Nutritional Supplement Based on Myo-inositol-D-chiro-inositoln in Long-term Survivors of Lymphoma
Condition: Lymphoma, Hodgkin; Menstrual Irregularity; Fertility Disorders
MeSH terms: Lymphoma; Hodgkin Disease; Menstruation Disturbances
Study type: Observational

Summary: 
      The progressive improvement of lymphoma treatment has led to an important prolongation of
      patient survival and life expectancy. Therefore, the principal International scientific
      societies of oncology, recommend Long-term Survivors of Lymphoma to join fertility programs.
      Specifically, fertile age patients should be assisted by a multi-disciplinary team including
      specialists dedicated to fertility preservation in oncology, in order to support the
      completion of the reproductive project. In general population, the use of Inositol was
      spready considered an effectives choice to contrast ovarian dysfunction with consequently
      improvement of reproductive outcomes, so it may represent an adjuvant strategy for this
      purpose. Therefore, the investigators conducted a pilot study to evaluate the potentialities
      of this nutritional supplement with the aim to optimize the reproductive function in
      Long-term Survivors of Lymphoma. Despite the limited number of cases and short observational
      time, this pilot investigation could represent a potential cornerstone for further insights,
      discussions, and applications
    

Detailed description: 
      Anticancer regimens are usually used to treat patients with lymphoproliferative neoplasms
      with a consequently transitory or permanent damage to their reproductive functionalities.
      Rates of gonadotoxicity of each chemotherapy could be modulated according to dose intensity,
      number of courses, and type of agent or combination. Classical Hodgkin lymphoma (cHL) and
      Diffuse Large B-cell lymphoma (DLBCL), including primary mediastinal Large B-cell Lymphoma
      (PMBL) have usually higher incidence in the 2nd or 3rd decade of life and presents cure rates
      of more than 75% 3,4 These histotypes need a poli-chemotherapy with ABVD (adriamycin,
      bleomycin, vinblastine, dacarbazine), which involves the association of alkylating and
      non-alkylating agents.

      The autologous hemato-poietic stem cell transplant (ASCT) is needed in about the 10% of cHL
      and the 40% of DLBCL and has higher impact on fertility compared to ABVD 6. Therefore, both
      the chemotherapy (damaging the primordial follicle pool and then the ovarian reserve, OR) and
      the radiotherapy (exclusively secondary to under diaphragmatic and pelvic irradiation) could
      represent a risk of gonadotoxicity . In this scenario, data concerning fertility in cHL have
      been mainly evaluated by the German Hodgkin Study Group (GHSG) and the European Organization
      for Research and Treatment of Cancer (EORTC) through amenorrhea and anti-Mullerian hormone
      (AMH) evaluation. Indeed, amenorrhea has been used in numerous research to assess the
      gonadotoxicity of oncological treatment and reflect ovarian function . Furthermore, AMH could
      represent a gonadotoxicity marker, since it decreases during chemotherapy and could improve
      after the end of treatment, depending upon specific treatment schemes . Literature showed
      that after early-stage disease treatment (2 -4 cycle), more than 90% of patients reported a
      low gonadotoxic effect with a regular menstrual cycle after therapy (median recovery of 1
      year). For advanced stage diseases (treated with 6 courses of ABVD) the gonadotoxic effect
      vary on base of patient's aged. Indeed, the complete AMH restoring during the 3-years
      follow-up period, was detected in all women under 35 years, and only 37% of older ones .
      Moreover, in a Cochrane meta-analysis, gonadotropin-releasing hormone agonist (GnRHa)seems to
      be effective in shielding the ovaries during chemotherapy, in terms of treatment-related
      premature ovarian failure, ovulation and menstruation recovery.

      Beyond the ovarian suppression with GnRHa, there are several well-established procedures
      (oocyte cryopreservation, ovarian cortex cryopreservation for woman and sperm
      cryopreservation for men) that could prevent impact of these therapies in young patients.
      Therefore, considering the increased life expectation nowadays of Long-term Survivors of
      Lymphoma (patients in complete remission of the disease for more than 5 years) a fertility
      program with multi-disciplinary counselling is indicated. Particularly, in order to assess
      the damages upcoming after anticancer therapies on reproductive organs, international
      scientific societies such as the American Society for Reproductive Medicine (ASRM) (Ethics
      Committee of American Society for Reproductive Medicine, 2013), the American Society of
      Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO) as well as the
      International Society for Fertility Preservation (ISFP), strongly recommend a personalized
      and multidisciplinary counseling for each patient. In particular, the surveillance programs
      for the management of long-term lymphoma survivors should involve a team with
      onco-hematologists, radiotherapists, cardiologists, an endocrinologist, a psychologist,
      gynecologist, urologist and a nutritional biologist. The goal is to provide individualized
      therapeutic possibilities to restore endocrine function. Following these recommendations, an
      ambulatorial service dedicated to fertile patients with oncological disease was instituted in
      our Clinic of Gynecology Oncology, aiming to perform a careful assessment of the fertility
      state and support the reproductive project of those patients.

      In these women,the investigators primarily estimated AMH, Follicle stimulating hormone (FSH),
      Luteinizing hormones (LH), 17β-estradiol ,in association to antral follicles count (AFC)
      assessed by ultrasonography during the cycle follicular phase. During this clinical
      evaluation, several patients often reported menstrual irregularities due to anovulatory
      cycles (50%), dysmenorrhea (20%) and abnormal uterine bleeding (30%).

      Considering these elements, one of the potential therapeutic options could be considered the
      oral supplementation with Myo-Inositol and D-Chiro-Inositol (MIC). Indeed, MIC over the years
      has tiptoed to come alongside the classic pharmacological therapies, with robust compliance,
      safety, and effectiveness. MIC showed great potentiality to contrast ovarian dysfunction and
      optimize the reproductive function.

      Therefore, the investigators conducted a prospective observational controlled study, with the
      aim to assess the effects of oral supplementation with MIC on ovarian function parameters in
      Long-term Survivors of Lymphoma.
    

Intervention name(s): Myo-Inositol and D-Chiro-Inositol (MIC)
Intervention type(s): Drug
Intervention description(s): Both groups were followed up for 12 months, in T0 (during first evaluation), and T12 (after twelve months) with blood test for AMH (ng/ml).
Intervention MeSH terms: Inositol
Observational model: Case-Control
Time perspective: Other
Sampling method: Probability Sample
Study population: 
        From January 2020 to January 2021, 90 Long-term Survivors of Lymphoma female patients,
        average age 34 years (range 25-44) were considered eligible for the study. Each patient was
        informed about the procedures and signed informed consent before the surgery to allow data
        collection for research purposes.