Christine M. Segeren1
(1)
Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands
Christine M. Segeren
Email: cmsegeren@gmail.com
22.1 Introduction
Hematopoietic neoplasms represent a heterogeneous group of malignant hematopoietic disorders such as leukemia, myelodysplastic syndrome, myeloproliferative neoplasm, malignant lymphoma, and plasma cell disease. In younger patients, malignant lymphoma has the highest incidence.
The outcome of hematological malignancies has improved tremendously over the last half century, with more patients cured and alive at the long term [1]. The treatment of hematological malignancies with chemotherapy, radiation therapy, and/or high-dose therapy with hematopoietic stem cell transplantation (HSCT) carries the risk of long-term toxicities such as cardiomyopathy, secondary malignancies, and infertility. Changes in the dose of radiation therapy, the introduction of nonmitogenic chemotherapy, and stratified therapy for high-risk patients have fortunately altered these risks [1].
Although in hematological malignancies there is more focus on the psychological side effects that take place during the treatment process, little attention has been paid to the impact on the psychological morbidity related to infertility and decreased sexual function [1]. It is not always easy to determine which problems are unique to the kind of malignant disease and its treatment and which is related to survivorship of a malignant disease in general [2]. Blood and lymph node cancer usually do not affect the sexual organs, but the effect of its treatment can significantly alter sexual functioning [3].
Some aspects of survivor’s adaptation in young patients are related to the specific illness, its treatment, and the demands they have placed on them, as discussed in this chapter. A biopsychosocial approach is warranted, as psychological, relational, cultural, and physiological factors have impact on patient’s sexuality.
22.2 General Aspects of Diagnosis and Treatment
Physical changes due to cancer may lead to alteration in sexual functioning. Patients often present with fatigue and fever, which can diminish sexual desire. Weight loss and less appetite are common, and patients may feel undesirable and depressed [3]. Changes in blood cell counts can directly reduce sexual desire and activity, but also indirectly as a result of fear for infections or bleeding tendency. Not only therapy for the disease itself, but also treatment for symptoms or side effects such as antidepressants may influence sexual functioning.
Infertility due to the gonadotoxic effects can be one of the important long-term consequences of combination chemotherapy and radiotherapy, and is a major concern in young male and female patients with Hodgkin’s lymphoma, acute leukemia, and after hematopoietic stem cell transplantation [4, 5].
Psychological factors can also have a major impact on sexuality, such as changes in body image, decreased self-esteem, depression, and loss of control over bodily functions and anxiety about the future and recurrence of the disease after treatment. The sexual relationship with the partner may change due to uncertainty, communication problems, and shifting role responsibilities [6]. All these factors may have effect on sexuality, from desire to overall sexual functioning.
22.3 Malignant Lymphoma
Only few data were published on sexual function in patients with malignant lymphoma. Most data address sexuality in long-term survivors of Hodgkin’s lymphoma. In contrast, little is known about sexuality in patients with non-Hodgkin’s lymphoma. In addition, little is known on the sexual function before, during, and after therapy [4].
Hodgkin’s lymphoma (HL) is the most common hematological malignant disease in younger patients (15–24 years). The survival rates of patients with Hodgkin’s lymphoma have improved dramatically with the combination of chemotherapy, and involved field radiotherapy with a cure rate of more than 95 % in patients with early stage HD and 75 % for those with advanced disease [7].
In the earlier days, chemotherapy regimens like MOPP, or MOPP/ABVD were highly effective. These regimens contained alkylating agents such as procarbazine and cyclophosphamide, leading to loss of fertility due to premature ovarian failure (POF) and primary hypogonadism, which can alter sexual function and decrease sexual desire. Historically, extended field radiotherapy and subtotal nodal irradiation contributed to these high survival rates, but at the cost of acute and long-term complications like heart disease and the risk of lung and breast cancer. This led to the introduction of combined modality treatment with nonalkylating agents containing chemotherapy regimens like ABVD and lower doses and smaller target volumes of radiotherapy. Treatment with ABVD has been shown to be more effective than MOPP and has less impact on fertility. In contrast to ABVD, BEACOPP used for the treatment of high-risk advanced HD contains high doses of alkylating agents. This regimen is associated with acute toxicity such as myelosuppression and infections, and results in lower sexual functioning compared with ABVD after treatment, which might be related to the gonadotoxicity of this type of therapy [4, 7].
