Impact of diabetes mellitus in cancer

Literature search strategy

A comprehensive literature search was conducted using PubMed, Google Scholar, and the Cochrane Library to identify published studies on the association between cancer and diabetes. Medical Subject Headings (MeSH) terms were used to guide the search, including “diabetes,” “cancer,” “toxicities,” “infections,” “treatment compliance,” “cancer mortality,” “survival,” “local control,” “treatment delay,” “quality of life (QoL),” “treatment outcomes,” and “cancer-directed therapy.” Articles were selected based on abstracts, and relevant references were further explored to identify additional studies related to the topic. Additional literature searches were conducted as new aspects of diabetes impact were identified, such as the management of diabetes during cancer therapy and its associated challenges. All searches were conducted between November 2024 and January 2025.

Study selection

We applied the following inclusion criteria to each study in consideration for the narrative review: randomized controlled trials (RCT), subset or pooled analysis of RCT, systematic reviews (SR) and/or meta-analyses (MA), population databases (PDB) such as National Cancer Databases (NCDB) and cancer registries, or retrospective cohort studies addressing the relationship between cancer and diabetes. All titles and abstracts were screened by the first author. Full texts of eligible articles were assessed for eligibility against the inclusion criteria.

Acute toxicities and treatment compliance to CDT

CDT in diabetic patients can potentially lead to increased acute toxicities which significantly impacts treatment compliance, outcomes and overall prognosis ( Table I^{14,16-20,22,23,27}). In head and neck cancer patients undergoing chemoradiation, patients with diabetes mellitus experienced higher rates of infection, hematologic toxicity, mucositis, weight loss and treatment related mortality patients.¹⁶ Diabetic patients particularly those on insulin therapy had a higher rate of hospital admissions compared to non-diabetics. Nearly 75% of diabetic patients required enteral feeding during the course of therapy due to infections and poor glycaemic control.¹⁴ Increased hospitalization and infection rates were observed in diabetics receiving chemotherapy, often resulting in treatment delays.¹⁷ Postoperative complications, including infections, cardiac events and renal failure rates were notably higher in diabetics, negatively affecting overall surgical outcomes.¹⁸ Tomasz et al¹⁹ found an increased incidence of hospital admissions for chemotherapy related toxicity, infections in carcinoma breast patients on adjuvant chemotherapy.¹⁹ Systematic review and meta-analysis by Caputo et al²⁰ found that diabetes mellitus in patients undergoing major HNC surgery is associated increased perioperative surgical complications.

Kuo et al¹⁶, in a retrospective analysis of head and neck cancer patients receiving chemoradiation, found that diabetic patients received significantly lower cisplatin doses compared to non-diabetics (P=0.014). A lower cumulative dose has been associated with decreased survival, as shown in the analysis by Bhattacharjee et al²¹. Diabetic cancer patients face higher surgical risks, with a ∼50% increased likelihood of mortality post-surgery.²² In breast cancer (BC) patients, diabetes is linked to a lower likelihood of undergoing surgery (adjusted OR 1.16, 95% CI 1.05–1.27) and a decreased chance of breast reconstruction after mastectomy in stage I-III BC.²³ Among HNC patients undergoing surgery, diabetes is associated with higher rates of flap failure²⁰ and prolonged hospital stays due to postoperative complications.¹⁸ This delay can extend the overall treatment time, which is critical in locally advanced HNC, where adjuvant treatment is required. An extension beyond 11 wk has been linked to reduced five-year locoregional control.²⁴

Completing radiation therapy without interruptions is crucial for achieving optimal local control. Treatment breaks exceeding two days have been associated with a fourfold increased risk of poorer local control and disease-free survival.²⁵ Curative radiotherapy for head and neck cancer often results in severe mucositis, dysphagia, odynophagia, and significant weight loss, with nearly 75% of patients requiring short-term enteral feeding.²⁶ In diabetic patients, grade 3-4 toxicities are also more frequent than in non-diabetics, increasing the risk of treatment-related side effects. These complications can compromise treatment completion and negatively impact overall outcomes.¹⁴ Compared to non-diabetic women, diabetic women are less likely to initiate radiation therapy within 90 days after definitive surgery for carcinoma breast which affects treatment compliance; however, there is no significant difference in the utilization or completion of radiotherapy.²⁷ The delay in initiation may be attributed to delayed healing and the management of diabetes related complications. Patients with diabetes mellitus undergoing surgery for gastric carcinoma have shown an increased susceptibility to postoperative complications, including anastomotic leakage and gastrointestinal dysfunction. These complications not only prolong recovery time but may also delay or impact the initiation and compliance with adjuvant therapies such as radiation therapy and chemotherapy.²⁸

