Osteosarcoma is the most common primary malignancy of bone, National Cancer Data Base Report on Osteosarcoma of the Head and Neck

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1 1670 National Cancer Data Base Report on Osteosarcoma of the Head and Neck Russell B. Smith, M.D. 1 Louis W. Apostolakis, M.D. 1 Lucy H. Karnell, Ph.D. 1 Brenton B. Koch, M.D. 1 Robert A. Robinson, M.D. 2 Weining Zhen, M.D. 3,4 Herman R. Menck, M.B.A. 5 Henry T. Hoffman, M.D. 1 1 Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa. 2 Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa. 3 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska. 4 Department of Otolaryngology-Head and Neck Surgery, University of Nebraska Medical Center, Omaha, Nebraska. 5 Cancer Surveillance Program of Los Angeles County, University of Southern California School of Medicine, Los Angeles, California. BACKGROUND. Osteosarcoma is the most common primary bone malignancy overall but is encountered infrequently in the head and neck. Limited data are available on the significance of prognostics factors and results of therapy for patients with head and neck osteosarcoma (HNOS). It is known that surgical therapy is critical to successful outcome. The impact of adjuvant chemotherapy has not been defined well. METHODS. The National Cancer Data Base has collected data on cases of HNOS by voluntary accrual from participating hospitals. This database was used to assess patient demographics, tumor characteristics, treatment, and outcome for an 11- year period extending from 1985 to RESULTS. The data set contained 496 cases of HNOS. Overall, the 5-year diseasespecific survival rate was 59.7%. Factors associated with a poor prognosis were age older than 60 years; nonmandibular tumor location; tumor size 6 cm; histologic type of osteoblastic, not otherwise specified (NOS); advanced disease stage; nonsurgical initial therapy; and positive margins of resection. Increased use of multimodality therapy was noted during the later years of the study. No substantial difference in the 5-year survival rate was noted between treatment with surgery alone (74.7%) and surgery with adjuvant chemotherapy (71.3%), despite the greater prevalence of tumors with poor prognostic factors in the surgery and adjuvant chemotherapy group. CONCLUSIONS. Surgery with clear margins is an important factor in successful therapy for patients with HNOS. Improved survival has been noted within the last 2 decades compared with historic controls. Multiple negative prognostic factors have been identified and should be considered in treatment planning. The role of chemotherapy has not been defined well, but its incorporation into treatment of patients with high-risk tumors may improve survival. Cancer 2003;98: American Cancer Society. Presented at the Fifth Research Workshop on the Biology, Prevention, and Treatment of Head and Neck Cancer, McLean, Virginia, August 26 30, From the Commission on Cancer at the American College of Surgeons (Chicago, Illinois) and the American Cancer Society (Atlanta, Georgia). Address for reprints: Lucy Hynds Karnell, Ph.D., Department of Otolaryngology Head and Neck Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; Fax: (319) ; lucy-karnell@uiowa.edu Received March 17, 2003; revision received July 7, 2003; accepted July 20, KEYWORDS: osteosarcoma, head and neck neoplasms, National Cancer Data Base, chemotherapy. Osteosarcoma is the most common primary malignancy of bone, with a reported incidence of 1:100, These tumors typically originate in the extremities and the pelvis, with only 6 10% of patients presenting with a head and neck primary tumor. 2,3 The mandible and maxilla are the predominate locations of head and neck osteosarcoma (HNOS), although extragnathic bone as well as soft tissues sites may be affected. The infrequency of HNOS has prohibited the execution of randomized studies to help establish treatment guidelines for patients with this disease. Most studies have been retrospective case series that included a small cohort of patients treated over a broad time span with multiple treatment modalities. This method limits meaningful analysis of treatment outcome. Con American Cancer Society DOI /cncr.11716

