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2022 CNS Annual Meeting
download pdf Neurosurgery, 2016
Congress of Neurological Surgeons (CNS) and the AANS/CNS Tumor Section
Joint Guidelines Committee of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS)
Joshua William Lucas, MD1, Mary E. Bodach, MLIS2, Luis M. Tumialan, MD3, Nelson M. Oyesiku, MD, PhD4, Chirag G. Patil, MD5, Zachary Litvack, MD6, Manish K. Aghi, MD, PhD7*, Gabriel Zada, MD1*
2 Guidelines Department, Congress of Neurological Surgeons, Schaumburg, Illinois, USA
3 Barrow Neurological Institute, Phoenix, Arizona, USA
4 Department of Neurosurgery, Emory University, Atlanta, Georgia, USA
5 Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
6 Department of Neurosurgery, George Washington University, Washington, DC, USA
7 Department of Neurosurgery, University of California, San Francisco, California, USA
*These authors contributed equally to this work.
Gabriel Zada, MDDepartment of NeurosurgeryUniversity of Southern California1200 N State St, Suite 3300Los Angeles, CA 90033E-mail: email@example.com
Background: Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary lesions and may present clinically with vision loss and hypopituitarism.
Objective: To characterize the existing literature as it pertains to the initial management of NFPAs.
Methods: A systematic literature review was conducted to identify and screen articles assessing primary treatment options (surgical, medical, radiation-based, or observation) for NFPAs. Outcomes assessed included vision-, endocrine-, and headache-related symptoms, as well as tumor response to therapy. Twenty-six studies met inclusion criteria for analysis.
Results: A considerable amount of Class II evidence (14 studies) was identified supporting primary surgical intervention in patients with symptomatic NFPA macroadenomas, resulting in immediate tumor volume reduction in nearly all patients and a residual tumor rate of 10% to 36%. One prospective, observational cohort study and multiple retrospective studies showed improved visual function in 75% to 91% of surgically treated patients and improved hypopituitarism in 35% to 50% of patients. Limited Class II evidence showed inconsistent benefits for observation alone (1 study), primary radiation-based treatment (3 studies), or primary medical treatment (8 studies) for improving vision, headaches, hypopituitarism, or tumor volume. One retrospective study implementing observation alone showed tumor progression in 50% of patients and a requirement for surgery in 21% of patients. Eight studies assessing primary medical therapy for NFPAs showed inconsistent tumor response rates using somatostatin analogues (12% to 40% response rate), dopamine agonist therapy (0-61% response rate), or combination therapy (60% response rate). Three studies reporting primary radiosurgery for NFPAs showed decreased tumor size in 38% to 60% of patients.
Conclusion: Multiple retrospective and some prospective studies have demonstrated consistent effectiveness of primary surgical resection of symptomatic NFPAs with acceptable morbidity rates. Limited and inconsistent reports are available for alternative treatment strategies, including radiation, medical treatment, and observation alone; these modalities may, however, play a valid role in patients who are not surgical candidates. Based on the available evidence, the authors recommend surgical resection as the preferred primary intervention for symptomatic NFPAs.
Question What is the consensus within the scientific literature for the primary treatment strategy for patients with symptomatic nonfunctioning pituitary adenomas?
Level III: Surgical resection is recommended as the primary treatment of symptomatic patients with NFPAs.
QuestionWhat is the consensus within the scientific literature for the primary treatment strategy for patients with asymptomatic nonfunctioning pituitary adenomas?
Recommendation There is insufficient evidence to make a recommendation for treatment versus observation of asymptomatic NFPAs.
The management of nonfunctioning pituitary adenomas (NFPAs) includes surgical resection, radiation therapy, medical management, or observation. Since the development and refinement of surgical approaches to the sella turcica, surgical intervention has been the preferred method of treatment in symptomatic patients. More recent developments in radiation therapy, including non-fractionated gamma knife radiosurgery, have led to alternative treatment options for NFPAs. Several studies have also investigated the role of medical management of NFPAs using various hormonal analogs. This chapter focuses on the preferred method of primary management of NFPAs based on evidence from the literature.
