Recurrence in Skull Base Chordomas and its Management

The outcome in chordomas has consistently improved since the 1960s with the advent of several new treatment modalities including microneurosurgery, skull base surgery, endoscopic and endoscopic assisted skull base surgery, neuronavigation, intraoperative MRI, stereotactic radiosurgery, particle beam irradiation and novel fractionated radiotherapy delivery technologies. ¹^,²^,³^,⁴^,⁵Despite such significant progress, the treatment of skull base chordomas still continues to be far from perfect. The clinical course in the majority of cases is characterized by slow but persistent growth despite surgical resection and adjuvant therapy. Chordomas are characterized by a benign but locally aggressive tumor biology. The locally invasive nature of the tumor within the deep central skull base, surrounded by vital neurovascular and skeletal structures, precludes an oncologic resection with negative borders in most cases. Reports of sacral chordomas, where the resection is less limited by vital structures than in skull base chordomas, has taught us that extensive resections do have a dramatic impact on the disease course. ⁶ However, surgery of skull base chordomas is complicated, demanding, and risky and the end results are often far from satisfactory. Most studies report “radical resection” rather than radiologic gross total resection, and even with such limited goals, a radical resection is reported only in a minority of cases. A recent analysis of 416 skull-base chordomas from the Surveillance, Epidemiology, and End Results (SEER) database (1983–2009 records) reported a radical resection in 29% of the cases. ¹⁵ The clinical course of chordomas is also impacted by the tumors’ relatively low sensitivity to radiation therapy and complete lack of response in chemotherapy. Newer studies are documenting the role of upfront radiation therapy in decreasing the risk of recurrences and extending the time to recurrences. Therefore, with modern therapy, more extensive surgeries and upfront radiation provide longer progression-free survival periods ( ▶ Table 28.1). Nevertheless, the typical course in a patient with skull base chordoma even in the modern era involves an initial challenging surgical attempt followed by adjuvant radiation therapy, to be followed by a lucid interval of variable duration and eventual recurrences that result in cumulative neurologic morbidity and progressive functional decline.