2 Head and Neck Osteosarcoma/Smith et al sequently, the current treatment for HNOS (specifically, the use of chemotherapy) has been based largely on experience with osteosarcoma of sites outside of the head and neck. Many question the validity of managing HNOS in a similar fashion to osteosarcoma outside the head and neck because of the differences in disease characteristics that have been noted at these sites. The peak age of incidence for osteosarcoma outside the head and neck is in the adolescent years. In contrast, HNOS most commonly affects patients in their 30s. 1,4 7 Distant metastases have been reported in 10 20% of patients with HNOS, compared with 53 75% of patients with disease arising outside the head and neck. 1,8 10 The 5-year, disease-specific survival rate for patients with HNOS has been poor, with most studies reporting survival rates of 23 37%. 1 3 Management of osteosarcoma outside the head and neck prior to the standardized use of chemotherapy resulted in worse 5-year survival rates of 10 20%. 11,12 It is widely accepted that wide surgical excision is the mainstay of therapy for patients with HNOS. Adjuvant treatment with radiotherapy and/or chemotherapy also has been administered. For patients with osteosarcoma arising outside the head and neck, surgery also is considered a key component in therapy, but the addition of neoadjuvant and/or adjuvant chemotherapy has improved survival markedly. The Multi-Institution Osteosarcoma Study identified an increase in the 6-year, event-free survival rate from 11% with surgery alone to 61% when chemotherapy was given postoperatively. 13 Over the last 2 decades, the standard therapy for patients with non head and neck osteosarcoma has evolved to routinely include both neoadjuvant and adjuvant chemotherapy. With these regimens, long-term survival rates of 70 80% are being obtained. 14,15 Whether these same results can be obtained in patients with HNOS is not yet known. Two recent meta-analyses addressing the role of chemotherapy in the treatment of HNOS reported opposing results. 1,6 The National Cancer Data Base (NCDB) has accrued cancer registry data for patients diagnosed with cancer from a broad spectrum of hospitals in the United States. Evaluation of this data set permits analysis of large numbers of cases of rare malignancies. In the current article, patterns of presentation, management, and outcome are presented using an NCDB data set of patients who were diagnosed with HNOS between 1985 and MATERIALS AND METHODS The NCDB is a joint project of the American College of Surgeons and the American Cancer Society. The data are submitted yearly on a voluntary basis from participating hospitals by their in-house cancer registries, as described previously. 16 The NCDB cancer registry data are coded as described in the Data Acquisition Manual, the International Classification of Disease for Oncology, (second edition; ICD-O2), and the American Joint Commission on Cancer (AJCC) Manual for Staging of Cancer (first through fourth editions) The current report includes patients with primary HNOS who were diagnosed or treated at the reporting hospital between 1985 and The histologic subtypes for osteosarcoma included osteoblastic, not otherwise specified (NOS); chondroblastic; fibroblastic; telangiectatic; juxtacortical; small cell; and osteosarcoma arising within Paget disease (ICD-O2 codes, M9180 M9185 and M9190). Because this coding system combines osteoblastic sarcoma with osteosarcoma, NOS, these two subtypes cannot be analyzed separately. Tumor sites included in NCDB studies of the head and neck have been defined previously. 24 In the current review, the site of origin was grouped into the following three categories: 1) skull and facial bones (C41.0); 2) mandible (C41.1); and 3) other head and neck sites (lip, oral cavity, pharynx, major salivary glands, sinonasal tract, and larynx [C00.0 C14.8, C30.0, C31.0 C31.9, and C32.0 C32.9, respectively]; middle ear, trachea, olfactory nerve, thyroid gland, parathyroid glands, and other endocrine-gland-related structures, excluding the pineal and pituitary glands [C30.1, C33.9, C72.2, C73.9, C75.0, C75.2, and C75.4 C75.9, respectively]; peripheral nerves and autonomic nervous system [C47.0]; connective, subcutaneous, and other soft tissues [C49.0]; lymph nodes [C77.0]; and other nonspecific or ill-defined head and neck sites [C76.0]). Because the ICD-O-2 coding system classifies bones of the head and neck as either the mandible or other craniofacial sites, the maxilla cannot be separated from the other extragnathic craniofacial sites. Tumors