Ri followed by R-CHOP (21) up to 6 cycles without Toripalimab then Toripalimab (RP2D) maintenance 6 cycles (q 30 days) after CR or CMR post R-CHOP. All cases more than 75-year-old received R-miniCHOP. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. This trial was registered at ClinicalTrials.gov (NCT04058470). Results: From December 2020 to July 2022, 37 eligible patients were enrolled. Median age 67 years (range, 60-83), 16 (43.2%) male, 20 (54.1%) patients with stage III/IV, 27(73.3%) patients with extranodal disease, 8 (21.6%) patients with IPI score ≥ 3 points, and non-GCB(n=25), double expression (DEL, n=7), EBV+DLBCL(n=5), double/triple hit lymphoma (DHL/THL, n=2). In phase Ib, no MTD or DLT events were observed, RP2D of Toripalimab was 240mg. Of 34 response evaluable patients, 14 patients completed To-Ri×4, 26 (59.1%) achieved response including 15 (44.1%) patients with CR post To-Ri treatment. Key responded to To-Ri including non-GCB (81.8%, n=18), GCB (58.3%, n=7), EBV+DLBCL (50%, n=2), DEL (87.5%, n=7), DHL/THL (100%, n=2), primary gastrointestinal tract involved (75%, 6/8) and primary nasal involved (87.5%, 7/8). Five patients are still under treatment, ORR and CR post R-CHOP were 100% (32/32) and 87.5% (28/32). With a median follow-up of 8.2 months, estimated 1-year PFS and were 81.2% and 88.4%. Thirty-six (97.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were abnormal liver function (43.2%), anemia (43.2%), lymphopenia (32.4%), neutropenia (27.0%), hypothyroidism (21.6%), nausea (18.5%). This clinical trial is still on going. Conclusion: Toripalimab plus Rituximab as a first-line treatment then followed by R-CHOP yielded high CR rate and manageable toxicities in elderly with newly diagnosed DLBCL, especially for patients with extranodal disease and high grade lymphoma. This therapeutic strategy deserves further clinical investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 3995: Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia

Abstract Cachexia is a multifactorial syndrome characterized by extensive body weight, lean muscle and fat mass loss. Cachexia worsens cancer patient prognoses and contributes to poor chemotherapy tolerance and response rates. About 80% of pancreatic cancer patients suffer from cachexia and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved cachexia therapies. A major contributing factor could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged murine model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative transcriptomic analyses of the muscles identified 3-methyladenine (3-MA), a known autophagy inhibitor, as a candidate anti-wasting compound. In vitro analyses confirmed anti-wasting effects while in vivo analysis demonstrated that 3-MA could rescue muscle wasting and suppress tumor growth. Surprisingly, transcriptome analyses of 3MA-treated tumor cells did not reveal autophagy-related signatures but instead implicated Perp as a novel 3-MA target. Probing further, we 1) observed significantly higher expression of Perp in pancreatic cancer cell lines compared to control cells, 2) noted a survival disadvantage associated with elevated PERP in the TCGA database, 3) found that PERP knockdown in cancer cells led to reduced tumor proliferation, and 4) confirmed that 3-MA-associated Perp reduction inhibited tumor growth. Moreover, we also demonstrate that survival benefits associated with 3MA is independent of tumor progression. Finally, we queried Perp expression in human tumor samples and observed increased Perp expression in adenocarcinoma regions compared to tumor adjacent tissue. Taken together, we report a novel mechanism linking 3-MA to Perp inhibition, and further implicate Perp as a novel tumor promoting factor in pancreatic cancer. Citation Format: Aneesha Dasgupta, Paige C. Arneson-Wissink, Rebecca E. Schmitt, Dong Seong Cho, Alexandra M. Ducharme, Tara L. Hogenson, Eugene W. Krueger, William R. Bamlet, Lizhi Zhang, Gina Razidlo, Martin E. Fernandez-Zapico, Jason D. Doles. Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3995.