**Table 28.1** Progression-free survival in chordoma cases as reported in the literature
Study	N	Follow-up (months)	5-Year progression- free survival	5-Year overall survival	Type of study-cohort; Risk factors for recurrence (Factors significantly associated with poor survival)
Choy et al 2015 ⁴⁸	57	N/A	41%	N/A	Surgical series; Age > 45, presence of visual deficits, no radiotherapy (no significant association with size, extent of resection, gender, histology, recurrent tumor)
Jahangiri et al 2015 ⁵⁰	50	41 median	N/A	N/A	Surgical series; Male gender, subtotal resection, location in the lower-third of clivus.
Di Maio et al 2012 ⁶	95	38.3 mean	56%	74%	Surgical series; 5-Year overall survival was higher in patients operated in 2000–2011, compared with those operated in 1988–1999. PFS and extent of resection were not different.
Kano et al 2011 ³⁷	71	60 median	66% (treated tumor control rate)	80%	Radiosurgery series; Age>45 and presence of visual symptoms indicative of worse local tumor control after Gamma-Knife radiosurgery.
Eid et al 2011 ⁵⁷	30 (7 in skull base)	N/A	73%	96%	Surgical series; No significant association with extent of resection, or tumor location.Recurrences significantly less in radiosurgery than in fractionated radiotherapy
Sen et al 2010 ¹²⁸	71	66 mean	64%	75%	Surgical series; Radical resection has positive impact on outcome
Ito et al 2010 ¹⁰	19	87.2 mean	47.9%	100%	Surgical series(Aggressive resection, RT in 4/19); MIB-1 proliferative index predictive of recurrence.
Hong Jiang et al 2009 ¹²⁹	12	19.4 median	N/A	N/A	Endosopic surgery series 33.3% recurrence and 8.3% mortality in less than 3 years.
Dassoulas et al 2009 ²²	15	38.3 mean	50.3%	N/A	Radiosurgery series; No predictive variables were found. Symptomatic progression seen in 75% of the patients.
Takahashi et al 2009 ¹³⁰	32	36.3 mean	29.3%	92.5%	Surgical series; 3 year recurrence-free survival significantly higher in particle beam treated patients
Cho et al 2008 ¹³¹	19	56 mean	40%	80%	Surgical series; severe disability with progressive disease in chordoma.
Yoneoka et al 2008 ⁶⁷	13	122 mean	69.2%	82.5%	Surgical series; Comparable outcome in particle beam treated and stereotactic radiosurgery treated patients.
Fatemi et al 2008 ¹³²	14	20 median	N/A	N/A	Endoscopic surgery series; improved cranial nerve deficits after surgery in 80%
Samii et al 2007 ¹³³	49	63 mean	15%	65%	Surgical series; Radical surgery extends recurrence free survival
Al-Mefty et al 2007 ¹³⁴	89	48 mean	51.4%	74.8%	Surgical Series; Chondroid chordoma survival is comparable to other chordomas
Foweraker et al 2007 ¹³⁵	9	38 mean	80%	62.8%	Radiotherapy series; High dose needed for local control
Schultz-Ertner et al 2007 ¹³⁶	96	31 mean	70%	88.5	Particle beam therapy series; Target dose of >60Gy and priary tumor status correlate with local control rate.
Martin et al 2007 ⁶⁸	18	88 median	53.4%	62.9%	Radiosurgery series; Multimodality treatment improves outcome
Stüer et al 2006 ¹³⁷	11	36 median	51.4%	N/A	Surgical Series; Better outcome with radical resection
Tzortzidis et al 2006 ¹²³	74	96 mean	41%	82.4%	Surgical Series; Aggressive surgical strategy is associated with long term tumor free survival.
Krishnan et al 2005 ¹³⁸	25	57.6 mean	32%	N/A	Radiosurgery series; High local complication rate when radiation combined with radiosurgery.
Noel et al 2005 ¹³⁹	100	31 median	53.8% (4 years)	80.5%	Particle beam therapy series; Homogeneity of dose within the tumor is a major determinant for local tumor control.
Igaki et al 2004 ¹⁴⁰	13	69.3 median	42.2%	66.7%	Particle beam therapy series; Preoperative and postoperative tumor volume are determinants of local control rate.
Pamir et al 2004 ⁹	26	48.5 mean	46.2%	76.9%	Surgical series; Preoperative tumor volume predictive of recurrence.
Pallini et al 2003 ¹⁴¹	22	62.8 mean	50%	61.5%	Translational research study; Telomere activation correlated with poor survival
Crockard et al 2001 ¹²⁵	32	51 mean	N/A	N/A	Surgical series; Age >50, high Ki-67 index are indicative of early recurrence.
Tamaki et al 2001 ¹⁴²	17	58.8 mean	51%	64%	Surgical series; Radical resection is correlated.
Debus et al 2000 ¹⁴³	37	27 mean	50%	82%	Stereotactic fractionated radiotherapy series.
Hug et al 1999 ²⁵	33	33.2 mean	59%	78.8%	Particle beam therapy series; Tumor volume and brainstem involvement influence outcome.
Al-Mefty and Borba 1997 ¹²⁴	25	25.4 mean	N/A	N/A	Surgical series; Mean disease-free interval 14.4 months.
Gay et al 1995 ¹²⁶	46	46 mean	65%	N/A	Surgical series; Total or near total resection is associated with better progression free survival.
Forsyth et al 1993 ¹⁴⁴	51	N/A	51% at 7years	N/A	Surgical series; Young age; Young age associated with better survival. Surgical resection and radiotherapy prolong disease free survival.

