Background Adjuvant chemotherapy is standard treatment for patients with resected colon cancer who are at high risk for recurrence, but the efficacy and toxicity of such treatment in patients more than 70 years of age are controversial Methods We performed a pooled analysis, based on the intention to treat, of individual patient data from seven phase 3 randomized trials (involving 3351 patients) in which the effects of postoperative fluorouracil plus leucovorin (five trials) or fluorouracil plus levamisole (two trials) were compared with the effects of surgery alone in patients with stage II or III colon cancer The patients were grouped into four age categories of equal size, and analyses were repeated with 10-year age ranges (≤50, 51 to 60, 61 to 70, and >70 years), with the same conclusions The toxic effects measured in all trials were nausea or vomiting, diarrhea, stomatitis, and leukopenia Patients in the fluorouracil-plus-leucovorin and fluorouracil-plus-levamisole groups were combined for the ef

https://www.nejm.org/doi/pdf/10.1056/NEJMoa010957

A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.

PURPOSE: To appraise the performance of Comprehensive Geriatric Assessment (CGA) in elderly cancer patients (≥ 65 years) and to evaluate whether it could add further information with respect to the...

Comprehensive Geriatric Assessment Adds Information to Eastern Cooperative Oncology Group Performance Status in Elderly Cancer Patients: An Italian Group for Geriatric Oncology Study

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68226-3.pdf

Male breast cancer

Purpose Older patients are significantly underrepresented in cancer clinical trials. A literature review was undertaken to identify the barriers that impede the accrual of this vulnerable population onto clinical trials and to determine what specific strategies are needed to improve the representation of older patients in research studies. Methods A systematic literature search was undertaken using several different strategies to identify relevant articles. Results Nine of 31 relevant papers from 159 citations were included. Age is a significant barrier to recruitment; only a quarter to one third of potentially eligible older patients are enrolled onto trials. Physicians' perceptions, protocol eligibility criteria with restrictions on comorbid conditions, and functional status to optimize treatment tolerability are the most important reasons resulting in the exclusion of older patients. Other barriers include the lack of social support and the need for extra time and resources to enroll these patients. Co...

Systematic Review of Barriers to the Recruitment of Older Patients With Cancer Onto Clinical Trials

Sixty percent of all cancer occurs in persons aged > or =65 years. This article provides an overview of aspects of the burden of cancer in the elderly, highlighting certain demographic and epidemiologic data. It served as a frame of reference for participants in the Oncology Geriatric Education Retreat, San Juan, Puerto Rico, February 21-26, 1997. Information comes from several major sources: U. S. Bureau of the Census; National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program; National Center for Health Statistics; National Institute on Aging (NIA)/NCI SEER Study on Comorbidity and Cancer in the Elderly; and NCI cancer prevalence estimates. Data on the aging population demonstrate an unprecedented expansion of the segment of the population aged > or =65 years. By 2030, 1 in 5 Americans will be aged > or =65 years. Because cancer incidence and mortality rates are highest in persons aged > or =65 years, expansion of this age group takes on great importance for medical professionals who provide treatment to older aged cancer patients. In addition, older aged cancer patients are likely to have preexisting conditions at diagnosis, creating a special clinical challenge. There is an urgent need to better understand the influence of aging on the early detection, diagnosis, and treatment of cancer. Clinicians who treat older persons (geriatricians, oncologists, and other health professionals) can benefit from the integration of the knowledge and approaches of each others' fields. The foundation for this multidisciplinary effort is linked with the education and training of future clinicians.

Cancer burden in the aged: an epidemiologic and demographic overview.

Cancer in the elderly: why so badly treated?

Introduction: Postoperative seroma formation is one of the most common and serious complications after breast cancer surgery. It frequently appears after simple or radical mastectomies. Data from our recently published pilot study on immunological processes in seroma formation, showed a specific immune response of CD3+/CD4+ T helper (Th) cells. A significant increase of Th2 and Th17 was observed in both, seroma fluid and peripheral blood of the same patients while no increase was found in healthy controls. 