ALK Inhibitor Plus Vinblasitine for Refractory/Relapsed Pediatric ALK+ Anaplastic Large Cell Lymphoma: A Prospective, One-Arm, Open-Label Real-World Study

Background: Refractory and relapsed (r/r) anaplastic lymphoma kinase (ALK)-positive anaplastic large cell Lymphoma(ALK+ALCL) have a poor prognosis. Studies had confirmed vinblastine (VBL) may be an effective treatment for relapsed ALCL and ALK inhibitors may have high efficacy and tolerability in patients carrying ALK fusions. Therefore, we put forward a hypothesis that for those r/r ALK+ALCL patients with poor chemotherapy tolerance and effect, combining ALK inhibitors with vinblastine may have a sustained anti-tumor effect and good tolerance.Aims: To assess the efficacy and safety of ALK inhibitors combined with VBL in pediatric relapsed/refractory (r/r) ALK+ ALCL.Methods: Patients aged between 0 and 18 years with r/r ALK+ ALCL were included in this trial. ALK inhibitors are given orally with a converted dosage according to body surface areaand VBL was given with injection once a week at 4-6 mg/(m2.week). And no intensive chemotherapy and hematopoietic stem cell transplantation will be in our study.We may decrease the dosage of VBL or delete VBL if patients suffer severe bone marrow suppression, repeated infections, and peripheral neuritis and other VBL-related toxicities. Available ALK inhibitors included crizotinib(CZ), alectinib(AL) and ceritinib(CER). Patients without CNS involvement took CZ, and patients with CNS involvement took AL or CER. A cycle of therapy is 28 days. Evaluation for responses toxicities were monitored and recorded.Results:27 patients were enrolled in this trial between April 2018 and April 2021. The median age was 8.3 years old(ranging from 0.75 to 16), male/female ratio is19:8. By St.jude's staging, 20 cases were in stage III (74.1%), 7 cases in stage IV (25.9%) including 3 cases (11.1%) with CNS involvement at initial diagnosis. Before being enrolled in our study, 6 patient (22.2%) failed to achieve CR with prior 4-10 chemotherapy regimens, 21 patients (77.8%) relapsed after an average of 5-16 courses of standard pulse chemotherapy regimens. After 1st cycle of treatments, 62.9%(17/26) achieved comlpele remission(CR) without measurable tumors and ALK gene transcription, no progressed cases. Additional 6 case got CR after 2-10 month(23.1%). In general, 7 patients withdraw due to death, progress, ineffectiveness, economics, adverse reactions. The treatment retention rate was ,7.1%（20/7），objective response rate (ORR) was 85.2%(23/27), best complete remission rate(CRR) was 85.2%(23/27), disease control rate(DCR) was 92.5%(25/27), average duration of CR was 14.85 months(0-36months).Toxicities included nausea and vomiting, stomachache, diarrhea(81.5%,22/27, one or more above toxicities), neutropenia (27/27), pneumonia(7.4%, 2/27), sepsis(7.4%, 2/27), creatine kinase-MB elevation (81.5%,22/27,all are in crizotinib group including 2 abnormal ECG cases), liver enzyme elevation (63.%,17//27), intestinal obstruction(7.4%, 2/26). 2 cases relapsed because of the treatment discontinuation due to severe elevated liver enzymes.Summary/Conclusion: ALK inhibitors combined with VBL may rapidly induce the tumor remission of r/r ALK+ALCL and the tolerance is good. Combination therapy may induce a more lasting remission in for patients without BM involvement. Patients with BM involvement are more likely to fail treatment. Sequential use of ALK kinase inhibitors may be an efficient strategy to counter drug resistance.More data and longer follow-up time are needed to support our study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders: beyond chemotherapy treatment.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of both allogeneic solid organ (SOT) and hematopoietic cell transplantation (HCT). The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma. Most commonly, PTLDs are Epstein-Barr virus (EBV) positive and result from loss of immune surveillance over EBV. Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different, resistance to treatment is unique, and there are specific concerns for organ toxicity. While recipients of HCT have a limited time during which they are at risk for this complication, recipients of SOT have a lifelong requirement for immunosuppression, so approaches that limit compromising or help restore immune surveillance are of high interest. Furthermore, while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy, the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms. Therefore, reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib, reduced dosing of standard chemotherapeutic agents, and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored. Here, we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.

Analysis of clinical characteristics, treatment and survival of elderly patients with large diffuse B-cell lymphoma