Estimated prevalence of long-term sexual problems after treatment has ranged from 12 to 62.5 %. Also, during treatment, sexual functioning may be impaired. Some studies suggest that sexual problems decrease after treatment, but others indicate that these may last longer. Conclusions of these studies are difficult to draw because of a small sample size, focus on poor prognosis of HL patients, and/or lack of control groups [7].
Behringer et al. recently published a longitudinal analysis of 3208 patients treated for HL. They had information about sexual functioning before starting treatment. Half of the patients never suffered from severe impairment of sexual functioning. Early favorable patients were more often symptom-free than the other patient groups. Fatigue had a negative impact on sexual functioning. Early unfavorable and advanced stage patients reported lower sexual functioning before treatment. In early favorable patients, this returned to normal. Patients with advanced disease reported lower sexual functioning than those with early-stage disease, before and after treatment. Improvement after therapy was especially seen in patients with poor baseline scores, but not in patients older than 50 years. Patients with advanced disease and patients older than 50 years had increased risk for long-term impairment of sexual functioning. Sexual functioning during follow-up was significantly and strongly negatively associated with lower previous sexual functioning, health-related quality of life, higher age, advanced stage, and to a lesser degree with female gender and type of chemotherapy, but not with radiotherapy intensity. Sexual functioning at 12–18 months was highly predictive for scores up to 27 months. Between 70 and 80 % of patients were without persisting impairment of sexual functioning [4].
Kiserud et al. studied in a cross-sectional study 246 male lymphoma patients. Low testosterone and/or elevated LH after treatment were associated with reduced sexual function as compared with male lymphoma survivors with normal gonadal hormones. Low testosterone may reduce physical health and impair sexual functioning as a result of gonadal dysfunction. Systemic illness may also result in reduced testosterone levels. It is unclear if the abnormal hormone levels directly cause reduced sexual functioning or whether a mediating factor is involved, such as age, comorbidity, emotional distress, and physical health. A higher prevalence of erectile and ejaculation dysfunction and poorer sexual satisfaction was found in all survivors, irrespective of testosterone levels [8].
22.4 Leukemia
Most patients with adult acute leukemia (AL) are treated with intensive chemotherapy. Treatment for AL is given on an in-patient basis in contrary to the treatment of HL, which may have an impact on intimacy and sexuality, but also on the availability of support. Compared to Hodgkin’s disease survivors, AL survivors reported less fatigue, a better sexual relationship with their spouse, higher global sexual satisfaction, better sexual functioning, and lower distress in general, while problems with erection, pain during intercourse, the feeling of sexual unattractiveness, and less acceptance by their partner were remarkably similar. Especially, male Hodgkin’s survivors had more psychological distress than AL survivors [2]. Most young patients with AL undergo HSCT after induction with intensive chemotherapy (see further).
22.5 Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) is mainly used for the treatment of leukemia and malignant lymphoma, and sometimes also for other nonmalignant hematological disorders. Patients are often relatively young with little comorbidity. HSCT is a very intensive therapy from which it may take a year or longer time to recover, especially in allogeneic stem cell transplantation (see further). It has a major impact on all aspects of patient lives, as well as on their intimate relations and families.
Sexual dysfunction is common after HSCT. Most studies are cross-sectional studies; only few studies have compared sexual function with case-matched controls. Although some recovery may occur, sexual dysfunction remains a major problem. Both sexes decline in sexual activity rates and function. Activity rates improve for men by 1 year (74 %) and in women by 2 years (55 %). After 5 years, 80 % of female survivors report sexual problems, such as vaginal dryness due to ovarian failure resulting in pain and bleeding, problems with desire, and orgasm. Forty-six percent of male survivors report problems such as obtaining and maintaining an erection and desire [9].
