The Effects of Radioligand Therapy on Quality of Life and Sexual Function in Patients with Neuroendocrine Neoplasms

Simple Summary Cancer therapies influence a patient’s health-related quality of life (HRQoL) and sexual function. Patients with neuroendocrine neoplasm (NEN) have impaired HRQoL and sexual function because of the long-lasting disease with a high tumor burden that requires multiple treatments with different mechanisms of action. Moreover, the complexity of symptoms may be due, at least to a certain extent, to the tumor secretion and release of polypeptides and biogenic amines that cause several clinical conditions including the carcinoid syndrome. Peptide receptor radionuclide therapy (PRRT) is an effective treatment in patients with NEN. Retrospective studies and randomized clinical trials have reported that patients with NEN treated with PRRT experienced an improvement in HRQoL evaluated by self-assessment questionnaires, such as the EORTC QLQ-C30 and QLQ-GINET21. The impact on sexual function has only been investigated in part through these questionnaires. This review discusses the current knowledge regarding the changes in HRQoL and sexual function in patients with NEN treated with PRRT. Abstract Peptide receptor radionuclide therapy (PRRT), also called radioligand therapy, is an effective antitumoral treatment in patients with neuroendocrine neoplasm (NEN). It improves the patient’s health-related quality of life (HRQoL), which is evaluated by self-assessment questionnaires. The aim of this narrative review was to report the current knowledge on the changes of HRQoL and sexual function in patients with NEN treated with PRRT. We conducted a literature search of the PubMed, Embase, and APA PsycInfo databases. We selected 15 studies (12 for HRQoL and three for sexual function). After treatment with PRRT, patients with NEN experienced a significant improvement in their global health status, disease-related worries, social and emotional functioning, and cancer-related symptoms such as fatigue and diarrhea. Other symptoms, such as nausea/vomiting, dyspnea, and constipation, as well as the economic impact, were unchanged by radioligand therapy. Data on sexual function were not equally promising; only a few studies investigated this issue by using appropriate questionnaires in patients treated with radioligand therapy. Therefore, additional studies are needed to draw a conclusion about the benefits from PRRT on sexual function.

. Flowchart showing the study selection.

Questionnaires to Assess HRQoL: QLQ-C30 and QLQ-GINET21
The EORTC Core QoL questionnaire (QLQ-C30) is a widely used generic questionnaire for cancers, and it has been developed to be modular, with the core general questionnaire that can be implemented with disease-specific modules containing those aspects of HRQoL relevant to patients with a specific type or site of cancer [12]. The QLQ-GINET21 was introduced and validated recently to be used in conjunction with the EORTC QLQ-C30, with the aim of evaluating specific and relevant HRQoL issues in patients with NEN [13]. Although the EORTC QLQ-C30 is the most widely used in oncology, it does not cover specific disease-and treatment-related issues such as flushing, abdominal pain, discomfort in joints and muscles, the effect of the disease on sexual behavior, and some specific psychological, emotional, and social aspects. The Social Functioning (SF) scale of the QLQ-GINET21 is a new type of scale, in which items are ordered to

Questionnaires to Assess HRQoL: QLQ-C30 and QLQ-GINET21
The EORTC Core QoL questionnaire (QLQ-C30) is a widely used generic questionnaire for cancers, and it has been developed to be modular, with the core general questionnaire that can be implemented with disease-specific modules containing those aspects of HRQoL relevant to patients with a specific type or site of cancer [12]. The QLQ-GINET21 was introduced and validated recently to be used in conjunction with the EORTC QLQ-C30, with the aim of evaluating specific and relevant HRQoL issues in patients with NEN [13]. Although the EORTC QLQ-C30 is the most widely used in oncology, it does not cover specific disease-and treatment-related issues such as flushing, abdominal pain, discomfort in joints and muscles, the effect of the disease on sexual behavior, and some specific psychological, emotional, and social aspects. The Social Functioning (SF) scale of the QLQ-GINET21 is a new type of scale, in which items are ordered to evaluate how difficult SF is for the subject. The SF scale of the QLQ-C30 correlated quite highly with the SF scale in the QLQ-GINET21, suggesting that both measure and evaluate similar aspects of the same problem [14]. However, the SF scale of the QLQ-GINET21 seems to be different and, thus, provides additional information about the changes in SF that occur over time. Moreover, none of the other scales of the QLQ-GINET21 and QLQ-C30 showed a high correlation, thus confirming that the QLQ-GINET21 provides additional information beyond the more generic QLQ-C30 [14]. Both EORTC QLQ-C30 and QLQ-GINET21 are used for research in many countries and can also be applied in clinical practice, because the first has been translated into more than 100 languages and the second has been translated into nine languages. The data comparing cancers of different origins suggests that the QLQ-GINET21 can be used for both pancreatic and nonpancreatic NETs, although it is accepted that there are not enough cases of pancreatic NETs for a proper validation in patients with this cancer type alone.
Additional details on the questions included in the EORTC QLQ-C30 and QLQ-GINET21 questionnaires and how scores are calculated according to patients' answers are provided in the Supplementary Materials.