Improved understanding of the disease biology and improved surgical techniques and technology have made a significant impact on treatment of skull base chordomas, and current treatment results are much improved as compared with two decades earlier. ⁶ Most of the current research effort focuses on three main issues: (1) how to increase the safety and efficiency of the initial resection; (2) how to increase the safety and efficiency of adjuvant radiation therapy; and (3) how to treat recurrences. In the heart of these efforts lies the process of recurrence, which will be discussed in this chapter.

28.2 Patterns of Recurrence

Recurrence in chordomas can be observed in different forms. In the order of decreasing incidence, these forms are local recurrence, cerebrospinal fluid (CSF) seeding, surgical seeding, and distal metastasis ( ▶ Fig. 28.1, ▶ Fig. 28.2). Despite radical surgical resection, the incidence of local recurrence in chordomas ranges from 43 to 85%. ⁵^,⁶^,⁷^,⁸ The most common pattern is local recurrence, which is most commonly observed in the form of continued growth of a treated or untreated tumor remnant. In untreated tumor remnants or in those that have been treated with adjuvant fractionated radiotherapy, recurrences were most commonly observed within the residual tumor mass. Exact delineation of the tumor remnant greatly facilitates reliable detection of recurrences and the differential diagnosis from treatment-induced changes. Therefore, determination of the surgical residuals and their localizations are of crucial importance, and immediate–early postoperative magnetic resonance imaging (MRI) examinations performed within 48 hours after surgery have been reported to be valuable in this regard. ⁷^,⁸Early identification of tumor remnants has important consequences and can direct further attempts on surgery or can direct adjuvant treatment. ⁹^,¹⁰ Surgery is by far the most effective form of treatment for chordomas, and therefore every attempt to improve surgical results are valuable. In the case of early postoperative identification of tumor remnants, a second reexploration with an attempt to achieving final gross total surgical removal was attempted in 10.6% of our earlier cases ( ▶ Fig. 28.3, ▶ Fig. 28.4). ⁹ Introduction of intraoperative MRI has largely eliminated the need for such reexplorations, as maximally safe resection in a single operation can be achieved using intraoperative MRI. ⁸^,¹¹^,¹²^,¹³^,¹⁴

Fig. 28.1 A 55-year-old man presented to clinical attention with double vision and was diagnosed with a clival tumor (a). The tumor was resected using an extended transsphenoidal approach, and no adjuvant treatment was administered after demonstration of radiologic gross total resection (b). The patient presented 4 years later with local recurrence (c).

Fig. 28.2 A 34-year-old right-handed woman presented to medical attention with numbness in the face and diplopia and was found to have a left cavernous sinus mass lesion (a), which was resected in toto using a left-sided Dolenc’s extradural approach (b) and was diagnosed as a chordoma. Six years later, the patient presented with neck ache and her imaging revealed multiple frontobasal metastases (c) as well as an epidural metastasis at cervical C5 (d). Supratentorial lesions were treated with Gamma Knife radiosurgery and the cervical lesion was resected with a corpectomy and adjuvant radiotherapy (e).

Fig. 28.3 This incidentally found clival mass lesion in a 46-year-old right-handed female patient (a) was resected using a transbasal approach (b). A recurrence 2 years later (c) was treated again surgically with a right-sided Dolenc’s approach (d).

Fig. 28.4 A 34-year-old female patient presented to clinical attention with double vision and numbness in the face and was diagnosed with a mass lesion in the left-sided Meckel’s cave (a and b). The tumor was resected using a left-sided Dolenc’s approach (c and d). No adjuvant treatment was administered. Six years later, a recurrent intrasellar mass was found with further extension into the Meckel’s cavity (e and f). The intrasellar portion was resected transsphenoidally, and the portion in the Meckel’s cavity was treated using Gamma Knife radiosurgery. Four years after treatment, the patient is without recurrence and does not have any permanent neurologic deficits (g and h).