22.6 Conditioning Regimen
Prior to transplantation, high-dose therapy is given to clear the bone marrow and make it possible to receive stem cells, but also to further reduce the tumor burden. Most conditioning regimens include chemotherapy, often consisting of high-dose alkylating agents such as cyclophosphamide and/or busulfan with or without total body irradiation (TBI), which reduce patient’s immune defense. After conditioning, stem cells from the patient can be infused (autologous) or can be obtained from a related or unrelated donor (allogeneic) [5].
High-dose chemotherapy, especially alkylating agents, and also TBI can lead to primary hypogonadism. In men, it causes decreased desire, erectile dysfunction (ED), and decreased semen volume as a result of low testosterone levels. Cavernosal arterial insufficiency induced by TBI can also attribute to ED. Although in most males testosterone levels return to normal 1 year post-transplant, patients still can suffer from loss of desire and ED due to testicular Leydig cell insufficiency. Testosterone replacement may be considered [10].
In women, it leads to premature ovarian failure (POF) with low estrogen levels and low total testosterone and androstenedione levels. POF results in loss of sexual desire, less sexual arousal, vaginal dryness, and dyspareunia due to reduced lubrication and vaginal tissue atrophy [11]. POF is induced in almost all women. Even if ovarian function returns, a postmenopausal status will eventually set in earlier than expected [5]. Hormone replacement therapy may be started to alleviate symptoms due to low estrogen levels.
The conditioning regimen also damages the hypothalamic–pituitary–gonadal axis. FSH and LH are elevated in almost all females. LH is normal in most males [5, 9].
Most studies published are based on myeloablative conditioning regimens. Recently, the reduced intensity conditioning regimen is introduced which makes transplantation at higher age possible. Studies on the impact on sexuality of this kind of conditioning in malignant hematological diseases are lacking.
22.7 Graft-Versus-Host Disease
After allogeneic transplantation, patients are at risk for acute and chronic graft-versus-host disease (cGVHD), as the donor cells see the malignant cells (graft-versus-leukemia effect) and also the patient’s body as foreign and fall upon it [5]. cGVHD can affect every organ system and can last for years. cGVHD can severely affect patient’s quality of life [12].
In women, genital cGVHD is reported in 2–52 % [13]. Genital cGHVD occurs late (on average, at 10 months after transplantation). It does not always correlate with the grade of systemic GHVD. It can present without any other sign of cGVHD. Symptoms include vaginal dryness, irritation and inflammation, dyspareunia, bleeding, scarring, and fibrosis; sometimes, complete obstruction and strictures can be present [5]. For prevention, genital hygiene with avoidance of irritants can be advised. First-line treatment consists of topical therapy with high-potency steroids or immunosuppressive agents. Hormone replacement therapy should be considered. Second-line treatment contains systemic immunosuppressive agents such as steroids or cyclosporine. In case of fibrosis or stenosis, dilator therapy or even surgery is recommended. Referral to a gynaecologist with expertise in these matters is mandatory [5, 12].
Mueller et al. found genital cGVHD in 12 % of 155 male recipients. It can cause inflammation of the glans penis and foreskin, penile curvature, pain, and sensitivity in the penile region, causing erectile dysfunction [14]. Topical steroids are the treatment of choice.
The long-term treatment of chronic GVHD with high-dose corticosteroids has an impact on sexual functioning. It changes body image, and decreases sexual desire and feelings of attractiveness; sexual responsiveness changes and can cause feelings of depression [5].
