Table 2.

Recommendations on the theme ‘Therapy’ with relevance assessment

Recommendations from the selected studies on the topic ‘Therapy’ with relevance assessment.
Statement	Assessment
The increased severity of both symptomatic and haematological adverse events in women treated with different therapeutic modalities confirms that there is a gender difference. This may be due to differences in the mode of reporting adverse events, pharmacogenomics, total dose received, and/or adherence to therapy. In particular, large gender differences have been observed in patients treated with immunotherapy, indicating that studying adverse events due to such therapies is a priority.5	9
5-FU is a clear example of the importance of gender pharmacology. Further prospective studies to determine sex-specific differences in clinical trials of colorectal cancer treatment using 5-FU as a therapeutic agent should be conducted to support appropriate 5-FU based-chemotherapy based on sex as a crucial factor and to enhance the effectiveness of chemotherapy and minimise adverse drug reactions to anticancer drugs.12,22, 23, 24, 25, 26	9
Future research should ensure greater inclusion of women in studies and focus on improving the efficacy of immunotherapies in women, perhaps by exploring different immunotherapy approaches in men and women.27	9
As women are underrepresented in chemotherapy trials cited by national guidelines, especially in head and neck cancers, and are therefore less likely than men to receive definitive chemoradiation therapy compared with definitive radiotherapy, further investigation as well as re-evaluation of eligibility criteria and enrolment strategies should be carried out to improve relevance of clinical trials in women with these cancers.28	9
Particularly in the field of immunotherapy, clinical trials should aim to explicate the role of factors such as race, histologic type tumour stage, and other factors to explicate the effect of gender on cancer treatment outcomes.29,30	8
As gender, age, and clinicopathological parameters have been correlated with chemoradiotherapy-associated acute toxicity and survival in rectal cancer, pretreatment baseline parameters that allow the identification of subgroups of patients at higher risk of severe acute organ toxicity should be defined to improve the clinical management of these patients and apply optimised standards of supportive care.31	8
High-performance liquid chromatography analysis of urinary levels of uracil and dihydrouracil from patients undergoing chemotherapy treatment should be further investigated because it appears to be promising for clinical use to predict and prevent the occurrence of treatment-related toxicities.32	7
Clinical trials that aim to investigate the relationship between radiotherapy and gender in terms of outcomes and adverse effects should provide specific information about treatment modality that might affect the analysis.33	7
Accrual and design of immunotherapy studies could be conducted separately for men and women, with appropriate sample size planning for both.4,29	7
Sex appears to be an independent prognostic factor in Chinese patients with ESCC undergoing definitive radiotherapy, with better survival in women than men. Sex would affect the radiosensitivity of patients with ESCC exposed to radiotherapy and the relationship between sex and radiosensitivity in ESCC should be investigated, for example, by focusing future efforts on the study of the relationship between androgen levels and the prognosis of patients with ESCC exposed to radiotherapy. From this starting point it would be useful to consider future clinical research comparing combined chemoradiotherapy and anti-androgen treatment with chemoradiotherapy alone in the ESCC.34	3

Recommendations promoted by the panel of experts on the theme ‘Therapy’ with relevance assessment.
Statement	Assessment
Women with metastatic melanoma and NSCLC may have a higher risk of immuno-related adverse events than men when treated with anti-PD-1 therapy.35	9
The increased severity of both symptomatic and haematological adverse events in women treated with different therapeutic modalities confirms that there is a gender difference. This may be due to differences in the mode of reporting adverse events, pharmacogenomics, total dose received, and/or adherence to therapy. In particular, large gender differences have been observed in patients treated with immunotherapy, indicating that studying adverse events due to such therapies is a priority.5	9
To date there is increasing scientific evidence of gender/sex differences in neuroendocrine neoplasms, especially pancreatic neuroendocrine neoplasms, both in incidence (higher in men) and in clinical behaviour (worse prognosis in males and a greater risk of recurrence after curative surgery). However, there is a lack of data on possible differences in response to treatments, which is therefore suggested to be investigated through gender-oriented clinical studies, including an equal representation of the sexes and a gender-disaggregated statistical analysis.36	9
Sex and gender have a role in inflammation, immune response to cancer, and carcinogenesis, so understanding these aspects is necessary to increase responses and reduce adverse events from immunotherapy. This gender perspective needs to be taken into account by clinicians and researchers to achieve personalised therapeutic strategies.37	9
Endocrine toxicities, frequent in patients treated with immunotherapy, may present gender differences in incidence and type: the female sex predicts the risk of developing thyroid toxicity, while males are more susceptible to pituitary toxicity. However, in the therapeutic management of adverse events, no sex and gender differences are known, so they should be investigated.38,39	9
Although women with melanoma generally have a better survival rate than men, combined immunotherapy appears to be disadvantageous for women compared with men; in fact, higher mortality rates have been reported. Through future clinical trials it is essential to investigate whether mortality depends on lower therapeutic efficacy or increased toxicity in women.40	8
Women with NSCLC treated surgically typically have a better long-term outcome than men, without significant differences in the severity of the disease. Better survival and lower frequency of post-operative complications among women should be taken into account in the therapeutic decision making and surgical treatment proposal, especially in uncertain cases.41	8
Immunotherapy in patients with NSCLC is more effective in males than in females. Gender should be considered in clinical practice in the choice of immunotherapy.42	8
Women with melanoma benefit more from adjuvant immunotherapy with monoclonal antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) than men, for greater activation of the type 1 immune response both in the circulatory and in the tumour microenvironment. In an adjuvant setting, this different response may suggest a therapeutic choice that is based on gender and that should be evaluated through dedicated clinical trials.43	7

5-FU, 5-fluorouracil; ESCC, squamous cell oesophageal carcinoma; NSCLC, non-small-cell lung cancer; PD-1, programmed cell death protein 1.