Abstract
In contrast to the clear indication for surgical treatment in symptomatic patients with clinically nonfunctioning pituitary adenomas (NFPA), there are no randomized controlled studies comparing therapeutic strategies such as watchful waiting, irradiation or medical therapy for the management of NFPA after surgery. Further, no medical therapy is currently approved for the treatment of NFPA. In this review, we summarize accumulating data on medications currently approved for secreting pituitary adenomas, used off-label in patients with NFPA. Perspectives on overall treatment optimization and potential future therapies are also detailed.
Invited Author’s profile
Yona Greenman MD is currently a senior lecturer in internal medicine at the Sackler Faculty of Medicine, Tel Aviv University, and the Senior Deputy Director of the Institute of Endocrinology, Metabolism and Hypertension at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Her research focuses on pituitary diseases, neuroendocrine aspects of stress.
Introduction
Pituitary adenomas are diagnosed as ‘nonfunctioning’ in the absence of clinical or biochemical evidence of tumor-related hormone excess. Nonfunctioning pituitary adenomas (NFPA) are usually large at diagnosis, presenting with symptoms secondary to mass effects on surrounding tissues, including headaches, visual disturbances and hypopituitarism (1). Surgery is the treatment of choice for decompression of the affected vital structures and rapid symptom amelioration: headaches are resolved in most subjects; visual fields are improved in 80% and full normalization is achieved in up to 40% of patients (2, 3). Although hypopituitarism per se in not an indication for surgery, post-surgical improvement or normalization of pituitary function reaches 30–70% in different series (4, 5, 6).
There are no randomized controlled studies comparing therapeutic strategies such as watchful waiting, irradiation or medical therapy for the management of NFPA after surgery. Further, no medical therapy is currently approved for the treatment of NFPA. In this review, we summarize accumulating data on medications currently approved for secreting pituitary adenomas, used off-label in patients with NFPA. Perspectives on overall treatment optimization and potential future therapies are also detailed.
The impact of surgical outcomes on long-term prognosis of NFPA
Although full resection of these mostly invasive macroadenomas is challenging, it is clear that the presence and size of a residual mass significantly affect the natural history of untreated tumors (7), the need for re-operation or radiation therapy, and the efficacy of additional treatments (8). A recent meta-analysis encompassing 15 studies and 971 patients showed that the recurrence rate for patients without detectable tumor after surgery was 12%, whereas 46% of the patients with postoperative remnants experienced disease progression, with a mean tumor volume doubling time of 3.4 years (9). Residual tumors with extrasellar extension had a higher progression rate (52.3–66.7%) compared to remnants confined to the sella (30–33.3%) (7, 10, 11). Hence, the importance of achieving maximal tumor resection cannot be overemphasized, and strategies to achieve this goal should be implemented. The endoscopic, endonasal approach is becoming the technique of choice for pituitary transsphenoidal microsurgery, as it allows better visualization of the operative field (12). Although there are no direct comparisons with the classical microscopic approach (13), improved outcomes have been reported with the use of the endoscope, with greater control of lateral and suprasellar extensions (14, 15). Intraoperative Magnetic Resonance Imaging (iMRI) is another valuable modality to maximize tumor resection. A significant increase in ‘gross total removal’ rates and facilitation of additional mass resection are uniformly reported in studies on iMRI-guided transsphenoidal surgery (16), leading to lower recurrence rates (17). Nevertheless, the Congress of Neurological Surgeons did not recommend its routine use, which is constrained by high costs of the equipment and its installation, prolonged surgical time and possible artifacts (18).
Accurate pathological diagnosis of NFPA – can it affect treatment strategy or choice of medical therapy?
NFPA comprise a heterogeneous group of lesions, consisting of gonadotropin-secreting tumors, silent adenomas and null cell adenomas (19). The majority belongs to the gonadotroph lineage, based on positive immunostaining for β-LH and β-FSH, or, rarely, by the detection of intact gonadotropins or their subunits in the peripheral blood (20). The vast majority of gonadotropin-secreting tumors is silent, presenting with symptoms related to mass effect (21). Rarely, excessive tumoral FSH secretion may cause menstrual abnormalities and symptoms characteristic of ovarian hyperstimulation syndrome in pre-menopausal women (22). FSH-induced testicular enlargement (23) and LH-induced testosterone hypersecretion (24) are the additional rare presenting symptoms of functioning gonadotropin-secreting tumors.