The evidence-based clinical practice guideline task force members and the Tumor Section of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) conducted a systematic review of the literature relevant to the management of NFPAs. Additional details of the systematic review are provided below and within the introduction and methodology chapter of the guideline.
Disclaimer of Liability
This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. The presentations are designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in its development are not meant to replace the individualized care and treatment advice from a patient’s physician(s). If medical advice or assistance is required, the services of a physician should be sought. The recommendations contained in this guideline may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in this guideline must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.
Potential Conflicts of Interest
All NFPA Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs.
The task force collaborated with a medical librarian to search for articles published from January 1, 1966, to October 1, 2014. Authors searched 2 electronic databases, PubMed and the Cochrane Central Register of Controlled Trials. Strategies for searching electronic databases were constructed by the evidence-based clinical practice guideline taskforce members and the medical librarian using previously published search strategies to identify relevant studies (Appendix A).1-8
Twenty-six studies met inclusion criteria for analysis, of which all were Class III observational studies (Table 1). A flow chart summarizing study selection can be found in Figure 1. No Class I evidence comparing any treatment modality was available. A considerable amount of Class III evidence (14 studies) was identified supporting primary surgical intervention in symptomatic patients with symptomatic NFPA macroadenomas. Limited Class III evidence was identified for NFPA patients treated with observation (2 studies), primary radiation-based treatment (3 studies), or medical treatment (8 studies). One prospective/retrospective study compared NFPA patients treated surgically with those treated with dopamine agonist therapy.
Observation of Asymptomatic NFPAs
Natural history studies implementing only observation of NFPAs alone have rarely been reported in the literature. Dekkers et al (2007), in a retrospective analysis of 28 asymptomatic patients diagnosed with NFPAs who received no treatment following diagnosis, showed that radiologic evidence of tumor growth was observed in 14 of 28 patients (50%) (Table 1). Spontaneous reduction in tumor volume was seen in 8 patients (29%). Six patients (21%) required surgical intervention due to onset of visual field deficits.9 Arita et al (2006) reported observation alone in the management of “incidentalomas” in 42 patients. Over the course of 4 years, 17 patients (40%) showed increase in size of the NFPA on repeat imaging. Ten patients (24%) became symptomatic and 4 patients (9.5%) developed pituitary apoplexy. Of these 42 patients, 12 (28.6%) underwent surgical intervention during the period of follow-up due to new symptoms or increasing tumor size.10 Due to the paucity of available studies, there is insufficient evidence to make a recommendation regarding the primary treatment modality for asymptomatic lesions.
