Natural History and Adjunctive Modalities of Treatment

Natural History and Adjunctive Modalities of Treatment


Keywords: meningioma, follow-up, adjuvant treatment, radiotherapy, radiosurgery, chemotherapy


Peter F. Morgenstern, Jonathan Forbes, Theodore H. Schwartz



Abstract


Follow-up and adjunctive modalities of treatment for meningioma are highly variable. Underlying biology and the expected natural history of meningioma are dependent on the tumor grade, with World Health Organization (WHO) grade I lesions exhibiting the most indolent, benign behavior and WHO grade III tumors behaving most aggressively. Need for, and selection of, adjuvant treatment modality is not standardized, but follow some general guiding principles in considering the goals of achieving long-term tumor control while minimizing neurologic compromise. Radiation, in the form of conventional radiotherapy, stereotactic radiosurgery or brachytherapy, has been employed with success. More recently, trials of medical therapies for more aggressive lesions have been undertaken and yielded promising results but these are not yet the standard of care.


19.1 Introduction


Adjunctive modalities for the treatment of meningioma have advanced substantially over the last 30 years. Recognition of variable underlying tumor biology affecting the aggressiveness of this entity has led to studies of adding radiation and other medical adjuncts to surgical resection, or in some cases independent of surgical intervention. In this chapter, we will review the natural history and recurrence rates for World Health Organization (WHO) grade I, II, and III meningiomas, as well as the current data supporting available adjunctive therapies.


19.2 Natural History


Long-term management of meningiomas is dictated in large part by the natural history of the tumor, which varies substantially by tumor grade and biological behavior, as well as the treatment modality that is applied. Surgery remains the first-line treatment of most meningiomas, and extent of resection as assessed by the Simpson grading scale was identified early on as a method for predicting recurrence (▶ Table 19.1). 1 Although this scale does not account for tumor biology, is subject to surgeon bias, and was formulated before the development of modern microsurgical techniques, it remains an effective predictor of recurrence for grade I meningiomas. 2,​ 3,​ 4 An important consideration, however, is that extent of resection is heavily influenced by tumor location. For example, a complete resection with wide margins may be accomplished relatively easily for a convexity lesion but not for one of the cavernous sinus. Thus, extent of resection combined with a clear understanding of biological behavior, tumor location, and adjuvant modalities can provide a more complete assessment of long-term prognosis and expected outcome, thus guiding the selection of appropriate adjuncts and timing of follow-up.



































Table 19.1 Simpson Grading Scale for extent of resection of meningioma as a predictor of postoperative recurrence or progression of disease.

Grade


Extent of Resection


Recurrence/Progression (%)


I


Compete tumor resection including dural attachment and abnormal bone


8.9


II


Complete tumor resection with coagulation of dural attachment


15.8


III


Complete intradural tumor resection without removal or coagulation of dural or extradural extension


29.2


IV


Partial resection


39.2


V


Decompression without resection, +/- biopsy


88.9


Adapted from: Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957; 20(1):22–39


Tumor location has been presented as an indicator of behavior, but the results are controversial. While some have proposed that skull base meningiomas may follow a more indolent course than previously thought, 5,​ 6 others find that many skull base lesions are aggressive, with a high recurrence rate when complete resection is not achievable. 7 These findings suggest that a multi-pronged approach and an eye toward medical therapies in development for unresectable tumors are critical for improving long-term outcomes in this population. Furthermore, the eloquent structures associated with many skull base lesions, in particular petroclival meningiomas, limit the surgeon’s ability to achieve a gross total resection without significantly increasing morbidity. Although gross total resection is preferred to maximize overall survival, it is often prudent to attempt subtotal resection with adjuvant radiation, an approach that has been shown to yield high rates of local control while minimizing surgical morbidity and maximizing quality of life. 8,​ 9,​ 10,​ 11,​ 12