Objective: To analyze the clinical feature,treatment and survival outcome of elderly patients older than 80 years with large diffuse B-cell lymphoma. Methods: A total of 46 patients aged over 80 years with large diffuse B-cell lymphoma who were treated in Third Hospital of Peking University during the period from 2002 to 2018 were retrospectively analyzed, and the clinical features, laboratory data, survival and prognostic factors were included in Kaplan-Meier and prognostic analysis. Results: Patients older than 80 years old accounted for 15.7% (46/293) in all elderly patients, and the median age was 83 years old. There were 78.3% (36/46)patients who belonged to stage Ⅲ or Ⅳ, 63%(29/46) who had more than two extranodal organ involvement, and the higher proliferation index(Ki-67≥80%) was present in 53.7%(22/41) patients. Immunohistochemistry showed that 37% patients in 27 cases were double-expressed DLBCL. With a median follow-up of 25 months, the overall response rate (ORR) for the whole group was 63.0%, the complete response (CR) rate was 36.4%, the 2, 3-year progression-free survival (PFS) rate was 49.9% and 41.7%, the 2, 3-year overall survival (OS) rate was 54.6% and 43.6% respectively. The ORR for patients who received anthracycline-based therapies and non-anthracycline-based therapies were 81.8% and 55.0%, and the 3-year OS rate were 50.0% and 39.0%, respectively, but the difference was not statistically significant (P>0.05). 45.5% patients had hematologic toxicity of Grade Ⅲ or above, and 56.8% patients experienced infections during the treatment. Among the patients who died, the treatment-related mortality rate in group with high score of Charlson comorbidity index(CCI) was higher (43.8% vs 16.7%, P=0.03) . The National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) score, nodal involvement area ≥3, 6 cycles of chemotherapy, CCI score, initial treatment outcome and refractory-relapsed were predictive of overall survival. Multivariate analysis indicated the CCI score (HR=6.463, P=0.008) and initial treatment outcome (HR=0.086, P=0.001) were independent prognostic risk factors. Conclusions: The clinical and pathological features of patients older than 80 years were highly aggressive with poor chemotherapy tolerance and high adverse reaction rate. Anthracycline-based therapies may be less important in the treatment of DLBCL patients aged over 80 years. Patients with high CCI score have higher treatment-related mortality and CCI can help identify elderly patients who are suitable for larger chemotherapy dose.

Cancer Incidence and Chemotherapy Tolerance in Patients with Sickle Cell Disease

With improved understanding and treatment of sickle cell disease (SCD), patients are more likely to live into the sixth decade. Survival into older adulthood may be associated with a concomitant risk of malignancy in this population. Past studies have yielded conflicting data regarding the incidence of cancer in SCD. Some studies show an increased risk of hematologic malignancies or solid tumors, while others demonstrate a decreased propensity for cancers in patients with SCD. Delays in treatment and dose reductions can adversely affect response and survival outcomes, but little is known about the ability of SCD patients to tolerate treatment for various malignancies. We studied the incidence of cancer and tolerance of chemotherapy over a 10-year-period at the University of Illinois at Chicago in a retrospective chart review. Our study included 1484 SCD patients of all ages seen at our institution from September 30, 2010 to April 29, 2020. The patient records were queried for common malignancies using ICD-9 and ICD-10 codes, including colorectal, lung, breast, prostate, renal, and cervical cancer as well as lymphoma, leukemia, and multiple myeloma. These cases were verified by manual chart review (Figure 1A). The incidence of cancer was compared to an African American (AA) control cohort of 22,260 patients matched for age, sex, and follow-up time. For patients who received chemotherapy, details on regimen and tolerability were obtained. Baseline variables were defined as the median of all available values three years prior to treatment. Dose limiting toxicities (DLT) were defined as any reason for which an expected dose could not be administered. Of the 1484 SCD patients, 48 (3.2%) had a cancer diagnosis according to ICD codes. Among the AA control population, 1282/22260 (5.8%) had cancer according to ICD codes. The incidence of common malignancies was significantly decreased in the SCD population (OR 0.55, p<0.001, 95% CI 0.40 to 0.73). Of the 48 SCD cancer cases, we were able to confirm 19 (39.6%) by manual chart review and 16 of these patients were diagnosed during the study period. Characteristics of the 16 SCD cancer patients are summarized in Table 1 and distribution of cancer types is shown in Figure 1B. Eight (50%) of these patients were known to receive chemotherapy, and treatment details are shown in Table 2. First-line treatment was not given in 2 (25%) cases due to comorbidities such as SCD, poor functional status, toxicity, age, and renal insufficiency. Grade 3 or 4 toxicities took place in 5 (62.5%) patients, including anemia, neutropenia, leukopenia, thrombocytopenia, dehydration, nausea and or vomiting, and hemorrhagic cystitis. Six (75%) patients had a vaso-occlusive crisis (VOC) and 1 (12.5%) had an acute chest syndrome episode during therapy. DLT in 4 (50%) patients included nephrotoxicity, infection, pain, and hepatotoxicity. Four (50%) patients did not receive all scheduled cycles for reasons including concern for cerebrovascular accident (CVA), fatigue, anorexia, dehydration, VOC, infection, and progression of disease. Two (25%) patients required change in chemotherapy regimen due to toxicity. Our study raises several questions regarding both the incidence and treatment of cancer in SCD. There was a significantly lower incidence of cancer among SCD patients compared to AA controls. Mechanisms by which SCD patients may be protected from cancer are unknown, but should be explored in future studies. Patients who received chemotherapy in our study experienced significant toxicities, delays, and dose reductions. Such issues were often SCD-related or due to other typical hematologic toxicities. Although the goal for treating SCD cancer patients may be with therapies that result in outcomes similar to the general population, our data suggests that this is difficult with routine protocols. Increased monitoring and a multimodal approach to symptom control may increase treatment tolerability and ensure adequate dose delivery. Evidence of poor chemotherapy tolerance in SCD patients highlights the need for further and larger studies to determine treatment strategies for this population. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Gordeuk:Novartis: Consultancy; CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding.