A considerable amount of Class III evidence (14 studies) was identified reporting outcomes following primary surgical intervention in symptomatic patients with symptomatic NFPA macroadenomas (Table 1). Overall, surgical resection resulted in immediate tumor volume reduction in nearly all patients and a residual tumor rate of 10%-36%. One prospective observational cohort study and multiple retrospective studies showed improved visual function in 75%-91% of surgically treated patients and improved hypopituitarism in 35%-50% of patients.10-20
Chen et al analyzed surgical outcomes in a prospective study of 385 patients with NFPAs that underwent surgical resection. Of these patients, 242 presented with visual symptoms, and 215 (87.6%) noted improvement in visual symptoms postoperatively. Residual tumor was identified on postoperative MRI at 4 months in 79 patients (20.8%), and 8 patients (2.1%) required lifetime pituitary hormone replacement postoperatively.11
Multiple retrospective analyses have reported clinical and imaging outcomes following surgical intervention for NFPAs (Table 1). Berkmann et al, in a series of 114 patients with NFPAs treated with surgical intervention at a single institution, showed that 42 of 83 patients (50.6%) presenting with preoperative hypopituitarism recovered significant pituitary function postoperatively. Additionally, of 79 patients presenting with preoperative visual field deficits, 78 (89%) demonstrated significant recovery of vision postoperatively.12 Comtois et al described the normalization or improvement of vision in 71 of 94 patients (75%) treated with surgical intervention for NFPAs who had initially presented with visual field deficits. Permanent pituitary dysfunction was seen in 7 of 126 total patients (5%), and the recurrence rate in their series was 21% (mean follow-up time of 6.4 years).13 Dallapiazza et al (2014) reported a gross total resection rate of 71% in 80 patients who underwent transsphenoidal resection of NFPAs. These patients were followed for at least 5 years, with tumor recurrence seen in 7 patients (12%).14 Dekkers et al (2006) showed that in 97 patients who underwent transsphenoidal resection of NFPAs without subsequent therapeutic interventions, 10 patients (10.3%) had evidence of tumor regrowth or recurrence on follow-up MR imaging (mean follow-up time of 6 years). The authors concluded that surgical intervention alone controlled tumor in 90% of all patients with NFPAs.15
In a separate study, Dekkers et al (2007) showed that visual acuity improved significantly within 3 months of transsphenoidal surgery; however, further improvement was seen 1 year postoperatively, indicating that the beneficial effects of tumor decompression can be seen in a delayed progressive fashion.16 Fleseriu et al demonstrated the efficacy of surgical resection of NFPAs on headaches. Of 15 patients with NFPAs that initially presented with headaches, 8 of 15 (53.3%) noted complete resolution of headaches postoperatively, and 4 of 15 (26.6%) reported improvement in headaches. Only 3 of 15 patients (20%) reported no change in headaches following surgical resection.17 Kurosaki et al showed improvement of visual field deficits in 19 of 23 patients (82.6%) treated with transsphenoidal resection of NFPAs.18 Mortini et al published a series of 378 patients with NFPAs treated with surgery in which 234 (64.8%) had gross total resection of tumor. In this series, 117 (40.5%) of the 289 patients with visual defects had normalization of vision, and another 148 patients (51.2%) showed improvement in vision postoperatively.19 Petruson et al published an early series of 48 patients with NFPAs treated with surgical resection. CT scans performed at an average of 4 years postoperatively in 44 patients revealed no signs of recurrent tumor in any patient. New hypopituitarism was evident in 6 of 48 patients (12%) postoperatively.20 Webb et al attempted to characterize the effects of surgical intervention for NFPAs on the postoperative endocrine status of patients. A retrospective analysis of 56 patients with NFPAs showed 24 (42.8%) with complete hormonal axis function postoperatively. Of the 56 patients, 3 (5%) developed new postoperative pituitary axis dysfunction. Some element of pituitary dysfunction was present preoperatively in 29 patients, and 19 of 29 (65%) had no change in function postoperatively, whereas 10 of 29 (35%) gained some function after surgery.21 This is contrasted by a report for Wichers-Rother et al, which retrospectively analyzed 155 patients with NFPAs treated with operative intervention and determined that anterior pituitary function did not significantly improve postoperatively.22
Ocular motility problems are commonly seen with patients presenting with pituitary apoplexy but less commonly in the absence of a bleed.23 Studies of pituitary patients who have suffered apoplexy have produced contradictory advice as to the role of surgical decompression, with 2 Class III studies favoring surgery,24 while another Class III study suggested observation may be as effective.23
The complication rate of surgical intervention has been demonstrated to be low. Halvorsen et al, in a retrospective analysis of 446 transsphenoidal procedures for NFPAs, describes a total complication rate of 7.1%. The most common complications included CSF leak (4.7%), meningitis (2.0%), and visual deterioration (2.0%).25