categorized as gum, NOS were included in the other category, because there was not adequate information to group these patients in the mandible or the skull and facial bones group. Information extracted from the NCDB included demographic data about patient age, gender, race, and income status. Patient income was estimated as the average for all individuals living within the zip code of their residence at the time of diagnosis and was stratified as low income ( $20,000; representing an approximation of the lowest 10%), high income ( $47,000 or more; representing an approximation of the highest 10%), or middle income (the approximate 80% that fell between these two ranges). 24

3 1672 CANCER October 15, 2003 / Volume 98 / Number 8 TABLE 1 Demographics for Osteosarcoma of the Head and Neck Characteristic No. of patients (%) Age (median, 38 yrs) 30 yrs 174 (35.1) yrs 203 (40.9) 60 yrs 119 (24.0) Total 496 (100.0) Gender Male 249 (50.2) Female 247 (49.8) Total 496 (100.0) Race/ethnicity White, non-hispanic 338 (68.1) African American 91 (18.3) Hispanic 37 (7.5) Other/unknown 30 (6.1) Total 496 (100.0) Income Low 67 (14.6) Middle 352 (76.9) High 39 (8.5) Subtotal known income 458 (100.0) Unknown income 38 (7.7) a Total 496 ( ) a Percent of all cases. Disease characteristics included anatomic site, histologic subtype, grade, tumor size, and stage. The AJCC staging systems for osteosarcoma of the bony sites and soft tissues were used to classify the extent of disease for patients with these types of lesions The staging system for bony sites (up to and including the 4th edition) takes into account extracortical extension and tumor grade. The three categories are Stage I (low-grade tumors without metastases), Stage II (highgrade tumors without metastases), and Stage IV (all tumors with regional or distant metastases; Stage III does not exist). The staging system for soft tissue osteosarcoma, which takes into account tumor size and grade, has the following categories: Stage I ( 1 tumors without metastases), Stage II ( 2 tumors without metastases), Stage III ( 3 4 tumors without metastases), and Stage IV (all tumors with regional or distant metastases). The combined AJCC stage presented in the current article represents pathologic stage that was augmented with clinical stage when pathologic stage was not reported. Because only a subset of patients in the current study could be staged using either AJCC staging system, the report incorporates general summary stage (GSS) in most analyses involving extent of disease. 25 The GSS staging system groups patients into those with local, regional, or distant disease. Like the AJCC stage groupings, GSS classifies patients according to TABLE 2 Disease Characteristics for Osteosarcoma of the Head and Neck Characteristic Count (%) Anatomic site Skull/facial bones 276 (55.6) Mandible 193 (38.9) Other 27 (5.5) Total 496 (100.0) (cm) 3 94 (36.9) (42.0) 6 54 (21.1) Subtotal known size 255 (100.0) Unknown size 241 (48.6) a Total 496 ( ) Osteoblastic, NOS 382 (77.0) Chondroblastic 78 (15.8) Fibroblastic 17 (3.4) Telangiectatic 2 (0.4) In Paget disease 10 (2.0) Juxtacortical 7 (1.4) Total 496 (100.0) 1 (well-differentiated) 42 (17.9) 2 (moderately differentiated) 48 (20.4) 3 (poorly differentiated) 84 (35.7) 4 (undifferentiated) 61 (26.0) Subtotal known grade 235 (100.0) unknown 261 (52.6) a Total 496 ( ) NOS: not otherwise specified. a Percentage of all cases. their highest level of involvement. Unfortunately, GSS cannot be broken down into the individual components (equivalent to the AJCC TNM classifications) to determine whether patients classified with distant disease also have regional metastases. Information regarding disease management included initial treatment administered for the index tumor; additional therapy to manage recurrent or persistent disease is not included. For patients who underwent resection as part of their initial therapy, surgical margins were reported when available. Statistical analysis was performed using the SPSS software package (SPSS, Inc., Chicago, IL). 26 Chisquare analyses were performed to determine statistical significance of the cross-tabulations comparing case-mix variables to site, tumor size, grade, histologic type, general summary stage, and type of treatment. Cancer registrars periodically update information about all patients vital and disease status. Because of the NCDB data collection methodology, 10-year follow-up data are available for patients diagnosed in 1985 and 1986, and 5-year follow-up data are available