Low lean mass and chemotherapy toxicity risk in the elderly: the Fraction study protocol

BackgroundHalf of cancer cases occur in patients aged 70 and above. Majority of older patients are eligible for chemotherapy but evidence for treating this population is sparse and severe toxicities affect more than half of them. Determining prognostic biomarkers able to predict poor chemotherapy tolerance remains one of the major issues in geriatric oncology. Ageing is associated with body composition changes (increase of fat mass and loss of lean mass) independently of weight-loss. Previous studies suggest that body composition parameters (particularly muscle mass) may predict poor chemotherapy tolerance. However, studies specifically including older adults on this subject remain sparse and the majority of them study body composition based on computed tomography (CT) scanner (axial L3 section) muscle mass estimation. This method is to date not validated in elderly cancer patients.MethodsThis trial (Fraction) will evaluate the discriminative ability of appendicular lean mass measured by dual-energy X-ray absorptiometry (DXA) to predict severe toxicity incidence in older cancer-patients treated with first-line chemotherapy. DXA is considered the gold standard in body composition assessment in older adults.Patient’s aged ≥70 diagnosed with solid neoplasms or lymphomas at a locally advanced or metastatic stage treated for first-line chemotherapy were recruited. Patients completed a pre-chemotherapy assessment that recorded socio-demographics, tumor/treatment variables, laboratory test results, geriatric assessment variables (function, comorbidity, cognition, social support and nutritional status), oncological risk scores and body composition with DXA. Appendicular lean mass was standardized using evidence based international criteria. Participants underwent short follow-up geriatric assessments within the first 3 months, 6 months and a year after inclusion. Grade 3 to 5 chemotherapy-related toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) were assessed at each chemotherapy cycle.DiscussionThe finding that body composition is associated with poor tolerance of chemotherapy could lead to consider these parameters as well as improve current decision-making algorithms when treating older adults.Trial registrationClinicalTrials.gov Identifier: NCT02806154 registered on October 2016.

Long-Term Follow-up of a PET-Guided Approach to Treatment of Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) in British Columbia (BC)