22.8 Recommendations
Routine assessment of sexual health before treatment is recommended for all patients. It is important to identify patients at high risk for sexual problems early in the course of their treatment, to look for possibilities for early interventions, and understand the long-term outcome of these patients. A discussion about anticipated sexuality issues and fertility should be started before treatment. The rate of treatment-related induced infertility and hypogonadism, and potential changes in sexuality such as desire, and the impact on quality of life should be addressed and should continue during treatment and the follow-up period [4]. Early information makes it easier to explore and discuss concerns and anxiety during and after treatment. The relation between depression and impaired sexual functioning highlights the importance of addressing the psychological well-being of patients. Counseling focusing on communication, fears, and barriers can improve intimacy and sexual activity after treatment [5]. Education, the possibility of interventions, treatment recommendations, and appropriate referral to a psychologist or sexologist can help patients and their partners to adapt to the changes they experience [6].
Given the limited studies about sexuality and hematological malignancies and the introduction of more targeted therapies with, e.g., imatinib, further research is required.
Conclusions
As more patients survive after treatment for hematological malignancies, there is more focus on the long-term side effects and psychological impact of disease and treatment. The presence of sexual problems in survivors remains underestimated, but needs appropriate medical and psychological evaluation and sometimes proactive prevention measures.
References
1.
Greaves P, Sarker SJ, Chowdhury K, et al. Fertility and sexual function in long-term survivors of haematological malignancy: using patient-reported outcome measures to assess a neglected area of need in the late effects clinic. Br J Haematol. 2014;164:526–35.CrossRefPubMed
2.
Kornblith AB, Herndon 2nd JE, Zuckerman E, et al. Comparison of psychosocial adaptation of advanced stage Hodgkin’s disease and acute leukemia survivors. Cancer and Leukemia Group B. Ann Oncol. 1998;9:297–306.CrossRefPubMed
3.
Katz A. The sound of silence: sexuality information for cancer patients. J Clin Oncol. 2005;23:238–41.CrossRefPubMed
4.
Behringer K, Muller H, Gorgen H, et al. Sexual quality of life in Hodgkin Lymphoma: a longitudinal analysis by the German Hodgkin Study Group. Br J Cancer. 2013;108:49–57.PubMedPubMedCentral
5.
Yi JC, Syrjala KL. Sexuality after hematopoietic stem cell transplantation. Cancer J. 2009;15:57–64.CrossRefPubMedPubMedCentral
6.
Tierney KD, Facione N, Padilla G, et al. Altered sexual health and quality of life in women prior to hematopoietic cell transplantation. Eur J Oncol Nurs. 2007;11:298–308.CrossRefPubMed
7.
Recklitis CJ, Sanchez Varela V, Ng A, et al. Sexual functioning in long-term survivors of Hodgkin’s lymphoma. Psychooncology. 2010;19:1229–33.CrossRefPubMed
8.
Kiserud CE, Fossa A, Bjoro T, et al. Gonadal function in male patients after treatment for malignant lymphomas, with emphasis on chemotherapy. Br J Cancer. 2009;100:455–63.CrossRefPubMedPubMedCentral
9.
Syrjala KL, Kurland BF, Abrams JR, Sanders JE, Heiman JR. Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years. Blood. 2008;111:989–96.CrossRefPubMedPubMedCentral
10.
Chatterjee R, Kottaridis PD, McGarrigle HH, et al. Management of erectile dysfunction by combination therapy with testosterone and sildenafil in recipients of high-dose therapy for haematological malignancies. Bone Marrow Transplant. 2002;29:607–10.CrossRefPubMed
11.
van der Stege JG, Groen H, van Zadelhoff SJ, et al. Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause. 2008;15:23–31.CrossRefPubMed
12.
Dignan FL, Scarisbrick JJ, Cornish J, et al. Organ-specific management and supportive care in chronic graft-versus-host disease. Br J Haematol. 2012;158:62–78.CrossRefPubMed
13.
Smith Knutsson E, Bjork Y, Broman AK, et al. Genital chronic graft-versus-host disease in females: a cross-sectional study. Biol Blood Marrow Transplant. 2014;20:806–11.CrossRefPubMed
14.
Mueller SM, Haeusermann P, Rovó A, et al. Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients. Biol Blood Marrow Transplant. 2013;19:1574–80.CrossRefPubMed