Cancer survival and mortality

Studies have shown that diabetes is associated with a 10% increase in cancer-related mortality,²⁹ highlighting its significant impact on survival outcomes ( Table II^{14,30-36,38-41,43,46-48}). A meta-analysis by Barone et al³⁰ involving 23 studies found that diabetes was linked to an increased mortality across all cancer types. Subgroup analyses revealed a higher mortality risk in endometrial, breast, and colorectal cancers.³⁰ In carcinoma cervix, studies have indicated that diabetes is independently associated with poor OS and recurrence-free survival (RFS).^31,32 Even in early-stage cervical cancer patients who underwent radical hysterectomy with pelvic lymphadenectomy, diabetes significantly impacted long-term RFS.³³ Similarly, a meta-analysis by McVeicker³⁴ on endometrial cancer patients concluded that diabetes is associated with poorer cancer-specific survival and OS. Comparable findings were observed in colorectal cancer, where a meta-analysis demonstrated significantly shorter OS in diabetic patients.³⁵ Multivariate analysis by Taussky et al³⁶ revealed that prostate cancer patients with diabetes mellitus had worse OS compared to non-diabetic patients. Diabetes was also linked to a significantly reduced 5-year OS (78% vs. 61%; P=0.004) in patients with squamous cell carcinoma (SCC).³⁷ In a retrospective analysis by Alshihere et al³⁸ on head and neck squamous cell carcinoma (HNSCC) patients, non-diabetics demonstrated a notably higher median OS, with a survival benefit of approximately two years compared to diabetic patients.³⁸ Similar trends of worsened survival were reported in a meta-analysis by Xu et al³⁹ on oral and oropharyngeal cancer patients. Notably, diabetes had a significant impact on survival even in early-stage cancers (stage I and II).⁴⁰

A study by Luo et al⁴¹ examining the impact of pre-existing diabetes on lung cancer prognosis in women found that diabetes increased overall mortality risk. According to a retrospective analysis by Worrell et al⁴², diabetic patients were less likely to achieve a pathological complete response after neoadjuvant therapy for esophageal carcinoma. However, diabetes was not identified as an independent factor influencing pathological complete response. But significant reductions in OS were also observed in gastric and esophageal (GE) cancers with diabetes.⁴³ These findings align with the study by Yancik et al⁴⁴ on breast cancer patients, which demonstrated that diabetes was associated with an increased risk of death. Diabetes mellitusis linked to a 25–41% increased risk of cancer-related mortality.² A prospective U.S. cohort study found that cancer mortality was 7% higher in men and 11% higher in women with diabetes mellitus.⁴⁵ Among head and neck cancer patients undergoing chemoradiation, diabetic individuals had a higher mortality rate compared to non-diabetics (10.2% vs. 3.5%; P=0.051).¹⁴ In pancreatic cancer, diabetes mellitus emerged as an independent predictor of poor post-resection survival, with median survival significantly lower in diabetics (18 vs. 34 months).⁴⁶ The negative impact of diabetes mellitus on survival was particularly evident in patients with resectable disease.⁴⁷ A Canadian analysis by Sheppard et al⁴⁸ on breast cancer patients further reinforced these findings. The study demonstrated that pre-existing diabetes significantly increased the risk of death, with a hazard ratio of 1.87 (95% CI, 1.12–3.13) after adjusting for age, diagnosis period, body mass index, other comorbidities, and cancer stage. Diabetic patients were less likely to achieve pathological complete response after neoadjuvant therapy in oesophageal carcinoma but not an independent factor associated with pathological complete response as per the retrospective analysis by Worrell et al.⁴²

Late toxicity/quality of life

Studies have investigated the impact of diabetes mellitus on late radiation-induced toxicities in various organs, including the lungs and rectum ( Table III^49-53,55,56). In prostate cancer patients undergoing androgen deprivation therapy and radiation therapy, those with diabetes mellitus exhibited a higher incidence of late genitourinary toxicity⁴⁹ and significant deceleration of resolution of radiation induced proctitis.⁵⁰ Additionally, there was a trend toward an increased incidence late grade 3/4 gastrointestinal toxicity and an earlier onset of genitourinary complications.⁵¹ Kong et al⁵² reported a 44% incidence of grade 3 radiation pneumonitis in lung cancer patients receiving external beam radiation therapy, with poor glycaemic control (HbA1c > 6.15% or fasting glucose > 121 mg/dL) associated with increased risks.

Diabetes mellitus significantly reduced physical function, impacting the quality of life (QoL) in cancer patients undergoing therapy.⁵³ It has also been identified as an independent predictor of delayed recovery. Furthermore, a cancer diagnosis and the side effects of cancer-directed therapy can negatively affect diabetic self-care, particularly affecting the ability to eat and drink, engage in physical exercise and monitoring blood sugar levels.⁵⁴ Evidence suggests that adherence to hypoglycaemic medications among patients with diabetes mellitus also decreases after a cancer diagnosis.⁵⁵ In a retrospective analysis by Barrio et al⁵⁶ on breast cancer patients receiving weekly paclitaxel, diabetic individuals experienced more severe and prolonged peripheral neuropathy. Even after two years, 68.7% of patients reported a significant impact on their QoL.