Decisions regarding frequency of follow-up imaging and the addition of adjuvants in the post-operative period are affected by predictors of recurrence. The most robust of these predictors are extent of resection as defined by Simpson, 1 the presence of brain invasion and the proliferation rate as observed histologically by MIB-1 (cell proliferation marker) index. However, other factors have been identified in observational data as potential additional data points to predict recurrence and push the practitioner to initiate more frequent follow-up or add adjuvant treatments. These include pial-cortical arterial supply, larger tumor size, presence of edema on preoperative MRI, absence of brain-tumor interface at surgery (a surrogate for brain invasion), and osteolysis. 13


19.2.1 WHO Grade I


Tumors classified as WHO grade I comprise the largest subset of meningiomas at diagnosis (81%). These tumors are considered benign, with a low recurrence rate (12% at 5 years). 14 Recurrences of WHO I cranial meningiomas may continue to exhibit benign clinical and histologic behavior, but some will demonstrate more aggressive activity at the time of recurrence. It has been suggested that convexity meningiomas behave in this manner more frequently than those of the skull base, though the evidence for this conclusion is limited to retrospective observation. 6


Despite their benign clinical behavior, the clinical course associated with these tumors is not entirely indolent. Recent evidence has shown that long-term neurocognitive outcomes in patients with WHO I meningioma following surgical resection are impaired when compared to age-matched controls. These patients have higher rates of epilepsy and demonstrate significant impairments in verbal memory, executive functioning, information processing capacity, psychomotor speed, and working memory. Patients with left-sided tumors also exhibit higher rates of verbal memory deficits. 15All of these factors directly impact quality of life and are critically important components of counseling and decisions to intervene for these patients.


Surgical extirpation is generally accepted as the primary treatment modality for low-grade meningiomas. Simpson I resection remains the goal, with the highest rate of long-term progression-free survival (PFS). However, recent evidence has called into question the importance of wide resections, with limited data suggesting that the differences between Simpson I, II, III, and even IV resections are nonsignificant and perhaps not clinically relevant in the modern era for grade I tumors. This point is supported by the excellent control rates associated with stereotactic radiosurgery (SRS) or radiotherapy (SRT) used as an adjuvant to near total resection. 16 Further prospective study of this question is needed for clarification, but the key guiding principle remains preservation of neurologic function for patients undergoing resection of grade I lesions given the high rates of local control afforded by adjuvant radiation treatment.


As an alternative to surgery, some have proposed radiotherapy alone for small, asymptomatic lesions in difficult locations, particularly for older patients. This approach has yielded long-term PFS rates as high as 90%, though care must be taken to ensure frequent follow-up imaging to ensure that the tumor exhibits benign behavior in the absence of a histologic diagnosis. 17


19.2.2 WHO Grade II


Compared to benign meningiomas, grade II, or atypical, meningiomas portend a more troublesome course. They represent approximately 15% of all meningiomas and have a 35 to 41% 5-year recurrence rate. 14,​ 18 Their high rate of recurrence and relatively high incidence has allowed for extensive study and a wide array of approaches to improving overall survival for patients with this disease.


Factors contributing to recurrence or progression for atypical meningioma include subtotal resection, advanced age at diagnosis, MIB-1 index more than 8%. 19,​ 20 More recently, attention has been focused on molecular and genetic markers of recurrence risk, with one group finding that a higher rate of copy number alterations correlates with recurrence rates in a cohort of completely resected atypical meningiomas. 21 Other molecular markers and driving pathways for this subtype are under investigation but have not clearly correlated with survival or risk of recurrence.


For these tumors, many recommend adjuvant radiation regardless of extent of resection, in order to reduce recurrence rates. In the optimal case, gross total resection in combination with adjuvant radiotherapy has been shown to achieve high rates of local control. 19,​ 22 However, recently, there has been some controversy over the role of adjuvant radiation to the tumor bed of completely resected grade II tumors. Some suggest immediate postoperative treatment while others advocate a delayed approach, treating only recurrent disease to reduce the radiation burden. The most effective approach is unclear, but most agree that adjuvant radiation is needed if any residual remains.