Approximately 15% of NFPA arise from other anterior pituitary cells, synthesizing hormones that are detected by immunohistochemistry, but are not significantly secreted, and as such are classified as silent tumors (21). Finally, 44.4% of over 2000 specimens from the German Pituitary Tumor Registry were classified as null cell adenomas, based on negative immunostaining for all anterior pituitary hormones (25). Using cytogenetic markers, Nishioka et al. recently demonstrated that truly null cell adenomas are in fact rare (26). In the initial routine analysis of 516 NFPA, 58.1% were classified as gonadotropin-secreting adenomas, 9.9% were silent corticotroph adenomas, 8.9% were grouped as other silent tumors (positive staining for GH, prolactin (PRL) or TSH), and 23.1% stained negative for all hormones. Following staining with antibodies to specific transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ER-α), pituitary specific transcription factor-1 (Pit-1) and t-box transcription factor (Tpit), 66.4 and 26.9% of these initially negative tumors were reclassified as belonging respectively to the gonadotroph and the corticotroph lineages (26). Two samples were found to belong to the Pit-1 lineage, and only 6 cases (5%) retained the initial diagnosis of null cell adenomas. ACTH-negative, Tpit-positive adenomas had identical clinical features to the ACTH-positive silent corticotroph adenomas in this series, with significant female preponderance, and a higher frequency of giant adenomas and marked cavernous sinus invasion, as compared with gonadotroph-secreting tumors (26).
An accurate pathologic classification is important for risk stratification. Silent corticotroph adenomas (27), as well as silent type 3 adenomas (28), now recognized as poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas (29), have been generally found to exhibit a more aggressive biological behavior, therefore requiring a more careful follow-up or perhaps a more active therapeutic approach. Further, plurihormonal adenomas were found to have a significantly higher rate of tumor progression after surgery (80%) in comparison with gonadotropinomas (34%) (30).
Another question to be explored is whether silent adenomas may respond to treatment in a similar way to their lineage specific functional counterparts. The somatostatin and dopamine receptor expression profile of these silent tumors have not been well characterized. In one study, somatostatin receptor (SSTR)1 mRNA expression was 17-fold higher and SSTR2 mRNA expression was 5-fold higher in silent corticotroph adenomas in comparison with ACTH-secreting tumors (31). On the other hand, SSTR5 mRNA was 15-fold higher in the functional ACTH-secreting tumors compared with the silent adenomas (31), suggesting that the latter may not be good candidates for pasireotide treatment. One silent ACTH tumor that responded to cabergoline treatment with substantial shrinkage was found to have dopamine 2 receptor (D2R) mRNA expression similar to that observed in control prolactinomas (32). Data on SSTR protein expression and response to specific receptor ligands is not available for silent adenomas. Therefore, the possible response of silent ACTH or Tpit expressing tumors to pasireotide or of silent GH, TSH or Pit-1 adenomas to preferential SSTR2 ligands remains to be investigated.
Medical therapy as an alternative to conservative follow-up or radiation therapy in NFPA
The currently accepted routine postoperative management of NFPA consists of conservative follow-up for most patients, with selective use of radiotherapy (33). Criteria for using either strategy are not well established, although, sensibly, the most aggressive tumors would usually be irradiated in most centers. Both therapeutic options have important drawbacks, which need to be carefully considered:
Conventional radiotherapy has a long record of effectiveness for the postoperative treatment of residual NFPA (10-year actuarial progression-free survival (PFS) of over 90%) (34, 35), but it is associated with a high rate of complications, the most prevalent of which is development of hypopituitarism in over 50% of patients (36). There is also a lower but not negligible increased risk of visual compromise, secondary brain tumors (37), stroke (38) and possibly neurocognitive or neuropsychological impairment.
Modern stereotactic radiotherapy allows delivery of localized irradiation to the tumor, sparing surrounding normal tissue, thus potentially translating into a better safety profile (39). Recent data are disappointing, in which this premise appears not to hold true. A recent multicenter study under the auspices of the North American Gamma Knife Consortium based on over 500 patients (40) confirmed treatment efficacy (actuarial PFS of 95% at five years and 85% at ten years post-radiosurgery), but worsening of a preexisting cranial nerve deficit or development of a new deficit was reported in 9.3% of patients, mostly involving the optic nerve (6.6%). Development of hypopituitarism could not be reliably estimated due to a relatively short median follow-up of 36 months. With longer follow-up (median 75 months) the actuarial incidence of new anterior pituitary deficits was 40% at five years and 72% at ten years (41), similar to the reported figures for conventional radiation. Hence, even modern radiotherapy techniques are associated with significant side effects, justifying its judicious use with careful selection of patients that may benefit from this treatment, mainly aggressive tumors with high Ki67 proliferation index, deemed to be at a higher risk for tumor progression (42, 43).