Radiation Therapy and Radiosurgery
Radiation therapy and radiosurgery has been firmly established as a secondary treatment modality in patients with recurrent or residual tumor. Assessment of the efficacy of radiation therapy in the primary treatment of NFPAs is sparse. In a retrospective analysis of 100 patients with NFPAs treated with Gamma Knife radiosurgery (GKS), 8 patients were treated with GKS as primary treatment. Of these 8 patients, 3 patients (38%) demonstrated decrease in tumor size on follow-up imaging, whereas 5 patients (62%) showed stable tumor size.26 Park et al published a retrospective analysis of 15 patients treated with GKS as a primary treatment. Of these patients, 9 (60%) demonstrated tumor size reduction on follow-up imaging and 4 (26.7%) showed no change. Two patients (13.3%) showed progression in tumor size.27 Lee et al published a series of 41 patients in which radiosurgery was performed as primary treatment due to high surgical risk. The tumor control rates at 5 and 10 years were 94% and 85%, respectively. Three patients required surgical intervention after initial treatment with radiation despite high-risk status. New onset cranial nerve deficit was noted in 1 patient.28
Evidence supporting consistent effective treatment of NFPAs with medical therapy alone is also sparse and inconsistent. Despite their inherent lack of hormonal functionality, the primary medical agents that have been assessed in NFPAs are dopamine agonist and somatostatin analogue agents. In a prospective observational study by Nobels et al, 8 patients with NFPAs were treated with quinagolide, a dopamine receptor agonist, and followed for more than 48 months. Of those 8 patients, 2 (25%) showed tumor shrinkage, whereas 6 (75%) showed an increase in tumor size of greater than 10%.29 Chakera et al attempted single-agent bromocriptine therapy in 5 patients with NFPAs, with no patients demonstrating any reduction in tumor size on serial CT scans.30 Van Schaardenburg et al reported the results of a prospective cohort study of 43 patients with NFPAs to assess efficacy of medical treatment with bromocriptine. Fifteen patients without prior history of surgery or radiation were treated with bromocriptine therapy, while 18 patients were treated with surgery alone. In the bromocriptine group, 3 patients of 15 (20%) showed tumor growth while 12 of 15 (80%) showed no changes on serial CT imaging. Visual field deficits worsened in 1 of the patients who had no change on CT imaging.31 Verde et al treated 20 patients with NFPAs using bromocriptine and serially assessed them via serial CT imaging and ophthalmologic examinations. One patient of 20 (5%) demonstrated a marked reduction in tumor size and improvement in visual fields. The remaining 19 patients (95%) showed no changes on imaging during treatment, and 4 of these patients required neurosurgical intervention for worsening visual deficits.32
Attempts have also been made to characterize the receptors for certain molecules present on NFPAs and differentiating the response to different medical therapies targeting these receptors. De Herder et al attempted to show differential response of NFPAs to dopamine agonist therapy based on uptake of 123I-epidepride, a D2 receptor agonist. NFPA stabilization or shrinkage with dopamine agonist therapy showed no significant difference between those NFPAs graded as 0, 1, or 2 on the scale of dopamine uptake on their grading scale.33
With regard to somatostatin-analogue therapy for NFPAs, Gasperi et al assessed the effect of single-agent octreotide therapy in patients with NFPAs. After 6 months of therapy, no significant change in visual fields or tumor size was seen in 7 of 8 patients (88%), whereas 1 patient (12%) demonstrated improvement in visual fields and decreased tumor size.34 Warnet et al followed 24 patients with NFPAs and visual changes treated with octreotide. Visual improvement was noted in 9 of 22 patients (40.9%) at 2 months; however, octreotide was stopped in 13 of 22 patients (59.1%) due to inefficacy.35
Combination medical therapy represents yet another avenue for treating NFPAs that is also lacking a strong evidence basis. In a prospective observational trial of 10 patients with NFPAs given a combination of octreotide and somatostatin for 6 months of therapy, Anderson et al found that 40% of patients showed stable or increased size of tumor, whereas 60% showed decrease in size. Those with decrease in tumor volume had tumors that demonstrated in vivo secretory potential.36
The treatment of NFPAs with surgical intervention has long been considered the primary treatment modality in symptomatic patients able to undergo surgery. The development of transsphenoidal and transcranial approaches to the sellar region has allowed for direct tumor decompression and rapid symptomatic relief with low complication rates in most series. The historical tendency to perform surgical resection first in these patients inherently limits the amount of Class I evidence available, as surgical resection has not been directly compared to either medical intervention, observation, or radiation-based therapy as primary intervention techniques in randomized controlled trials.