Effect of PRRT on HRQoL
Twelve studies evaluated HRQoL in patients with NEN treated with PRRT ( Table 1). Eight of these studies were retrospective analyses [15][16][17][18][19][20][21][22], and four studies were prospective analyses [23][24][25][26]. 177 Lutetium was the radioisotope administered in 11 of the 12 studies, and only in one study patients were treated with 225 Ac-DOTATATE [24]. The cumulative administered activity of 177 Lu-DOTATATE was quite similar among the selected studies, which ranged on the average from 22.2 to 29.6 GBq. This was achieved by administering an intended dose of 7.4 GBq per cycle up to 3-4 cycles. Larger doses were administered in the study by Del Prete et al. [26] because injected activity was calculated through a quantitative SPECT/CT-based dosimetry; therefore, the median cumulative administered activity was 36.1 GBq (range 6.3-78.6). Premedication with intravenous amino-acid infusion to protect the renal function was described in nine studies. This was performed with a similar protocol through a solution of lysine and arginine infused over 4-6 h and starting 30 to 60 min before the therapy. By considering all the selected studies, HRQoL was evaluated in a total of 1005 patients, including 524 males and 481 females, with a mean age ranging from 52 to 70 years old. The study populations included mainly patients with midgut and pancreatic NET and less frequently bronchial NET. Changes in HRQoL were analyzed only by the EORTC QLQ-C30 in 10 of the studies, only by the QLQ-GINET21 in two of the studies, and by both questionnaires in one study. Scores at baseline, before PRRT treatment, were compared with those recorded at the end of treatment (i.e., from 6 weeks to 3 months after the last PRRT cycle). The quantification of the mean changings for each item of the questionnaires was described in eight of the 12 studies, whereas these data were not available in three studies [16,21,25]; in the study by Strosberg et al. [23], the authors considered as outcome the time to deterioration, i.e., the time from random assignment to the first deterioration of 10 or more points (on a 100-point scale) compared with baseline score for the same domain. Therefore, to summarize our findings by including all the selected studies we used a graphical method. Tables 2 and 3 display the changes from the baseline values of each item score of the QLQ-C30 and QLQ-GINET21, respectively.

Symptoms scales
Fatigue = significant improvement of the item score compared with the baseline; ~ = no difference worsening of the item score compared with the baseline. * QLQ-C30 scores were compared with a were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroendocrine tumor; P ** EORTC QLQ-C30 items SI-NET P-NET Global health status ~ ** Functional scales

Symptoms scales
Fatigue = significant improvement of the item score compared with the baseline; ~ = no difference of the item worsening of the item score compared with the baseline. * QLQ-C30 scores were compared with age-and sex-m were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroendocrine tumor; P-NET= panc EORTC QLQ-C30 items

SI-NET P-NET
Global health status ~ ** Functional scales

Symptoms scales
Fatigue = significant improvement of the item score compared with the baseline; ~ = no difference of the item score compared with the baseline; = significant worsening of the item score compared with the baseline. * QLQ-C30 scores were compared with age-and sex-matched population-based controls. ** These changes were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroendocrine tumor; P-NET= pancreatic neuroendocrine tumor.