The alternative to radiation therapy would be conservative follow-up with annual MRI imaging for the detection of tumor progression. This strategy is perfectly adequate for patients who underwent gross total tumor removal, and probably also for those left with minimal or very small tissue remnants, in view of their low rate of recurrence (7). On the other hand, passive observation for patients left with more significant tumor volumes after surgery, are associated with high relapse rates of 23.1, 46.7 and 67.9% at 5, 10 and 15 years respectively, as reported by Reddy et al. (11). This is a poor outcome, considering that many of these patients will require additional surgery and/or radiotherapy, which have been associated with an elevated standardized mortality ratio (SMR) of 1.65 (1.18–2.24) (44) in patients with NFPA. Consequently, medical therapy for the prevention of tumor progression in these patients would be of high clinical significance.
Receptor-targeted medical therapy
Dopamine agonists
DR expression in most NFPA (45, 46, 47), constitutes the basis for their targeting with medical agents. Dopamine agonists (DAs) reduced gonadotropin secretion in vitro (48) and in vivo (49) and inhibited thymidine incorporation in two-thirds of NFPA in vitro (50). Bromocriptine induced tumor shrinkage leading to improvement in visual fields, has been reported in small series (51) and case reports (52) now over three decades old. Nevertheless, the effects were modest in comparison to the exuberant effect seen in prolactinomas, hampering the enthusiasm for its use on a routine basis. We have proposed a conceptual change in the treatment goal for NFPA, in that stabilization and prevention of tumor growth, rather than tumor shrinkage (53) is sufficient in cases without mass effect on vital structures. In our initial small study, treatment of 33 patients with bromocriptine at a mean dose of 8 mg/day achieved tumor control in 78.8% of patients, in comparison to 33.3% in the untreated control group. We have recently published our experience in a larger series of patients, using the long-acting DA cabergoline (54). Seventy-nine patients after partial transsphenoidal resection of NFPA (remnant size >10 mm in 80% of patients) were treated with cabergoline (mean weekly dose: 1.5 mg, range: 0.5–3.5 mg) during a mean period of 8.8 years (range 1–24 years), either following detection of tumor remnant in the first postoperative MRI (n = 55), or when there was already evidence for tumor growth during conservative follow-up (remedial treatment, n = 24). Preventive treatment resulted in overall tumor control in 87.3% of patients (38.2% tumor shrinkage, 49.1% tumor stabilization), in comparison with 46.7% in the untreated control group (n = 60). Further, cabergoline treatment induced tumor shrinkage or restraint of tumor growth in over 58% of patients treated when there was already evidence for active tumor enlargement. The hazards ratio for growth in treatment groups vs control was 0.3 (0.16–0.56). The fifteen-year PFS rate was 0.805 and 0.24 for the preventive and remedial treatment groups respectively, compared with 0.04 in the control group (Fig. 1). Importantly, the increase in treatment-associated tumor control detected by imaging translated in improved clinical outcomes, as only 13% of patients in the preventive treatment group required additional surgery or radiotherapy, compared with 42% in the control group (54).
Actuarial tumor progression-free survival in patients with post-operative tumor remnants according to treatment group: Preventive treatment group (PT) – treatment was initiated upon residual tumor detection on postoperative MRI; remedial treatment group (RT) – treatment was initiated upon tumor growth detection during follow-up; control group – untreated. At five years: log rank test P = 0.052; PT vs RT P = 0.045; n = NS for other comparisons. At 10 years: log rank test P = 0.0002; control vs PT P = 0.0001; control vs RT P = 0.06; PT vs RT P = 0.019. At 15 years: log rank test P < 0.0001; control vs PT P < 0.0001; control vs RT P = 0.039; PT vs RT P = 0.0053 (from Ref. (54)).