4 Head and Neck Osteosarcoma/Smith et al TABLE 3 Percentages of Case-Mix Characteristics by Tumor Size and Anatomic for Osteosarcoma of the Head and Neck a Characteristic Skull/facial Mandible Other Count P value < 3 cm > 3 6 cm > 6 cm Count P value All cases Age 30 yrs yrs yrs Gender Male Female Race/ethnicity White African American Hispanic Other/unknown Skull/facial bones Mandible Other a Data are presented as row percentages, which total 100% when added from left to right. for patients diagnosed between 1985 and Actuarial survival analyses include both observed and disease-specific survival, with date of diagnosis as the starting point. Disease-specific survival uses death with disease present as its endpoint. Univariate analyses of survival experience were performed using the Wilcoxon statistic. Multivariate analyses could not be performed due to the small counts within numerous variable values. RESULTS Demographics The median age at presentation for the 496 patients with HNOS was 38.0 years (Table 1). The distribution by gender essentially was equal, with males representing 50.2% of patients. The median age at presentation was significantly younger for males (34 years) than females (44 years; P 0.001). Non-Hispanic African Americans comprised 18.3% of this patient sample, although United States Census Bureau data indicated that this racial/ethnic group represented approximately 13% of the United States population in Patients in the low-income group, which, by definition, reflected approximately 10% of all cancer patients in the NCDB, represented 14.6% of the patients with HNOS. Disease Characteristics Anatomic site The majority of patients (55.6%) had HNOS of the skull and facial bones, with HNOS of the mandible in most of the remaining patients (38.9%) (Table 2). Approximately 5% of patients had HNOS tumors in the other category, which included the soft tissues of the head and neck (n 18); the parotid gland (n 2); the nasopharynx (n 2); the gum, NOS (n 2); the glottic larynx (n 1); the laryngeal cartilages (n 1); and the tongue (n 1). No significant differences in anatomic site were found for the various case-mix characteristics, although there was a trend toward the older population having tumors classified as other, which included mainly nonbony tumors (Table 3). Size The size of the primary tumor was known for 51.4% of patients (Table 2). Most tumors measured 6 cm (78.9%), with tumors measuring 3 6 cm reported most commonly. Older patients and African-American patients had significantly larger tumors (Table 3). Histologic subtype The majority of osteosarcomas were classified as osteoblastic, NOS (77.0%), followed by chondroblastic (15.8%) and fibroblastic (3.4%) (Table 2). Patients older than 60 years were more likely to be diagnosed with other histologic types compared with patients 60 years or younger (Table 4). Osteosarcoma arising within Paget disease usually was observed in older, female patients, with 7 of 10 such tumors occurring in women older than age 65 years.

5 1674 CANCER October 15, 2003 / Volume 98 / Number 8 TABLE 4 Percentages of Case-Mix Characteristics by and Histologic Type for Osteosarcoma of the Head and Neck a Characteristic Low (1 2) High (3 4) Count P value Osteoblastic, NOS a Chrondoblastic Other b Count P value All patients Age 30 yrs yrs yrs Gender Male Female Race/ethnicity White African American Hispanic Other/unknown Skull/facial bones Mandible Other cm cm cm Osteoblastic, NOS Chondroblastic Other b NOS: not otherwise specified. a Data are presented as row percentages, which total 100% when added from left to right. Cases with unknown grade have been omitted from this table. b Other histologic types include fibroblastic, telangiectatic, osteosarcoma in Paget disease, and juxtacortical. Tumor grade was reported for 47.4% of patients (Table 2), a proportion that increased from 39.6% in the first years ( ) to 55.9% in the later years ( ; data not shown). Of the patients with a reported grade, 38.3% had well differentiated or moderately well differentiated tumors, 35.7% had poorly differentiated tumors, and 26.0% had undifferentiated tumors (Table 2). The percentage of high-grade tumors increased as tumor size increased (Table 4). Although mandibular tumors were distributed evenly, with 