One potential treatment paradigm based on extent of resection includes MRI of the brain every 3 months for 1 year, then every 6 months for 1-year follow-up by annual follow-up for those undergoing complete resection of an atypical meningioma. Supporters of this approach advocate radiosurgery or resection depending on the nature of recurrence (location, size, and growth rate). Incompletely resected tumors that can undergo radiosurgery are best treated with this adjuvant approach, while those without a target that is amenable to radiosurgery can either be treated with conformal radiation or expectant management. Expectant management of residual disease after surgery is generally reserved, however, for those who are considered high risk radiation candidates (poor wound healing, prior radiation, genetic tumor predisposition) or for whom recurrence at the site could be easily reresected or treated with radiosurgery (i.e., noneloquent convexity tumors). 23


19.2.3 WHO Grade III


These are the most aggressive meningiomas, occurring in 1 to 4% of cases and accumulating a 56% 5-year recurrence rate. 14,​ 24 Their rarity makes large studies challenging, and outcome data is primarily limited to case series. 18 Based on the limited data available, however, outcomes are quite poor for these tumors, with a 5-year mortality of 40 to 83%, 10-year mortality of 40 to 100% and median survival of 1.5 years. 24,​ 25,​ 26,​ 27,​ 28 The benefits of complete surgical resection for this disease are clear, with more recent data showing those undergoing gross or near-total versus subresection having a 64.5% versus 41.1% 5-year survival rate. 20,​ 24 High mitotic count, proliferation indices, and the presence of brain invasion on histologic analysis have been shown to independently predict poor outcome for this meningioma type, as with the other grades. 29 Younger patients (<60 years) appear to have improved outcomes over older patients as well. 28


Because of their aggressive behavior and high early recurrence rate, frequent radiographic and clinical follow-up is mandatory for these patients. Most authors agree that adjuvant radiation, either in the form of RT or SRS, is an important component of the clinical paradigm. 25,​ 27,​ 28,​ 30 Although data to support this paradigm is retrospective in nature, the survival differences when compared to historic controls are significant, 40% with radiation versus nearly zero without. 24,​ 25,​ 28 Repeat surgical resection with or without radiation is applied for recurrences. Medical therapies, typically on investigative protocols, are applied for patients with multiply recurrent disease. 27


19.3 Adjunct Treatment Modalities


19.3.1 Radiation


Meningioma management increasingly employs adjuvant therapies, including radiation, when a curative resection is not possible or when more aggressive pathology is identified. This can include a variety of circumstances, such as eloquent location, aggressive biology, or in cases of recurrence. Although many radiation modalities and treatment plans exist, those most frequently discussed in the published literature on meningioma management are SRS, conformal external beam radiotherapy (EBRT), and brachytherapy.


 Conformal External Beam Radiotherapy


Conformal EBRT is applied in the management of meningioma with the expectation of delaying or arresting tumor growth, rather than reducing tumor size. Some tumors will shrink in a delayed fashion with this modality, and there are reports of dramatic responses to therapy, but this is not typical. 17,​ 31,​ 32,​ 33 This makes it a useful adjunct to prevent or slow recurrence for tumors that have been partially debulked, particularly those adjacent to critical radiosensitive structures, and are therefore, not amenable to radiosurgery. RT may also be useful for patients who are not surgical candidates due to medical comorbidities.