Citation: European Journal of Endocrinology 177, 3; 10.1530/EJE-17-0216
Actuarial tumor progression-free survival in patients with post-operative tumor remnants according to treatment group: Preventive treatment group (PT) – treatment was initiated upon residual tumor detection on postoperative MRI; remedial treatment group (RT) – treatment was initiated upon tumor growth detection during follow-up; control group – untreated. At five years: log rank test P = 0.052; PT vs RT P = 0.045; n = NS for other comparisons. At 10 years: log rank test P = 0.0002; control vs PT P = 0.0001; control vs RT P = 0.06; PT vs RT P = 0.019. At 15 years: log rank test P < 0.0001; control vs PT P < 0.0001; control vs RT P = 0.039; PT vs RT P = 0.0053 (from Ref. (54)).
Citation: European Journal of Endocrinology 177, 3; 10.1530/EJE-17-0216
Actuarial tumor progression-free survival in patients with post-operative tumor remnants according to treatment group: Preventive treatment group (PT) – treatment was initiated upon residual tumor detection on postoperative MRI; remedial treatment group (RT) – treatment was initiated upon tumor growth detection during follow-up; control group – untreated. At five years: log rank test P = 0.052; PT vs RT P = 0.045; n = NS for other comparisons. At 10 years: log rank test P = 0.0002; control vs PT P = 0.0001; control vs RT P = 0.06; PT vs RT P = 0.019. At 15 years: log rank test P < 0.0001; control vs PT P < 0.0001; control vs RT P = 0.039; PT vs RT P = 0.0053 (from Ref. (54)).
Citation: European Journal of Endocrinology 177, 3; 10.1530/EJE-17-0216
Five small studies (55, 56, 57, 58, 59) encompassing 54 patients have reported the use of various doses of cabergoline (1–3 mg/week) during short periods (6–12 months) for the treatment of NFPA patients. Despite the small number of patients in each study and the lack of untreated control groups in most of them, the pooled results indicated tumor stabilization in over 80% of patients, similar to our findings (Table 1). Taken together, DA treatment to prevent tumor remnant growth after surgery seems superior to the currently practiced expectant follow-up. High dose cabergoline-induced valvular heart disease (60) has not been reported with the lower doses used in endocrine disorders (61), thus reducing safety concerns.
Studies on cabergoline treatment of NFPA.
| Reference | Number of patients | F/U | Dose/week | Shrinkage | Stable | Growth | |
|---|---|---|---|---|---|---|---|
| (55) | 13 | 12 | 1 mg | 7 | 5 | 1 | |
| (56) | 9 | 12 | 3 mg | 5 | 1 | 3 | |
| (57) | 4 | 60 (mean) | 1–2 mg | 1 | 3 | 0 | |
| (58) | 19 | 6 | 2 mg | 6 | 9 | 4 | |
| (59) | 9 | 6 | 3 mg | 6 | 3 | 0 | |
| Total | 54 | 25 (46%) | 21 (39%) | 8 (15%) | |||
| (54) | |||||||
| Total | 79 | 105 ± 78 | 1.5 ± 0.7 mg | ||||
| Preventive | 55 | 21 | 27 | 7 | |||
| Remedial | 24 | 7 | 7 | 10 | |||
| Total | 133 | 53 (40%) | 55 (41.3%) | 25 (18.7%) | |||
Surprisingly, tumor response to DA treatment was not related to DR2 protein or mRNA expression in tumor tissue as examined by immunohistochemistry and quantitative RT-PCR (54). Therefore, the surmise that a lesser response to DA treatment in NFPA compared to prolactinomas derives from lower D2R expression levels (62) could not be confirmed by our findings. Further, the expression of D2Rlong and D2Rshort mRNA isoforms in DA resistant prolactinomas was higher than in DA responsive NFPA (54), suggesting that factors additional to D2R abundance are involved in the clinical response to treatment.
Ideally, a prospective randomized control study should be performed to confirm the effectiveness of cabergoline treatment for NFPA. This would be a challenging endeavor in view of the lack of commercial incentive involved in studying a generic drug, the slow growing nature of these tumors and the lack of serum markers to reflect treatment effectiveness that would necessitate a long follow-up.