Background: Treatment practices for patients with limited-stage DLBCL are varied and include combined-modality treatment (3 cycles immunochemotherapy + radiation therapy) or immunochemotherapy alone. Since 2005, patients (pts) in BC with limited-stage DLBCL (stage I/II, no B-symptoms, mass < 10cm) have been treated according to a PET-guided algorithm. Following 3 cycles of R-CHOP, pts undergo FDG-PET/CT scan; PET-negative pts receive one additional cycle of R-CHOP, while PET-positive pts receive involved-site radiation therapy (RT). We present long-term follow-up of this population-based experience. Methods: Using the BC Cancer Lymphoid Cancer Database we identified all pts who were diagnosed with limited-stage DLBCL from Mar 2005 to February 2019 and underwent a PET/CT after 3 cycles of curative-intent R-CHOP, in keeping with the PET-guided policy. Pts with primary CNS, primary testicular, PMBCL, PTLD, and transformed/discordant/composite lymphoma were excluded. Pts with evidence of progressive disease prior to or on mid-treatment PET/CT were also excluded. All PET/CT scans were performed and reviewed centrally. Prior to 2014, interpretation was based on the International Harmonization Project (IHP) criteria, and subsequently according to Deauville criteria. Importantly, uptake greater than the mediastinal blood pool was consistently used to determine PET-positivity (ie. PET-positive by IHP, or D3-5 by Deauville). Results: Clinical characteristics of the 319 pts identified are as follows: median age, 68 y (range 19-92); 48%, male; 59%, stage I; 41%, stage II; 8%, PS>1; 13%, elevated LDH; 52%, at least 1 extranodal site; 37%, mass size ≥ 5cm. Stage-modified IPI risk score: 19%, 0; 45%, 1; 27%, 2; 9%, 3-4. Median follow-up is 6.25 yrs (range 0.42-14.25). After 3 cycles of R-CHOP: 254 pts (80%) were PET-negative; 59 pts (18%) were PET-positive; and 6 pts (2%) were considered PET-indeterminate (by IHP). Elevated serum LDH (p<0.001), mass size ≥ 5cm (p=0.008) and stage-adjusted IPI (p=0.025) were predictive of PET-positive status. Of the 254 PET-negative pts, 234 (92%) completed treatment with one additional cycle of R-CHOP, 7 (3%) stopped treatment after 3 cycles R-CHOP and 13 (5%) received RT due to poor chemotherapy tolerance or physician choice. 21/254 PET-negative pts have relapsed and 2/254 died of treatment-related toxicity. 8/21 (38%) PET-negative relapses were late, occurring more than 4 years post initial diagnosis. 55/59 (93%) PET-positive pts received RT, 2 pts refused RT and received only 3 cycles R-CHOP, and 2 pts received 1 additional cycle of R-CHOP alone due to physician preference. 13/59 PET-positive pts have relapsed, only 2/13 (15%) relapses were late >4 years from diagnosis. Of the 6 PET-indeterminate patients, 2 received RT and 3/6 have relapsed. Overall 5-year time-to-progression (TTP) censoring deaths from unrelated causes is 89% (92% for PET-negative and 80% for PET-positive pts). Overall 5-year PFS is 84% (88% for PET-negative and 74% for PET-positive pts) and 5-year OS is 87% (90% for PET-negative and 77% for PET-positive pts). On univariate analysis, age>60, PS>1, stage-modified IPI, and PET status were significant predictors of TTP. On multivariate analysis controlling for age>60, stage, PS, LDH, presence of extranodal involvement, mass size ≥ 5cm, and PET status, only age (p=0.002) and PET status (p=0.004) remained independent predictors of TTP. Conclusion: Using a PET-guided approach to treatment, the majority of patients with limited-stage DLBCL have negative PET scans after 3 cycles of R-CHOP. Patients with negative PET scans have an excellent outcome when treated with 4 cycles of R-CHOP alone, without exposure to radiation. Patients with a positive PET scan who complete treatment with radiation therapy have a slightly less favorable outcome, and may be appropriate for alternative approaches. A detailed analysis of patterns of relapse, as well as efforts to identify clinical factors, PET parameters and biomarkers associated with poor outcome and delayed relapse are ongoing. Figure Disclosures Sehn: Acerta: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Freeman:Seattle Genetics, Janssen, Amgen, Celgene, Abbvie: Consultancy, Honoraria. Pickles:TarSera: Honoraria, Other: Participated in advisory board meeting; Abbvie, Sanofi: Consultancy, Honoraria; Astellas Inc.: Research Funding. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria.

Outcomes in immunosuppressed anal cancer patients

BackgroundImmunosuppressed patients have an increased risk of developing anal cancer, but little data exists regarding outcomes of this population. MethodsA retrospective review of anal cancer patients at a single academic institution from 2006 to 2017 was performed. Results19 (14%) of 136 anal cancer patients were immunosuppressed. Immunosuppressed patients were more likely to be hypoalbuminemic (21% vs. 6%, p = 0.025), less likely to complete chemotherapy (58% vs. 80%, p = 0.031) or exhibit a complete response to chemoradiation (57% vs. 82%, p = 0.037), and more likely to experience recurrence (53% vs. 25%, p = 0.013). Hypoalbuminemia was significantly associated with worse overall (HR 6.4, CI 2.2–19.2, p < 0.001) and progression-free (HR 4.4, CI 1.8–10.4, p < 0.001) survival. ConclusionsImmunosuppressed patients have poor tolerance of chemotherapy and response to chemoradiation, and an increased rate of recurrence. This finding is possibly due to the relationship between immunosuppression and hypoalbuminemia, which was associated with worse overall and progression-free survival.

