Outcome and Quality of Life of Patients with Chordomas

Chordomas are unusual, slow-growing neoplasms that are presumed to originate from notochordal remnants that may persist anywhere along the axial skeleton, ¹^,² with a predominance in the sacrococcygeal region (50%) and in the clivus (35%). ¹^,³^,⁴^,⁵^,⁶

Skull base chordomas usually appear as encapsulated tumors in soft tissues, but they infiltrate bones along the lines of least resistance. ¹ Because of its origin from the bone at the skull base, the recurrence rate of these lesions, even after exceptionally complete resection, remains high. ⁷ The clinical course of chordomas is one of slow but relentless progression. Nevertheless, their proximity to important nervous system structures, such as cranial nerves, brainstem, and spinal cord, their tendency to recur, and their locally aggressive behavior give these tumors a malignant potential, often impacting neurologic function, leading to disability and death. ⁸ The burden of disease increases over time and affects the physical, social, and mental well-being of patients and increases the demand for caregiver support. ⁸ The objective of this chapter is to analyze the factors that influence the outcome and the quality of life in patients with chordomas.

29.2 Factors Influencing the Outcome

Several factors, such as patient age at onset of symptoms, the pathologic patterns of the tumor, extent of resection, adjuvant radiotherapy, and genetic abnormalities, are thought to influence the clinical outcome of patients with chordomas.

29.2.1 Age

Some authors have suggested that the age of the patient has an important role in the prognosis of skull base chordomas. ²^,⁷^,⁹^,¹⁰^,¹¹^,¹² Patients younger than 40 years of age are reported to have significantly better prognosis than for the older population ¹¹^,¹²^,¹³^,¹⁴ (5- and 10-year survival rates for patents < 40 years were 75% and 63%, respectively, compared with 30% and 11% for the patients ≥ 40 years). ¹¹ However, other authors have not shown age stratification to be a prognostic factor in the evolution of the disease. ¹⁵^,¹⁶^,¹⁷^,¹⁸

Chordomas in children behave very aggressively and have high levels of mitotic activity, hypercellularity, and pleomorphism. Many authors agree that patients with age over 5 years have a better survival rate. ²^,¹⁰^,¹²^,¹⁹ Histologic patterns are different in patients under 5 years and in patients ≥ 5 years. Classic chordomas and chondroid chordomas were found in only 35% and 0%, respectively, of the younger group. Atypical histologic findings with aggressive behavior occurred in 65% of the tumors in the younger group compared with 4.2% of the older group, and in patients with classic chordomas, a greater range of cellularity was noted in patients younger than 5 years of age. Similarly, the incidence of metastases was more than 7 times higher in children less than 5 years of age (57.9%) than in older patients (8.5%). ⁹ Therefore, the factor found to be determinant in the outcome of children with cranial chordomas is atypical histologic findings, a characteristic of this age.

29.2.2 Gender

The role of gender in the outcome of patients with chordomas is controversial. In 2014, Rachinger et al ¹⁷ reported that male patients had worse survival curve and recurrence-free survival (RFS) than female patients, both in univariate and multivariate analyses. In 2013 Kitamura et al ¹⁶ and in 1994 O’Connell et al ²⁰ reported that females had significant shorter survival and RFS rates than males, but most authors did not find difference in survival and RFS rates regarding gender. ²^,¹⁵^,¹⁸

29.2.3 Histopathologic Patterns of the Tumor

Chordomas are classified into three histologic types: classic chordoma, chondroid chordoma, and dedifferentiated or atypical chordoma. ²¹^,²² The chondroid chordoma has been found by some authors to follow a more benign clinical course. ¹^,⁴^,²³^,²⁴^,²⁵ However, other authors did not find a significant difference between survival and RFS curves for patients with typical chordomas and those with chondroid chordomas, ¹¹^,¹²^,¹⁵^,¹⁸^,²⁰^,²³^,²⁶ supporting the idea that the distinction of these subtypes has no practical meaning. Dedifferentiated and atypical chordomas with high levels of mitotic activity, hypercellularity, necrosis, and cellular pleomorphism are associated with shorter overall survival and RFS. ²⁷^,²⁸ Patients with chordomas with MIB-1> 5% had shorter RFS than patients with MIB-1 < 5%, ¹⁶ and patients with higher MIB-1 had more recurrence than patients with lower MIB-1. ²⁸^,²⁹

29.2.4 Size of the Tumor

Reports using data of patients with chordomas from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (USA), between 1973 and 2009 ¹⁴ and between 1983 and 2009, ¹² have shown that small tumor at the time of treatment predicts improved survival, and this is also reported for patients with chordomas treated with adjuvant radiation therapy. ²⁰^,³⁰^,³¹

29.2.5 Extent of Resection

Patients with untreated chordomas have average survival estimated as being 28 months after the onset of symptoms. ³² For patients who underwent surgery or radiation therapy, or both, overall survival ranges from 3.6 to 6.6 years, and all tumors will recur with time. ⁵^,¹⁴^,²⁵^,³³ On average, recurrence is observed from 2 to 3 years after primary treatment, but sometimes the tumor recurs more than 10 years after initial treatment ³⁴ or in the first months posttreatment. Surgery alone beyond biopsy has been considered to improve the survival of patients with cranial chordomas. ¹²^,¹³^,¹⁴ Complete resection obtained with one or more surgical procedures had a RFS rate of 41%. ⁶