Somatostatin receptor ligands
Despite the abundant data on somatostatin antisecretory and antiproliferative effects in vitro, the cumulative reported clinical experience with somatostatin receptor ligands (SRLs) for the treatment of NFPA is very sparse. Colao et al. reviewed small uncontrolled studies encompassing 100 patients treated with s.c. octreotide for an average of 6 months (52). Tumor volume decreased in 5%, increased in 12% and remained unchanged in 83% of patients. In a case–control study, 26 patients pre-selected by positive tumor uptake in somatostatin receptor scintigraphy were treated with the long-acting somatostatin analog Sandostatin LAR. Tumor size increased in 19% and remained unchanged in the remaining patients during a mean follow-up time of 37 months (63). It can be concluded that SRL with predominant SSTR2 binding do not effectively induce tumor shrinkage, but long-term well designed studies are necessary to assess their value in controlling tumor growth. When considering SRL for the medical therapy of NFPA, attention should be given to the wide heterogeneity in the SSTR expression pattern in pituitary tumors. The predominant SSTR subtypes expressed in NFPA, SSTR3 and SSTR2 (64, 65) correlate with somatostatin inhibition of chromogranin A and glycoprotein α-subunit secretion in NFPA cultures (66). SSTR1 (67) and SSTR2 (68), specific analogs have been shown to inhibit NFPA cell proliferation in vitro, but a SSTR5 selective agonist in fact promoted NFPA cell viability (67). Further, a truncated SSTR5 receptor variant, sst5TMD4, associated with aggressive features and resistance to SRL treatment in somatotropinomas, has been detected, albeit with low expression levels, in 50% of NFPA (69). The effects of sstrTMD4 on NFPA biology and response to treatment remain to be established. The multi-receptor ligand pasireotide reduced NFPA cell viability through the inhibition of vascular endothelium growth factor secretion (70) in a sub-group of tumors characterized by lack of SSTR5 and abundant SSTR3 expression. Predominant SSTR3 expression was confirmed by immunostaining in a large series (n = 118) where moderate-to-high SSTR3 expression was found in 83% of NFPA samples, while only 16% of cases had this degree of SSTR2 expression (71). Ligand binding of SSTR3 induces p53-associated apoptosis (72), inhibits mitogenic pathways through thyrosine phosphatases activation and suppresses endothelial cell proliferation with resultant anti-angiogenic effects (73). Based on these data, SSTR3 is a promising target for the medical treatment of NFPA. Although pasireotide effectively binds SSTR3, its highest affinity binding to SSTR5 potentially could have untoward effects in selected tumors preferentially expressing this receptor, based on the in vitro study by Zatelli et al. (67). Further, the high number of new cases of impaired glucose metabolism and diabetes reported in patients with Cushing’s disease (74) and acromegaly (75) treated with pasireotide would probably not justify its use as a preventive therapy for NFPA tumor stabilization. Nevertheless, if proved effective, it could be of value to control actively growing tumors. The clinical development of selective SSTR3 analogs should be prioritized to advance targeted medical treatment for NFPA.
Combined DA and SRL therapy has been proposed based on enhanced receptor activity secondary to D2R and SSTR5 heterodimerization (76). A somatostatin–dopamine chimeric compound (BIM-237A760) inhibited thymidine incorporation in 70% of NFPA in culture, but this response was equivalent to that obtained with the D2R agonist cabergoline (50). The clinical experience of combined therapy is very limited (77), precluding adequate efficacy evaluation.
GnRH receptor agonists and antagonists
GnRH desensitization does not occur under chronic GnRH analog treatment. In fact GnRH analogs cause augmentation of gonadotropin secretion by most tumors, and have no beneficial effect on tumor volume, therefore they are not indicated for the treatment of NFPA (78). Gonadotropin receptor antagonists have been used in a few patients, leading to suppression of gonadotropin secretion, but no effect on tumor size was noted after 3–12 months of treatment (79). A GnRH antagonist was successfully used in a patient bearing a functioning FSH-secreting adenoma who presented with ovarian hyperstimulation (80), leading to reduction in abdominal pain and ovarian volume. Due to limited drug availability, this patient eventually underwent bilateral oophorectomy, as did most patients with sustained ovarian stimulation syndrome whose pituitary tumors could not be effectively controlled with medical treatment or surgical excision (22).