The growing experience in chordomas indicated that untreated chordomas had a very high likelihood of local recurrence and that adjuvant radiation therapy increased the recurrence-free survival. ¹^,²^,³^,⁴^,⁵^,¹⁵^,¹⁶^,¹⁷ In such cases, where safe delivery of high-dose radiosurgery was feasible, another pattern of local recurrence was noted: the use of radiation doses above 70 Gy provided effective control of the treated tumor volume. ¹⁸ Safe local delivery of such high doses is possible with particle beam irradiation, Gamma Knife radiosurgery or intensity-modulated radiation therapy (IMRT), all of which minimize the radiation dose delivered to the surrounding “normal” tissues. ¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶ This is in the form of recurrence just outside the margin of a radiosurgically treated volume that originally appears normal at the time of radiosurgery session. ¹⁰^,²⁰^,²³^,²⁷ Metastatic recurrence can also be observed in chordomas, and this takes the form of CSF dissemination, dissemination along the surgical path, or distant metastases. Seeding metastasis is rare but can be observed in chordomas. ²⁸^,²⁹^,³⁰^,³¹^,³²^,³³ Such seeding is observed in two different patterns in chordomas: It can either take the form of distant seeding along the CSF pathways or occur along the surgical path. Varying incidences of surgical seeding have been reported, and these range from 2.8 to 7.3%. ³⁰^,³¹^,³²^,³³Distant seeding along the CSF pathways can be focal or disseminated and in either case such lesions are mostly difficult surgical targets and also relatively resistant to radiation treatment. The most dreaded complication of distant metastasis in chordomas is most commonly observed in the lung, lymph nodes, skin, liver, and bone. ³⁴ The metastatic spread occurs via hematologic or lymphatic routes. When all chordomas of the skull base, axial skeleton, and the sacrum are considered, the reported incidence is in the order of 30%. ³³^,³⁴^,³⁵^,³⁶ However, chordomas in all anatomical locations are not associated with the same risk of distant metastasis. Distant metastases are significantly more common in chordomas in the sacrococcygeal region and in pediatric cases that are younger than 5 years and in those cases that carry anaplastic histopathologic features and high Ki-67 proliferative indexes (> 5%). ³⁶ In skull base chordomas, the incidence of distant metastasis is reported to be in the order of 7 to 14%. Management of recurrence is another issue. As noted earlier, the majority of chordomas will recur despite best efforts at initial treatment. The treatment at recurrence is not standard. Small and local recurrences are managed with repeat surgical resections and/or radiosurgery. ¹⁰^,²²^,²⁴^,³⁷ In more extensive recurrences, options are limited. Reirradiation and reoperation have been reported. ³⁸^,³⁹^,⁴⁰^,⁴¹