Several authors consider that most cases of chordoma should be treated by aggressive resection. ¹⁵^,¹⁶^,¹⁷^,¹⁸^,²⁷^,³⁵^,³⁶^,³⁷ However, because the tumor originates from the bone at the base of the skull, complete resection is many times precluded by bone invasion and proximity to the cranial nerves and brainstem. Macroscopic total removal of chordoma frequently is followed by finding residual tumor in postoperative computerized tomography (CT) and magnetic resonance images (MRI). ⁷^,¹¹^,²¹ The survival rates after the primary resection at 5 and at 10 years range respectively from 30 to 87.8% and from 10 to 69%. ³^,¹⁵^,²⁷^,³⁸ The recurrence rate, even after radical resection, remains high (28%). ³² Current data in the literature support the idea that extensive resections of skull base chordomas allow increase in the survival rate to 80% or more at 5 years. ³^,⁶^,¹²^,¹⁴^,¹⁵^,¹⁷^,¹⁹^,²⁷^,³⁶^,³⁸^,³⁹ Patients who underwent gross total resection were reported to have better RFS (55–84% with the mean difference of 20.7% ³⁶^,⁴⁰ at 5 years) than patients submitted to partial resection (36–64%). ³^,¹⁵^,²¹^,³⁸^,³⁹^,⁴¹ George et al ¹⁹ found 20.5% deaths and 28% recurrences after total resection as compared with 52.5% and 47.5% after subtotal resection, indicating that quality of resection was the major factor of prognosis in their series.

Complications after radical surgery varies from 26 to 80%. ⁴^,²⁷ Morbidity rates of these complications are reported to range from 22.6 to 60.3%, and mortality rates vary from 2.05 to 7.85%, ⁶^,¹⁵^,²¹^,²⁷^,³⁵^,³⁸^,⁴⁰ and 28.6% sustained additional permanent postoperative deficits. ¹⁵ Cranial nerve deficits are the most frequent, varying from 34.9 to 80%, ¹⁵^,²¹ and many of these deficits completely or partially resolved during the follow-up period. ¹⁵^,²¹^,²⁷ Other complications reported were cerebrospinal fluid leakage (9.4–30%), meningitis (3.8–10%), and hydrocephalus (5.7%). ¹⁵^,²¹^,²⁷ No difference regarding postoperative complications has been reported for patients who underwent total or subtotal resection. ¹⁵^,¹⁷

29.2.6 Adjuvant Radiotherapy

Several retrospective studies based on information from SEER and NCA have shown that postoperative radiotherapy in general is considered to be a factor that improves survival ¹², ¹³, ¹⁴. The same results were reported in a systematic review of studies published in the English language. ² However, these studies involved patients who underwent several modalities of radiotherapy or surgery associated with radiotherapy, and these differences were not available or were not analyzed.

Conventional Radiation Therapy

Chordomas are considered relatively resistant to conventional radiotherapy, and this treatment does not appear to increase survival duration because it does not allow delivery of the doses necessary for chordoma cell death without severe side effects. ¹¹^,¹⁵^,²⁴^,³³^,³⁴^,⁴² In a review of the literature, Amichetti et al ⁴² reported 5- and 10-year overall survival of 53.5% and 50.3% and local tumor control at 5 and 10 years were 36% and 23.8%, respectively. Complications, especially worsening of preexisting cranial nerve deficits, were reported in 0 to 5%. ⁴²

Proton Beam or Proton–Photon Beam Irradiation

Proton beam radiation therapy has been demonstrated to be a valuable adjuvant modality that improves local tumor control. ⁴^,¹¹^,¹⁵^,¹⁹^,³⁸ The 5- and 10-year tumor control rates for patients with primary chordomas treated with aggressive resection and with photon, proton, or proton–photon beams therapy in the MRI era range respectively from 46 to 88% and from 35 to 60%, ⁴^,⁶^,⁷^,¹¹^,¹⁵^,²¹^,²²^,⁴²^,⁴³^,⁴⁴^,⁴⁵ and for recurrent tumors the 5- and the 10-year survival rates range respectively from 42 to 54% and from 0 to 31%. ⁴^,⁶^,²²^,⁴³ Better results of photon, proton, or proton–photon beams therapy were obtained for small tumors (in all patients with tumor volume smaller than 25 mL, the tumor remained controlled, compared with 56% of tumors greater than 25 mL). ³⁰^,³¹ Therefore, the surgical resection should be as extensive as possible to maximize the effect of the radiotherapy. ⁴^,²² Another important fact is that the dose necessary for tumor cell death in chordomas is 67 to 82 cobalt gray equivalent (CGE). ⁴^,²²^,³⁰

The incidence of local recurrences after photon, proton, or proton–photon beam therapy is reported to occur in 15 to 33% of patients (median time to local treatment failures of 32 to 60 months), ³⁰^,⁴⁴^,⁴⁶ with rates of 33% in 3 years, ³⁰ and local recurrence generally occurs in places that have been shielded, such as brainstem, cervical spinal cord, optic chiasm, and optic nerves. ⁴⁵

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