Cytokine identification in seroma fluid after mastectomy in breast cancer patients – first results of SerMa pilot study subgroup


 Folates mediate one-carbon (C1) transfers, which are essential for cellular homeostasis and survival. C1 metabolism encompasses distinct cytosol (Cyto) and mitochondria (Mito) pathways connected by an interchange between serine, glycine and formate. Mito C1 metabolism provides cellular glycine and C1 units (as formate) for de novo synthesis of thymidylate and purine nucleotides in the Cyto. Polyglutamyl folates are the predominant folate forms in cells and are generally preferred for C1 transfers. Thus, folate polyglutamylation is essential for cellular homeostasis. Folate polyglutamylation is catalyzed by folypolyglutamate synthetase (FPGS), including Cyto (cFPGS) and Mito (mFPGS) isoforms. C1 metabolism is critical for tumor growth and thus offers a plethora of therapeutic targets for cancer. Of particular interest are Mito C1 inhibitors including “non-classical” pyrazolopyran compounds SHIN1 and SHIN2, and “classical” pyrrolo[3,2-d]pyrimidine antifolate compounds typified by AGF347, all targeting serine hydroxymethyltransferase 2 (SHMT2). Both SHIN1 and AGF347 effected in vitro anti-tumor efficacy, and SHIN2 and AGF347 showed in vivo efficacy toward tumor xenografts. We systematically explored the roles of cFPGS and mFPGS levels as critical determinants of C1 inhibitor target engagement and net Cyto versus Mito C1 flux, resulting in anti-tumor efficacy. We found that FPGS transcript levels significantly correlated with the effects of AGF347 toward a panel of human pancreatic cancer cell lines including MIA PaCa-2. We engineered MIA PaCa-2 cells with FPGS gene knockout to stably express inducible mFPGS or cFPGS form. FPGS in mFPGS-transfected cells (mFPGS#32) was expressed mainly in Mito over Cyto, whereas FPGS in cFPGS-transfected cells (cFPGS#3) was expressed exclusively in Cyto. Accumulation of radiolabeled folate and AGF347 increased with increasing FPGS in both Cyto and Mito for mFPGS#32, but only in Cyto for cFPGS#3. Metabolomics with [2,3,3-2H]serine in cFPGS#3 and mFPGS#32 established FPGS levels in Mito versus Cyto as important determinants of C1 fluxes. Increased FPGS levels in mFPGS#32 enhanced C1 flux in Mito far greater than in Cyto, and greater than for the increased FPGS in cFPGS#3. As a result, Cyto-targeted antifolates pemetrexed and AGF94 were only modestly impacted by increasing FPGS levels in both mFPGS#32 and cFPGS#3 (~3x). In contrast, increasing FPGS levels dramatically enhanced the inhibitory effects of Mito-targeted antifolates such as AGF347 in mFPGS#32 (~8-25x), and to a greater extent than in cFPGS#3 (~6-8x). Conversely, increasing FPGS levels substantially attenuated the cytotoxic effect of SHIN1 in mFPGS#32 (~19x). In summary, FPGS levels are an important determinant of C1 fluxes, particularly in Mito where they contribute to cytotoxic potencies of Mito-targeted C1 inhibitors at SHMT2.
 Citation Format: Carrie O’Connor, Jade Katinas, Mathew Schneider, Md. Junayed Nayeen, Xun Bao, Jing Li, Charles Dann, Aleem Gangjee, Larry H. Matherly, Zhanjun Hou. Mitochondrial and cytosolic folylpolyglutamate synthetase in one-carbon metabolism and anti-tumor efficacy of mitochondrial-targeted antifolates. [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 4902.

Abstract 4902: Mitochondrial and cytosolic folylpolyglutamate synthetase in one-carbon metabolism and anti-tumor efficacy of mitochondrial-targeted antifolates

M. Schneider

Papers

Cancer in the elderly: why so badly treated?

Cytokine identification in seroma fluid after mastectomy in breast cancer patients – first results of SerMa pilot study subgroup

Abstract 4902: Mitochondrial and cytosolic folylpolyglutamate synthetase in one-carbon metabolism and anti-tumor efficacy of mitochondrial-targeted antifolates