Symptoms scales
Fatigue = significant improvement of the item score compared with the baseline; ~ worsening of the item score compared with the baseline. * QLQ-C30 scores were c were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroen ~~ = significant improvement of the item score compared with the baseline; ~ = no difference of the item score compared with the baseline; = significant worsening of the item score compared with the baseline. * QLQ-C30 scores were compared with age-and sex-matched population-based controls. ** These changes were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroendocrine tumor; P-NET= pancreatic neuroendocrine tumor.          = significant improvement of the item score compared with the baseline; ~ = no difference of the item score compared with the baseline; = significant worsening of the item score compared with the baseline. * QLQ-C30 scores were compared with age-and sex-matched population-based controls. ** These changes were observed only in patients treated by 177 Lu. SI-NET= small intestine neuroendocrine tumor; P-NET= pancreatic neuroendocrine tumor.       The diagnosis was made through the 15D questionnaire [28], which explores HRQoL with only one specific question on sexual activity. Specifically, this instrument comprises 15 dimensions: mobility, vision, hearing, breathing, sleeping, eating, speech, excretion (includes both bladder and bowel function), usual activities, mental function, discomfort and symptoms, depression, distress, vitality, and sexual activity. The authors found that PRRT did not predict or correlate with impaired HRQoL or sexual function. Furthermore, van der Horst-Schrivers et al. [29] found that patients with well-differentiated NEN did not experience sexual problems more often than a reference population. However, the sample was limited to patients with metastatic midgut NEN, and the questionnaire used was the same for both male and female patients, namely, the short version of the Questionnaire for Screening Sexual Dysfunction (QSD) [30]. This instrument assesses the frequency and experienced distress of sexual problems on different subscales, such as orgasm, erection, arousal, and pain. Interestingly, plasma tryptophan levels were lower and urinary 5-HIAA concentrations were higher in patients with sexual dysfunction. The authors concluded that these patients represent the population with more extensive and longstanding disease and, therefore, are more affected by sexual dysfunction [29]. However, no patient was treated with PRRT. Lastly, limited data are available regarding sexual dysfunction in female patients with neuroendocrine carcinoma of the cervix. Specifically, Zaid et al. [31] enrolled a heterogeneous group of patients through social media from eight countries across four continents and reported similar prevalence of sexual dysfunctions in the study group compared with the controls. However, only 50% of the patients had filled out the items regarding sexuality, explored by the Patient-Reported Outcomes Measurement Information System (PROMIS) on sexual functioning [32]. Of note, the authors did not perform a sub-analysis on the population that had received PRRT. Although sexual health is an integral part QoL, both in the general population and in the cancer population, this aspect has not been sufficiently investigated in NET patients. Moreover, to date, no data are available regarding the study of sexual function through the use of more specific questionnaires (i.e., International Index of Erectile Function (IIEF)-5 or -15 questionnaires, as well as the specific item in the Beck Depression Inventory (BDI)-II questionnaire).