Impact of cancer and cancer-directed therapy(CDT) on diabetes mellitus

Several targeted and immunotherapy drugs, unlike chemotherapy agents, can cause hyperglycemia, which limits their use in cancer management.⁵⁷ Immune checkpoint inhibitors (ICI) are known, albeit rarely, to cause new-onset diabetes, often through irreversible β-cell impairment, and this can be potentially life-threatening.⁵⁸ Corticosteroids, commonly used to prevent chemotherapy-induced nausea and vomiting, can also unmask underlying diabetes or worsen pre-existing diabetes by increasing glucose production, reducing insulin sensitivity, and inhibiting insulin secretion by pancreatic beta cells.⁵⁹ CDT can also increase the risk of developing a new diagnosis of diabetes. In an analysis by Kim et al⁶⁰, nearly 11% of patients without a prior history of diabetes who underwent chemotherapy were later diagnosed with the condition. Over 70% of these patients had received short-course steroids.⁶⁰ Furthermore, glucocorticoids, the primary treatment for radiation pneumonitis, can negatively impact blood glucose control.⁶¹ The risk of developing new-onset diabetes mellitus in patients treated with glucocorticoids has an odds ratio ranging from 1.5 to 2.5, and diabetic patients often require adjustments in insulin dosage.⁵⁹ Additionally, a study by Denise et al⁵⁴ highlighted three major challenges faced by diabetic patients undergoing chemotherapy after at least eight weeks of treatment: difficulties with self-care, general health issues, and balancing diabetes management with cancer treatment.

Management of diabetes mellitus in cancer patients

Diabetic patients with cancer require close monitoring of blood glucose levels throughout cancer treatment, as maintaining optimal glucose control can improve overall health outcomes. Anticipating steroid-induced hyperglycaemia and using insulin prophylactically is the most effective treatment strategy.⁵⁹ Patients on oral hypoglycaemic drugs may need a short course of insulin therapy, while those already on insulin may require dose adjustments during treatment. Treatment-related complications, particularly in advanced cancer, can reduce oral intake, increasing the risk of hypoglycaemia from insulin and oral hypoglycaemic agents. In such cases, less aggressive glucose-lowering strategies may be considered. Diabetes management includes dietary modifications, exercise, and the use of oral hypoglycaemic drugs with or without insulin.⁵⁷ Although CDT and steroid use predominantly cause hyperglycaemia, the risk of hypoglycaemia should not be overlooked. Poor oral intake and nausea/vomiting caused by CDT increase the likelihood of hypoglycaemia. To mitigate these risks, maintaining blood glucose levels within the range of 108-225 mg/dL is recommended.⁶²

Managing diabetes in cancer patients presents a significant challenge for both oncologists and endocrinologists. All patients should undergo baseline blood glucose or HbA1c screening before starting cancer therapy. Effective communication and collaboration among healthcare providers and patients are essential to optimizing care and improving treatment outcomes.⁶³ For ICI-induced type 1 diabetes mellitus, lifelong insulin therapy remains the mainstay of management.⁶⁴ In patients with advanced or end-stage cancer and poor performance status, diabetes management guidelines recommend relaxing glycaemic targets, with the primary goal being avoidance of symptomatic hyperglycaemia and hypoglycaemia rather than strict control.⁶⁵

Impact of oral hypoglycaemic agents (OHA) on diabetes Mellitus

Oral hypoglycaemic agents (OHA) are widely used in diabetes management,⁶⁶ either alone or in combination with insulin.⁶⁷ Antidiabetic medications may influence cancer risk both directly, by affecting tumour cell metabolism, and indirectly, by altering underlying risk factors of malignancy.⁶⁸ Among OHAs, metformin has been most extensively studied, with several reports suggesting potential anticancer properties and an association with reduced risk of colorectal and pancreatic cancers.^69,70 No significant increase in cancer risk has been observed with sulfonylureas.⁷¹ In contrast, insulin therapy has raised concerns, with early observational studies and subsequent meta-analyses indicating a possible association with increased cancer incidence,⁷² particularly colorectal cancer, in a dose-dependent manner.⁷³ These findings highlight the complex and evolving relationship between antidiabetic drugs and cancer, underscoring the need for further well-designed studies to clarify causality.

The strength of this review lies in its broad coverage of multiple clinically relevant outcomes, including toxicity, quality of life, compliance, survival, and the interplay between diabetes and cancer. By consolidating evidence from numerous studies, it provides a comprehensive overview that enables readers to access a large body of data in a simplified manner. However, certain limitations need to be acknowledged. First, this review was not conducted as a systematic review with a predefined methodology and statistical support, which restricts the rigor of evidence synthesis. Second, the availability of data across different cancers and treatment settings is not uniform, and published studies specifically addressing the interaction between diabetes and cancer remain limited. Another limitation is that potential confounders such as age, gender, and coexisting medical conditions may not have been consistently accounted for in the available studies, which could influence the reported association between diabetes and cancer outcomes. These gaps highlight the need for further focused and standardized research in this area.

Diabetes is often overlooked in cancer patients undergoing any form of CDT. The existing evidence on its impact is limited, with most studies being retrospective cohort analyses. Through our extensive literature review, we found that diabetic patients receiving CDT experience increased acute and late toxicities. Diabetes also negatively affects compliance with CDT, compromises local control, and increases the risk of recurrence, ultimately leading to reduced overall survival. These factors collectively impact the quality of life of cancer patients, highlighting the need for better management and tailored interventions for this population.