28.3 Factors Predictive of Recurrence

28.3.1 Age and Gender

The effect of age at presentation on the course of chordomas has been addressed in various studies. Chordoma is a disease of the elderly. In an early analysis of the SEER database, McMaster et al reported the median age at presentation for chordomas in general to be 58.5 (3–95) years. ² The authors also concluded that there was a progressive increase in the incidence with increasing age. A more recent analysis of 416 skull base chordomas from the same SEER database by Bohman et al ¹⁵ reported that only 9% of cases were younger than 18 years of age; 63% were older than 40 years and 29% were older than 60 years of age. As is evident from these figures, chordomas in the pediatric population are rare. However, several reports have documented that when observed in the pediatric population and especially in the infant and toddler, chordomas tend to have a more aggressive biolgy. ⁴²^,⁴³ A comprehensive analysis of previously reported patients indicated that patients younger than 5 years had poor prognosis when compared with those older than 5 years or adult patients. ⁴⁴ The difference between adult and infant forms of chordoma is not only individual survival patterns. Morphologically, the chordomas observed in children younger than 5 years tend to be more aggressive in appearance. Atypical and anaplastic histopathologic features are much more commonly observed, and metastases are far more common. ⁴²^,⁴⁵ These atypical features include small-round cell morphology, hypercellularity, and pleomorphism. Similarly, several molecular markers that have been established as indicators of an aggressive course in the adult chordoma population are observed more commonly in pediatric chordomas: These include high MIB-1 labeling index, nuclear TP53 expression, loss of INI1 (SMARCB1) expression and low E-cadherin (CDH1) expression. ⁴⁶^,⁴⁷ Borba, Al-Mefty, and colleagues reported that an aggressive surgery followed by radiation treatment was not correlated with a better prognosis in children younger than 5 years with an atypical or anaplastic tumor. ⁴² In the adult population, there is a reciprocal association: There is compelling evidence that older age is associated with a more aggressive tumor biology and poor survival in adult chordomas. In the analysis of SEER 1973–1995 results, McMaster et al ² have reported that the 10-year survival rate decreases from 62.1 to 31.4 to 18.4% at 2nd, 3rd, and 4th quartiles (26–48, 49–71, and 72–95 years) for chordomas in general. In a more recent report on the SEER database by Bohman et al, ¹⁵ decade of diagnosis was correlated with tumor-specific survival as well as overall survival in skull base chordoma patients both in univariate and multivariate analyses. Several smaller studies have used cutoff values of 40, 45, or 50 years for their analysis, but most studies indicate that the older population has a comparatively poorer progression-free survival and overall survival. ²^,³^,⁴^,⁵^,⁶^,¹⁵^,¹⁶^,⁴⁸

The effect of gender on the disease course in chordomas is a more controversial issue. In chordomas, a slight male predominance has been reported. ¹^,²^,⁴^,¹⁷^,⁴⁹ However, to date, no studies have demonstrated a mechanistic explanation of the effect of gender on disease biology of chordomas such as that for the strong female predominance in meningiomas. Conflicting results have been reported on the effect of gender on survival. Jahangiri et al ⁵⁰ in 2014 and Rachinger et al ⁵¹ have reported that recurrences are more commonly observed in male patients. Rachinger et al ⁵¹ reported the results of a multivariate analysis for their cohort of 47 chordomas and showed that male sex was associated with significantly shorter progression-free survival and significantly shorter overall survival and that this association was not confounded by other variables, including the extent of resection and adjuvant radiation therapy. These findings are in contrast with the findings of O’conell et al ⁵² and Halperin et al., ⁵³ who in the 1990s have shown that survival is worse in female patients. Several studies, on the other hand, have concluded that there is no effect of gender on survival. ⁴⁴^,⁵⁴^,⁵⁵ Smoll et al ³ have studied the effect of gender on chordoma survival using the SEER database and concluded that sex did not influence the outcome of the disease in cranial or extracranial chordomas. This study involved the largest study population to date to analyze the effect of gender on disease course in chordomas, and other studies only report results of small cohorts. It is highly likely that the observation that gender has an effect on survival in chordomas is related to selection bias.

28.3.2 Initial Tumor Size and Extent

It is not unexpected that with increasing tumor size, chordoma surgery would become more complicated and that these cases would be associated with larger tumor residuals, which would eventually result in regrowth/recurrence events. Unfortunately, most chordomas are large at presentation. Bohman et al ¹⁵ reported that only 50% of the 416 skull base chordomas in their analysis were limited within the periosteum of the primary site. Their analysis also demonstrated that size larger than 4 cm was associated with significantly poorer overall survival.

Chordomas grow with an infiltrative pattern within the bone. Benign, expansile tumors of the skull base such as meningiomas or schwannomas exhibit a radial growth pattern and grow centered around an epicenter. In contrast, chordomas exhibit an unpredictable growth pattern and in the majority of cases do not grow in a radial linear fashion like meningiomas. During surgery, new tumor compartments are commonly observed beyond normal-looking, intervening bone tissue. Therefore, studies promoting aggressive surgical approach for chordomas point to the need for drilling of peritumoral normal-appearing bone. ⁶^,¹⁰^,⁵⁴^,⁵⁶