Discussion
Cancer therapies are aimed at controlling tumor growth and cancer-related symptoms. Moreover, NENs are often characterized by hormone production and release that eventually influence the patient's symptoms. Therefore, available cancer treatments for patients with NET should be addressed to control three main targets: tumor growth, hormone secretion, and the patient's symptoms. The best hypothetical therapeutic agent should not negatively influence an additional fourth parameter that is closely related to the abovementioned three parameters, i.e., the patient's quality of life and sexual function.
In recent years, PRRT has dramatically changed the management of patients with advanced NET by offering them a safe and effective therapeutic option. In this review, we focused our efforts to determine whether the benefits of PRRT also extend to HRQoL and sexual function. We identified a number of manuscripts with sufficient data for clinical consideration of this matter. Most of the selected studies were consistent with a general improvement in HRQoL. This finding concerns the global health status and some scales regarding emotional and social functions. Interestingly, the global health status has been considered a predictor of a good prognosis in patients with advanced cancer [33,34]. Teunissen et al. [15] reported better quality of life in patients who had achieved tumor regression after PRRT. Similarly, as shown in Tables 2 and 3, the scores for several items concerning the functional and symptom scales were improved in series in which patients had had a high percentage of complete or partial response [16,20,24]. Additionally, in about half of the selected studies, PRRT was associated with a significant reduction from baseline in symptom seriousness such as fatigue and diarrhea. The reduction in diarrhea after PRRT was obtained despite previous treatment with somatostatin analogs in most patients.
Noteworthily, all studies also documented a neutral effect on nausea/vomiting, dyspnea, and constipation. This finding may have a double interpretation. Indeed, on the one hand, we can speculate on the good toxicity profile of the PRRT; it is generally well tolerated and only rarely worsens the patient's symptoms. On the other hand, we should expect a certain improvement after the treatment, but this was not observed because the abovementioned symptoms are in most of cases due to an obstructive syndrome, e.g., secondary to the typical mesenteric desmoplastic reaction, which may be not responsive to PRRT. Moreover, the EORTC QLQ-C30 was developed to assess HRQoL in patients with cancer regardless of the primary site [12] and may not be totally appropriate to investigate all issues concerning HRQoL in patients with NEN. Therefore, the EORTC QLQ-GINET21 was developed in a phase 1-3 study to supplement the QLQ-C30 and to provide a more specific assessment of disease and treatment-related issues in patients with NEN [13]. By using the GINET21 questionnaire, Ballal et al. [24] documented that endocrine and gastrointestinal symptoms had been ameliorated after PRRT, whereas, in the phase 3 NETTER-1 trial, these symptoms were not different from the baseline after PRRT [23]. Recently, a secondary analysis of the NETTER-1 trial reported that PRRT was associated with a significant reduction in diarrhea, flushing, and abdominal pain [35]. For this analysis, the authors investigated symptoms that patients had recorded in a daily diary, namely, general symptoms, respiratory symptoms, and gastrointestinal symptoms. This apparent inconsistency may be explained in part by the different conception and aim between the daily dairy, where the patient reports their experience day by day, and the EORTC questionnaire, with summarizes the patient's symptoms occurring over a longer time (i.e., 1-4 weeks). At the 2020 ENETS Annual Conference, researchers presented the phase 1-3 study for developing a new questionnaire specific for patients with pancreatic NEN (panNEN) [36]. According to the literature review and healthcare experts, researchers from seven countries developed a provisional phase 3 questionnaire and tested it on 59 patients with functioning (gastrinoma and insulinoma) or nonfunctioning panNEN [37]. Because panNENs display some biological and clinical differences from the other gastrointestinal NENs, the QLQ-C30 does not address the issues deriving from functioning NENs, and the QLQ-GINET21 is not dedicated to panNEN, this new questionnaire, when validated, will be helpful to fill this lack in the next future.
In a recent review and meta-analysis, the authors investigated HRQoL in patients with NEN treated with different therapies, including somatostatin analogs, PRRT, chemotherapy, and targeted therapy [38]. The authors reported that HRQoL was stable in patients who had been treated with somatostatin analogs alone or chemotherapy, whereas it improved in patients who had been treated with PRRT or targeted therapy. This observation is consistent with the findings of this review; therefore, the therapeutic sequence in patients with NEN should be driven not only by expected antitumor activities, but also by the effect on HRQoL changes. Moreover, body image is an important aspect of HRQoL of cancer survivors [39], and, in this regard, PRRT could be a treatment with a low impact on physical appearance and a good perceived global health status.
The long natural history of NENs, as well as the necessity of long-lasting and stepwise therapies, could have a negative impact on the patient's sexual health. These events may occur independently of the primary site and patient's sex. In fact, the cancer and its treatments have consequences for the sexuality of the patients and their partners, and it could be associated with detrimental effects on erection, ejaculation, and orgasm in male, as well as decreased desire in female [40]. However, studies exploring sexual functioning, sexual health, and sexual satisfaction in patients with NEN are limited [24,27,29,31]. Moreover, data on this issue in patients treated with PRRT are derived from a single question included in the QLQ-GINET21 that investigates whether the disease or treatment has affected the patient's sex life during the past 4 weeks. The only two studies with available data [23,24] reported that PRRT did not influence sexual function. Interestingly, a recent study highlighted that carcinoid syndrome (CS) could negatively affect sexual function [41]. It is known that 5-hydroxy-tryptamine (5-HT), which is recognized as an important modulator of female and male sexual ejaculatory/orgasmic function, is increased in CS, and a higher level of 5-HT inhibits erectile function, lubrification, and sexual interest [42]. Furthermore, male subjects affected by CS had a higher serum luteinizing hormone concentration, as well as a decreased libido and erectile dysfunction, even with normal testosterone concentrations [43]. However, according to the results of this review, additional studies considering sexual dysfunctions in patients with NEN are needed.
This review had some limitations mainly due to the heterogeneity of the HRQoL evaluation among the selected studies (see the last row of Table 1). However, to minimize this measurement bias, in each study, we compared only the pretreatment HRQoL estimation with the values obtained after the last PRRT cycle. Furthermore, we expected a different HRQoL response to PRRT relative to the different percentage in each series of patients with functioning NEN. We speculate that the impact of this element should not be relevant because, in all studies, most patients were on somatostatin analog therapy before they began PRRT. Lastly, we could have selected more studies by considering other questionnaires used in patients with NEN (i.e., the Norfolk QoL-NET), but we only focused on the two most used questionnaire with the aim of obtaining more homogeneous data.

Conclusions
In conclusion, HRQoL assessment may help clinicians to perceive a patient's needs, providing a guide to select the most appropriate treatment for each patient. PRRT is not only effective and safe, but may also allow an improvement in HRQoL in patients with NEN. However, more accurate and personalized evaluations, especially on sexual function, are still needed; therefore, a new HRQoL questionnaire should be validated for this purpose.