Temozolomide
Temozolomide (TMZ) is an alkylating agent routinely used for the treatment of malignant gliomas. It has also shown efficacy in metastatic melanomas, neuroendocrine tumors and aggressive pituitary adenomas and carcinomas (81). Roughly one hundred TMZ-treated pituitary tumors have been reported, 35% of which were carcinomas (82, 83, 84, 85, 86). Between 46 and 80% of patients were classified as responders (disease stabilization, complete or partial response) (84, 85, 86), without a discernible relationship between pituitary tumor type and treatment outcome. NFPA and carcinomas consisted of almost one third of these tumors. Low tumor expression of the DNA repair protein O6-methyl-transferase (MGMT) (86) and immunopositivity of the DNA mismatch repair protein MSH6 (84) have been variably correlated with response to TMZ treatment. Although TMZ is a valuable and maybe the only effective chemotherapeutic agent available for aggressive, progressive and recurrent atypical pituitary adenomas and carcinomas resistant to conventional multimodal treatment, it should be used with caution in view of the lack of controlled trials. Tumor shrinkage or stabilization is usually seen early in the course of treatment, but unfortunately escape and relapse are reported in up to 50% of patients (84). Strategies to sensitize pituitary cells to TMZ treatment using disulfiram (87), pyrimethamine (88) and HIF-1α inhibition (89) proved to be effective in vitro in pituitary cell lines, and in xenograft tumor-bearing mice models.
Investigational therapies
Somatostatin receptor-mediated drug targeting
Peptide receptor radionuclide therapy (PRRT)
PRRT with radiolabeled somatostatin analogs is an important and routinely used modality for the treatment of metastatic gut neuroendocrine tumors (90). The efficacy of this treatment depends on high somatostatin receptor expression, mainly SSTR2 in the tumoral tissue. PRRT has been used so far in four patients with pituitary tumors, with mixed results (91, 92). Still, this is a conceptually promising treatment option for SSTR expressing progressive pituitary tumors resistant to conventional treatment, and deserves further investigation.
Octreotide-mediated tumor-targeted cytotoxic drug delivery
Potent chemotherapeutic agents such as camptothecin, methotrexate, paclitaxel and doxorubicin have been coupled to SSTR2-preferential somatostatin analogs (93), thus enabling delivery of cytotoxic agents to receptor-specific sites, potentially enhancing antitumor efficacy, while reducing toxic side effects to normal tissue. Although effective in vitro, many drug–somatostatin analog hybrids are prone to hydrolysis of the ester bond linking between the drug and the ligand, thus limiting its use in vivo. A doxorubicin–octreotide bioconjugate using a cleavable disulfide-intercalating linker has been recently shown to have promising applicability. It suppressed ACTH secretion in AtT20 mouse pituitary cells and was cytotoxic in pituitary, pancreatic and breast cancer cell lines (94). The clinical value of this drug for cancer patients or subjects with aggressive pituitary tumors remains to be established.
Folate receptor-mediated drug targeting
Folic acid receptor alpha (FR-α) is overexpressed in several tumors of epithelial origin such as breast, endometrial, non-small cell lung and ovarian cancer. In view of the restricted FR-α expression in normal tissues, it is an attractive therapeutic target for delivering tumor-selective drugs (95). Different treatments have been developed including FR-α-specific monoclonal antibodies and conjugates of folate with chemotherapeutic agents, which are in early-stage clinical testing for lung and ovarian cancer. FR-α is overexpressed both at the mRNA and protein levels in NFPA but not in normal pituitary or secretory pituitary tumors (96), being more abundant in invasive and larger tumors with high Ki-67 proliferation index (97). Folate receptor-α targeted liposomal doxorubicin had antiproliferative, antiinvasive and proapoptotic activity in primary cell cultures derived from patients with NFPA (98), thus potentially being of value for treating aggressive tumors. FR-α-expressing NFPA can be detected with 99mTc-Folate SPECT-CT, thus identifying tumors amenable to folate receptor-targeted therapy (99).