RT dosing and fractionation for meningioma are variable, but doses are typically in the range of 50 to 60 Gy spread over approximately 30 fractions. 32 Postoperative radiotherapy has been attempted in all meningioma types, but the most consistent benefit has been observed in those with grade II and III tumors with incomplete resection. In these patients, RT has been shown to improve local control and survival. 34,​ 35,​ 36


Radiation sources, in particular particle (proton or carbon) and photon, have been evaluated for efficacy in grade II and III meningiomas, partially resected and recurrent lesions. Both have been shown to achieve higher rates of local control than surgery alone. Small series have suggested that proton beam therapy or combinations of proton and photon beams may be more effective than photon beam alone, though evidence to support this conclusion remains limited. And while proton beams may afford more precise targeting, both sources have been shown to be well-tolerated with low rates of radiation necrosis and other complications. 31,​ 33,​ 35,​ 37,​ 38 The primary benefit of particle therapy is a potential reduction in the rate of secondary malignancy. This, however, is difficult to demonstrate as it requires very long-term follow-up, for which studies are ongoing. 39


Patients with low-grade lesions may also benefit from fractionated radiation therapy. For example, RT at the time of initial resection, rather than recurrence, has been advanced as an option for patients with pathology predicting higher recurrence rates, such as papillary meningioma and even for other grade I tumors, and has been shown to improve overall survival in a small cohort. 40,​ 41 Recurrent low-grade tumors in difficult surgical locations have also been shown to achieve high local control rates with the addition of radiation therapy (93% at 5 years, 86–91% at 10 years). 39,​ 41


Complications of conformal radiotherapy are uncommon with careful planning around critical structures. But delayed toxicities including cranial neuropathies, in particular optic neuropathy, and radiation necrosis of healthy brain tissue do occur in 0 to 19% of patients among modern studies of patients with skull base lesions. Patients with convexity lesions experience complications at a lower rate. 32 Patients with convexity lesions experience complications at a lower rate.


 Stereotactic Radiosurgery


SRS has been extensively studied for all grades of meningioma, both as a stand-alone treatment and as an adjuvant to surgery. Initially, this modality was applied to unresectable or incompletely resectable skull base lesions with tumor control rates of 85 to 100% using either gamma knife or linear accelerator-based technologies. 42,​ 43,​ 44,​ 45 Margin doses for SRS to meningiomas typically range from 12 to 18 Gy. 9,​ 43,​ 46,​ 47


This role as an adjuvant or second-line treatment is well-established with strong supportive data when tumor volume and location accommodate this modality. Tumor control rates are improved for higher grade lesions with SRS compared to without radiation, and high rates of control have been achieved for incompletely resected grade I lesions as well. 46,​ 48


Indications for SRS in the management of meningioma have expanded as technology has improved and impressive tumor control rates with low rates of toxicity have been demonstrated. SRS has been studied as an upfront treatment for surgically inaccessible or difficult lesions, in particular those of petroclival origin. While these studies are inevitably confounded by a lack of histologic data to confirm tumor grade, they do provide some evidence that ablative doses of focused radiation may provide long-term tumor control without surgery. Predictors of good tumor response include small size and no history of prior radiation. Furthermore, careful SRS planning has been shown to preserve cranial nerve function when tumor volumes are small. 46,​ 49,​ 50,​ 51 Thus, for small lesions that, due to location, are difficult to access safely with surgery, SRS may be a useful tool to achieve tumor control.


Limited studies have been undertaken to evaluate hypofractionated stereotactic RT as well, a potentially useful adjunct for patients with skull base lesions that cannot be safely targeted with single fraction ablative doses of radiation. Hypofractionated treatment plans vary widely in both prescribed dose and fraction number depending on morphology of the lesion and proximity to sensitive structures. 52This approach appears to be safe and well-tolerated and may afford some level of tumor control, though further investigation is needed to confirm this assertion. 53


Open questions about SRS include its role as an upfront treatment compared to surgery, and its position in multidisciplinary approach to more aggressive lesions. Comparisons of rates of tumor control for low-grade lesions show similar results between conformal EBRT and SRS, while control rates appear to be slightly better with radiosurgery for high grade lesions (▶ Table 19.2

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Jul 31, 2019 | Posted by in NEUROSURGERY | Comments Off on Natural History and Adjunctive Modalities of Treatment
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