Present status and research progresses in treatment of acute myeloid leukemia patients aged over 80 years

The number of acute myeloid leukemia (AML) patients aged over 80 years are increasing year by year. They have poor treatment effects and shorter survival period because of elderly age, more underlying diseases, poor tolerance to chemotherapy. At present, there are many treatments reported, including supportive therapy, standard-dose chemotherapy, reduced-dose chemotherapy, demethylation therapy, hematopoietic stem cell transplantation(HSCT) and adoptive cellular immunotherapy, and various treatments have achieved some good effects in AML patients aged over 80 years. However, the survival of this group of patients is still poor. And there are lack of unified and effective therapeutic strategies for elderly patients with AML. This article reviewed the present status and research progresses on treatment of AML aged over 80 years. Key words: Leukemia, myeloid, acute; Aged; Life support care; Prognosis; Drug therapy

Prognostic Significance of Sarcopenia for Patients Treated by Surgery and Radiation for Uterine Cancer

Sarcopenia (low skeletal muscle mass) has recently been recognized as an independent indicator of poor prognosis in newly-diagnosed cancer patients, regardless of baseline body mass index. Although the underlying mechanism remains unknown, sarcopenia has traditionally been associated with poor tolerance and compliance to treatment, including chemotherapy and surgery. Since patients undergoing radiation therapy for uterine cancer, many of whom are overweight and/or obese, might be at particularly high risk for clinically unrecognized sarcopenia, they comprise a potentially ideal group to investigate its prognostic significance. The medical records of consecutive patients treated for histologically-proven uterine cancer at a tertiary-care academic medical center between 2007 and 2015 were reviewed. Analysis was limited to newly-diagnosed patients receiving definitive surgery and external beam radiation with or without chemotherapy. Sarcopenia was objectively defined as skeletal muscle index (SMI) of < 41 cm2/m2, a previously validated measure. SMI calculations were based on radiation treatment planning computed tomography (CT) scans, using the average skeletal muscle cross sectional areas of two sequential axial CT slices at the L3 vertebral level. A single trained observer performed image analysis using NIH ImageJ software with a Hounsfield unit threshold of -29 to 150 to define skeletal muscle. Actuarial estimate of overall survival and progression-free survival were calculated using the Kaplan-Meier method with comparison between groups performed using the log-rank test. Forty-five patients satisfied inclusion criteria. Eighty-seven percent of patients in our study population were overweight or obese (as defined by body mass index greater than 25), and 42% met our standardized definition for sarcopenia. Stage and tumor histology did not differ, although sarcopenic patients were significantly more elderly than those without sarcopenia (median 66.3 vs 58.2 years, p=0.02). Sarcopenic patients were also more likely to miss one or more cycles of planned chemotherapy (35% vs 5%, p=0.04), but unplanned missed radiation treatment days or likelihood of completing planned radiation therapy did not differ. There was a trend towards decreased overall survival in sarcopenic versus non-sarcopenic patients (median: 2.7 versus 3.1 years, p=0.12), but progression free survival did not differ (median 1.3 versus 1.7 years, p=0.62). Sarcopenia is common in uterine cancer patients undergoing perioperative external beam radiation therapy and is associated with poor tolerance of chemotherapy, but not radiation. A trend was identified suggesting decreased overall survival for patients with sarcopenia.

Modified docetaxel regimen for prostate cancer patients who got poor tolerance to chemotherapy

Objective To evaluate the efficacy and safety of the modified docetaxel plus prednisone scheme for the metastatic castration resistant prostate cancer patients who got poor tolerance to chemotherapy. Method The clinical data of 50 metastatic castration resistant prostate cancer who received docetaxel+ prednisone chemotherapy from March 2010 to October 2015 were analyzed retrospectively. 23 cases received the modified DP regimen (modified group), 27 cases received the standard DP regimen (standard group). The median age of the modified group and the standard group were 69 years (47-80 years) and 63 years (52-77 years)(P=0.005). There were 19 and 24 cases with pain in modified group and standard group respectively; 10 and 19 cases with lymph node metastasis respectively; 3 and 4 cases of visceral metastasis respectively; all of the 50 patients were complicated with bone metastasis. For the pathological Gleason score, there were 7 cases scored ≤7 points, 13 cases scored ≥8 points and 3 cases unscored in the modified group; 7 cases scored ≤7 points, 15 cases scored ≥8 points and 5 cases unscored in standard group. There was no significant difference of the pain, metastasis, and Gleason score between the two groups (P>0.05). Progression free survival(PFS), overall survival(OS)and adverse events were analyzed using Kaplan-Meier curves, and the differences were assessed using the log-rank test. Results In the modified group and standard group, the median follow-up times were 11.0 months and 14.0 months respectively, the median chemotherapy cycles were 4.5 cycles and 5.0 cycles respectively; OS were 18.0 months and 27.5 months respectively (P=0.746). The PFS of the two groups were 6.0 months and 5.2 months, respectively (P=0.822). The PSA response were 13 cases and 17 cases in the modified group and standard group respectively(P=0.615), and the pain response were 8 cases and 7 cases (P=0.927), grade 3 to 4 adverse events were 3 cases and 14 cases (P=0.003). The main adverse events were blood toxicity , neutrophils, gastrointestinal reaction, edema, fatigue and oral mucositis etc. Conclusions Compared with the standard DP scheme, the modified DP scheme had no significant difference in OS, PFS, pain response rate and PSA response rate, while the incidence of grade 3 to 4 adverse events was significantly reduced. Modified DP scheme may be a better choice for patients with metastatic castration resistant prostate cancer who get poor tolerance to chemotherapy. Key words: Metastatic castration resistant prostate cancer; Docetaxel; Chemotherapy