Targeting of PI3K/AKT/mTOR pathway
The phosphatidyl-inositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been found to be overactivated in pituitary adenomas (100, 101). NFPAs have high AKT and cyclin D1mRNA expression levels in comparison with other pituitary tumors (100). Further, high phosphorylated AKT levels were associated with early recurrence of NFPA (102), and the expression levels of the mTOR pathway regulator proteins RAPTOR and RICTOR correlated with tumor size and invasiveness (103). Therefore, inhibition of PI3K signaling may be a valuable therapeutic target for pituitary tumors and specifically for NFPA (104). Accumulating in vitro data are encouraging. The mTOR inhibitor everolimus, a derivative of rapamycin, significantly reduced cell viability and promoted apoptosis in NFPA primary cultures (105). The dual PI3K-AKT-mTOR inhibitor NVP-BEZ235 had antiproliferative effects against NFPA both in vitro and in vivo (106). Combination treatment with octreotide decreased AKT phosphorylation and conferred sensitivity to NFPA cells resistant to rapamycin monotherapy, and augmented the antiproliferative effect in rampamycin sensitive cells (107). Unfortunately, the combined use of everolimus and octreotide failed to control an ACTH pituitary carcinoma resistant to TMZ treatment (108). Although promising in preclinical models, the role of mTOR inhibitors for the treatment of NFPA remains to be established.
Clinical issues beyond local tumor control
Hypopituitarism, repeated surgeries and radiation therapy have all been associated with increased mortality rates and decreased quality of life (QoL) in NFPA patients. Although it is difficult to dissect the individual contributions of these inter-related factors to the adverse outcomes, it is clear that efforts should be made to limit the need for additional invasive interventions with their associated complications, after the initial surgery.
Hypopituitarism
Hypopituitarism is highly prevalent in patients with NFPA, primarily or secondarily to surgery and/or radiation therapy. In a recent large study from two referral centers in England and Ireland, only 17.2% of patients remained with intact pituitary function, whereas 9.9, 24.9 and 47.9% had single or multiple hormone deficiencies and panhypopituitarism respectively (109). Relative mortality rates increased with the severity of pituitary failure and with the presence of ACTH and gonadotropin deficiencies (RR: 2.56 and 2.26 respectively) (109). Importantly, increased hydrocortisone (109, 110), and lower levothyroxine doses were associated with increased risk of death. These findings underscore the importance of striving to achieve the most physiologic replacement regimen possible.
Quality of life
Many (111, 112) but not all studies (113) have found decreased QoL in NFPA patients. In more recent studies although the overall QoL was near normal (114), single dimensions (energy, depression, sexual activity and vision) were variably affected (113, 114). Hypopituitarism (112), female gender (112, 113) and unreplaced male hypogonadism (113) were variables associated with worse QoL. Subjects who received radiotherapy, those who had tumor recurrence and patients who underwent repeated surgery scored worse in areas of energy levels and anxiety (113), underscoring the importance of efficient medical therapies that decrease the need for these interventions.
Mortality
Standardized mortality rate (SMR) is increased in NFPA. In a large cohort from Oxford the overall SMR was 3.6 (2.9–4.5) (115). Data from Denmark (116) and Sweden (116) revealed a significantly increased mortality rate for women (SMR: 1.97 and 1.37 respectively), but not for men. The increased relative rate of death (1.62) in irradiated patients appears to be secondary to hypopituitarism, as shown by multivariate analysis of the data (109). Improvement in treatment quality (114) and reduction in the prevalence of hypopituitarism (117) are leading to a time trend decrease in SMRs. Main causes of death were cardio/cerebrovascular (33.7%), infections (30.1%) and malignancy (28.9%) (115).
Conclusions
In the absence of randomized controlled trials comparing therapeutic options for the management of NFPA after surgery, electing the most appropriate treatment for the individual patient cannot be based on the principles of evidence-based medicine. Currently, only data derived from observational studies together with our clinical judgment are available to guide our decisions, with the aim of providing the best ‘informed based medicine’ to our patients. Based on our recent data, DA treatment emerges as an attractive therapy for patients with clinically significant tumor remnants after surgery, in view of its association with superior tumor control and a lesser need for repeated surgery and radiation therapy, compared with conservative follow-up. Although SSTR2-selective SRLs appear to be of limited therapeutic value for NFPA, SSTR3-selective ligands may prove to be of superior efficacy, based on limited in vitro data. Radiation therapy remains central for the treatment of aggressive NFPA, and TMZ is the first-choice chemotherapy for tumors with relentless growth despite irradiation. PRRT with radiolabeled somatostatin analogs, folate receptor-mediated drug targeting and inhibitors of the PI3K/AKT/mTOR pathway are investigational treatment modalities that may prove effective for tumors resistant to the available agents. Finally, optimal hormonal replacement therapy for patients with hypopituitarism is essential to improve QoL and reduce mortality.
Declaration of interest
The author declares that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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