A large amount of Class III evidence supporting the use of surgical intervention as the primary treatment method for NFPAs exists in the literature. Most studies have been retrospective observational analyses of large series of surgical patients with a few prospective observational studies identified for surgical, medical, and observation treatment strategies alone.
Based on the available evidence, surgical management is the preferred method of primary treatment of symptomatic NFPAs with symptoms of visual field deficit or visual loss, ophthalmoplegia, compression of the optic apparatus on MRI, endocrinologic dysfunction including hypopituitarism or stalk effect causing hyperprolactinemia, pituitary apoplexy, refractory headaches not attributable to other headache syndromes, or other neurologic deficits related to compression from the tumor. A decision to treat asymptomatic, incidentally discovered NFPAs is a separate question for which there was insufficient evidence to make a recommendation. Numerous retrospective analyses highlight the efficacy of surgical resection in the improvement of vision and pituitary endocrine function in symptomatic NFPAs. No studies were found that directly compare primary treatment of NFPAs with surgical resection vs radiation therapy or medical therapy in a randomized, controlled fashion, likely because surgical intervention has been the mainstay of treatment for several decades.
Studies of radiation therapy as a primary treatment method have not shown superiority or equivalence to surgical resection of NFPAs. Radiation therapy has been shown to be an effective adjunct to surgical resection in the case of postoperative residual tumor or recurrence. Radiation therapy may also have a role in primary management of patients that are unfit for surgical intervention based on severe medical comorbidities or preoperative functional status. Primary radiation-based treatment in patients with NFPAs has not been adequately assessed in published series in which patients have clinical equipoise between surgical and nonsurgical treatments. Although there remains a possibility that radiosurgery may play a valid role in the primary treatment of NFPAs, there is limited and inconsistent data available to currently support this treatment strategy, and the risk of tumor progression and radiation-induced hypopituitarism are major disincentives.
Similarly, medical therapy has not been proven effective in the primary management of NFPAs. Neither the use of dopamine agonists nor somatostatin analogs, whether alone or in combination, have been shown to have a significant and consistent therapeutic effect on these tumors. A strategy of observation alone showed tumor progression in over half of patients, with over 20% requiring surgery as a result of progressive clinical symptoms.
Limitations and Future Research
The current study is limited by its systematic review methodology, which is inherently susceptible to various sources of bias, including publication, selection, and information bias. Similarly, the recommendations made are based on Class III evidence, without any prospective, randomized, controlled trial data available to truly compare efficacy of the treatment modalities in question (Table 1). Nevertheless, the results of this review highlight the existing evidence available, showing a dearth of observational data supporting the primary role of surgical resection in the treatment of symptomatic NFPAs. Future research may be directed toward primary treatment of NFPAs in patients who are unable to undergo surgical intervention based on medical comorbidities, a subset of patients in which the current literature is limited.
Based on the available evidence, surgical management is the preferred method of primary treatment of symptomatic NFPAs in patients with symptoms of visual field deficit or visual loss, ophthalmoplegia, compression of the optic apparatus on MRI, endocrine dysfunction, including hypopituitarism or stalk effect causing hyperprolactinemia, pituitary apoplexy, refractory headaches not attributable to other headache syndromes, or other neurologic deficits related to compression from the tumor, when compared to radiation, medical therapies, or observation alone as primary treatment strategies. Limited and inconsistent reports are available for alternative treatment strategies, including radiation, medical treatment, or observation alone; these modalities may, however, play a valid role in patients who are not surgical candidates.