Incidence of chemotherapy-induced neutropenia in HIV-infected and uninfected patients with breast cancer receiving neoadjuvant chemotherapy.

Chemotherapy-induced neutropenia (CIN) can result in poor tolerance of chemotherapy, leading to dose reductions, delays in therapy schedules, morbidity and mortality. Actively identifying predisposing risk factors before treatment is of paramount importance. We hypothesised that chemotherapy is associated with a greater increase in CIN and its complications in HIV-infected patients than in those who are not infected. To establish the incidence of CIN in HIV-infected and uninfected patients undergoing chemotherapy. A retrospective chart review and analysis was conducted in the oncology departments at Inkosi Albert Luthuli Central Hospital and Addington Hospital, Durban, South Africa. The study population consisted of 65 previously untreated women of all ages with stage II - IV breast cancer and known HIV status treated with neoadjuvant chemotherapy from January 2012 to December 2015. HIV-infected patients formed 32.3% of the group, and 95.2% of them were on antiretroviral therapy. The mean age (standard deviation (SD)) of the cohort was 48.5 (13.2) years (40.6 (9.6) years for the HIV-infected group v. 52.0 (13.1) years for the uninfected group; p&lt;0.001). Ninety-five neutropenia episodes were observed (rate 0.85 per 1 year of follow-up time). Following multivariate adjustment, patients with HIV infection were almost two times more likely to develop CIN (hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.06- 2.92; p=0.029. A high baseline absolute neutrophil count(ANC) (HR 0.80, 95% CI 0.68 - 0.95; p=0.005) remained significantly associated with protection against CIN. HIV-infected patients were younger than those who were not infected, and presented at a more locally advanced stage of disease. HIV infection was an independent predictor for CIN. HIV-infected patients had an almost two-fold increased risk of developing CIN and developed neutropenia at a much faster rate. A high baseline white cell count and ANC were protective against CIN.

P1.06-003 Anamorelin in Cachectic Patients with Advanced NSCLC, a Post-Hoc Pooled Efficacy Data Analysis of Two Phase 3 Trials

Anorexia-cachexia is a multifactorial syndrome frequently experienced by patients with non-small cell lung cancer (NSCLC). It is characterized by decreased body weight (mainly due to muscle loss) and is associated with worsen morbidity, poor tolerance of chemotherapy and reduced survival. The randomized, double-blind ROMANA 1 and ROMANA 2 phase 3 trials in cachectic NSCLC patients, demonstrated that the ghrelin receptor agonist anamorelin was well tolerated, improved body weight, lean body mass (LBM), fat mass (FM) and anorexia/cachexia symptoms and concerns, with no difference in handgrip strength compared to placebo. Here we assessed pooled efficacy and numbers needed to treat (NNT) from ROMANA 1 and ROMANA 2 studies. Stage III/IV NSCLC patients with cachexia (≥5% weight loss during prior 6 months or BMI<20 kg/m2) were randomized (2:1) to daily oral 100 mg anamorelin or placebo for 12 weeks. Endpoints included changes in LBM, FM, total body mass (TBM) and in self-reported anorexia/cachexia symptoms and concerns. We present the pooled efficacy data from a post-hoc analysis from both trials (anamorelin, N=552; placebo, N=277); treatment differences, 95% CI, NNT and nominal p values from baseline to end of study. At the end of study, compared with placebo, anamorelin-treated patients significantly increased body composition parameters (LBM, appendicular LBM, FM and TBM), and a greater proportion of patients showed improvements in these parameters (Table). The anamorelin group also significantly improved anorexia/cachexia symptoms and concerns, and compared to placebo, more patients in the anamorelin arm achieved the minimally important difference of 4 points. Anamorelin has anabolic activity while improving symptom burden in cachectic patients with NSCLC. A significantly greater proportion of patients increased lean mass, fat mass and improved anorexia/cachexia symptoms and concern score in the anamorelin arm versus the placebo arm, with favorable NNT.