Disclosure of Funding
These evidence-based clinical practice guidelines were funded exclusively by the CNS and the Tumor Section of the CNS and the AANS, which received no funding from outside commercial sources to support the development of this document.
The authors acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Committee for their review, comments, and suggestions throughout peer review, and Pamela Shaw, MSLIS, MS, for assistance with the literature searches. Also, the authors acknowledge the following individual peer reviewers for their contributions: Sepideh Amin-Hanjani, MD, Kathryn Holloway, MD, Odette Harris, MD, Brad Zacharia, MD, Daniel Hoh, MD, Isabelle Germano, MD, Martina Stippler, MD, Kimon Bekelis, MD, Christopher Winfree, MD and William Mack, MD. Lastly, and most significantly, the authors would like to acknowledge Edward Laws, MD, for serving as an advisor on this nonfunctioning adenoma guidelines project and providing comprehensive critical appraisal.
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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1. (("Pituitary Neoplasms/surgery"[Majr] AND "Adenoma"[Mesh]) OR "Sella Turcica/surgery"[Majr] OR "Adenoma, Chromophobe/surgery"[Majr])
2. (microadenoma* OR adenoma* OR macroadenoma* OR incidentaloma* OR chromophobe*[Title/Abstract]) AND (pituitary OR hypophyse* OR sellar[Title/Abstract])
3. (1 or 2) AND ((asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
4. NOT Comment[pt] NOT Letter[pt]
5. Limits: English and Humans, publication date to 10/01/2014
1. (("Pituitary Neoplasms"[Majr] AND Adenoma[Mesh]) OR ("Adenoma, Chromophobe"[Majr] OR "Sella Turcica"[Majr])
3. (1 or 2) AND (asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
4. 3 AND (("Bromocriptine/administration and dosage"[Mesh] OR "Bromocriptine/pharmacology"[Mesh] OR "Bromocriptine/therapeutic use"[Mesh]) OR ("Dopamine Agonists/administration and dosage"[Mesh] OR "Dopamine Agonists/pharmacology"[Mesh] OR "Dopamine Agonists/therapeutic use"[Mesh]) OR ("Adrenal Cortex Hormones/administration and dosage"[Mesh] OR "Adrenal Cortex Hormones/pharmacology"[Mesh] OR "Adrenal Cortex Hormones/therapeutic use"[Mesh]) OR ("Octreotide/administration and dosage"[Mesh] OR "Octreotide/pharmacology"[Mesh] OR "Octreotide/therapeutic use"[Mesh]) OR ("Dexamethasone/administration and dosage"[Mesh] OR "Dexamethasone/pharmacology"[Mesh] OR "Dexamethasone/therapeutic use"[Mesh]))
5. NOT Comment[pt] NOT Letter[pt]
6. Limit to English, Humans, publication date to 10/01/2014
1. (("Pituitary Neoplasms/radiotherapy"[Majr] AND Adenoma[Mesh]) OR "Adenoma, Chromophobe/radiotherapy"[Majr] OR "Sella Turcica"[Majr])
4. 3 AND (radiosurgery[mesh] OR radiotherapy[mesh] OR "gamma knife" OR cyberknife OR "brainlab" OR "brain lab" OR "proton beam")
5. NOT Comment[pt] NOT Letter[pt] Limit to English, Humans, publication date to 10/01/2014
1. MeSH descriptor Pituitary Neoplasms
2. MeSH descriptor Adenoma
3. 1 and 2
4. ((pituitary OR hypophyse* OR sellar) NEAR/4 (microadenoma* OR adenoma* OR macroadenoma* OR incidentaloma* or chromophobe*)):ti,ab,kw
5. 3 or 4 and (asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
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