Prophylactic cranial irradiation in small cell lung cancer: A single institution experience.

To compare patient demographics, prophylactic cranial irradiation (PCI) utilization and overall survival (OS) of patients with small cell lung cancer (SCLC) referred to a large tertiary center with those reported in large clinical trials. A retrospective review was conducted of consecutive patients with limited stage (LS) and extensive stage (ES) SCLC diagnosed at the Princess Alexandra Hospital between January 2008 and December 2013. Two hundred and three patients with a mean age of 65.4 (±10.7) years were followed for a median duration of 7.6 months (range 0.5-76.5). At diagnosis, 129 (64%) patients had ES-SCLC, including 39 (19.2%) with cerebral metastases. Median OS in LS-SCLC patients receiving PCI was 18.8 months (0.9-69.4), compared with 8.2 months (0.1-34.4) in patients who did not receive PCI (P < 0.001). Median OS in the ES-SCLC cohort receiving PCI was 13.6 months (5.2-37.5) compared to 5.6 months (0.1-73.6) in patients who did not receive the therapy (P < 0.001). There was a significant improvement in intracranial disease-free survival of 7.1 months in patients with ES-SCLC who received PCI. Forty-two LS-SCLC patients (57%) did not receive PCI due to patient suitability. In our SCLC cohort, median OS following PCI in LS-SCLC and ES-SCLC is comparable to published data. PCI use at our institution was lower than utilization rates in large meta-analyses, predominately due to poor chemotherapy tolerance and patient suitability. This may be more representative of patients treated in clinical practice rather than those recruited into large phase III trials.

How should older adults with cancer be evaluated for frailty?

Traditionally used as a descriptive term, frailty is now a recognized medical syndrome identifying individuals with decreased physiologic reserve. Frailty is characterized by diminished strength, endurance, and reduced physiologic function. Several valid frailty screening tools exist in the literature, and these measures have been used to relate frailty to outcomes important to the older patient with cancer. Frail adults are at increased risk of adverse surgical outcomes and early findings suggest that frailty predicts poor chemotherapy tolerance. While much research is needed to explore the biologic relationships between frailty and cancer, there is an urgent need to implement frailty screening and management into the care of the older patient with cancer in order to improve outcomes in this vulnerable subset. The purpose of this paper is to provide an introduction of frailty to oncologists including a review of the definition, frailty screening tools, its clinical relevance to older patients with cancer, and a brief guide to frailty management.

Phase III trials of anamorelin in patients with advanced non-small cell lung cancer (NSCLC) and cachexia (ROMANA 1 and 2).

9500 Background: Patients with advanced cancers frequently experience anorexia and cachexia, which is associated with decreased functional status and poor tolerance of chemotherapy. ROMANA 1 and 2 ...

Nutritional Risk Screening Predicts Tumor Response in Lung Cancer Patients

Background: Malnutrition in cancer patients may be associated with poor tolerance of chemotherapy and lower response rate after oncological treatment.Methods: Nutritional Risk Screening 2002 (NRS) adapted for oncological patients was used to assess the risk of undernutrition in a group of 188 patients with lung cancer. The risk was evaluated on a 6-point scale according to common signs of nutritional status (weight loss, body mass index, and dietary intake), tumor, and its treatment risk factors. A score of 3 or more (called “nutritional risk”) means significant risk of malnutrition and poor outcome.Results: Acceptable NRS score was found in 50.6%, and in 45.3% a score of 3–5 suggested the risk of malnutrition (nutritional risk). Unexpectedly, the toxicity of anticancer treatment was not significantly different between the subgroups (acceptable score vs nutritional risk). The rate of treatment response evaluated by imaging techniques was significantly higher in patients with an acceptable score compared to nutritional risk. Overall survival rate was significantly higher in cytostatically treated patients with lung cancer with an acceptable score.Conclusion: Nutritional risk screening is a significant predictor of tumor response in patients with lung cancer. Early detection of malnutrition is important to determine the prognosis of cancer patients as well as to plan effective supportive care.