46.9% low-grade tumors ( 1 2) and 53.1% high-grade tumors ( 3 4), a greater percentage of skull and facial bone tumors were high-grade lesions (67.4% and 70%, respectively). Staging The percentage of bony and soft tissue osteosarcoma lesions with a reported AJCC stage increased from 48.6% in the earlier years ( ) to 70.5% in the later years ( ; data not shown). Nine tumors, two in the parotid gland and seven juxtacortical osteosarcomas, did not have AJCC staging guidelines. Of the 487 patients with tumors that could be staged, an AJCC stage was recorded for only 56.1%. The vast majority (83.9%) of the patients with these staged tumors presented with advancedstage disease (Table 5). GSS was used in all remaining analyses involving extent of disease because it was available for 87.7% of patients. Disease was confined locally in 87.1% of patients (Table 5), which is comparable to the 90.1% of patients with locally confined (Stage I, II, and III) disease according to AJCC guidelines. The GSS was classified as regional for 5.6% of patients and distant for 7.6% of patients. The actual percentage of patients with lymph node disease may have been higher, because patients who were classified with distant disease also may have had regional disease according to this staging system. A difference was noted with regard to stage distribution by tumor location (Table 6). Man-

6 Head and Neck Osteosarcoma/Smith et al TABLE 5 Extent of Disease for Patients with Osteosarcoma of the Head and Heck Extent of disease No. of patients (%) General summary stage Local 379 (87.1) Regional 23 (5.3) Distant 33 (7.6) Subtotal known stage 435 (100.0) Unknown stage 61 (12.3) a Total 496 ( ) Combined AJCC stage b I 123 (45.0) II 106 (38.9) III 17 (6.2) IV 27 (9.9) Subtotal known stage 273 (100.0) Unknown stage 214 (43.9) c Subtotal staged patients 487 ( ) Patients without staging 9 (1.8) Total 496 ( ) AJCC: American Joint Committee on Cancer. a Percentage based on all patients. b Combined stage represents AJCC pathologic stage, augmented by clinical stage where path stage is not available. c Percentage based on the subtotal of patients with disease staged using the AJCC staging system. dibular tumors were more likely to remain localized, whereas the other craniofacial bony sites and tumors at the other sites had a higher rate of metastases. Treatment Modality Surgery was included as part of the treatment regimen in 84.5% of patients with HNOS and was the sole modality of treatment in 33.3% (Table 7). The second most common treatment regimen (28.2%) was multimodality treatment with surgery and chemotherapy. An increased use of multimodality therapy was evident across the study years, increasing from 42.7% in the earlier period ( ) to 57.3% in the later period ( ) (data not shown). The type of treatment differed by patient and tumor characteristics. Patients older than 60 years were most likely to undergo surgery alone. If multimodality therapy was administered to patients in this age group, then it most likely was surgery and radiotherapy. The most common multimodality treatment for patients age 60 years and younger was the combination of surgery and chemotherapy. Patients who had tumors that measured 3 cm were equally likely to undergo surgery alone or surgery with adjuvant therapy, whereas patients who had tumors that measured 3 cm were more likely to undergo surgery and TABLE 6 Case-Mix Characteristics by General Summary Stage for Patients with Osteosarcoma of the Head and Neck a General summary stage Local Regional Distant Count P value All patients Age 30 yrs yrs yrs Gender Male Female Race/ethnicity White African American Hispanic Other/unknown Skull/facial bones Mandible Other cm cm cm Osteoblastic, NOS Chondroblastic Other Low (1 2) High (3 4) Unknown grade NOS: not otherwise specified. a Data are presented as row percentages, which total 100% when added from left to right. Patients with unknown general summary stage have been omitted from this table. adjuvant therapy than surgery alone. Treatment also differed based on histologic type, with patients who had tumors classified as other most frequently undergoing surgery alone or, if multimodality therapy was used, surgery with radiotherapy. Significant differences were found with respect to grade and disease stage. Surgery alone was used most often to manage low-grade tumors and localized disease, whereas combined surgery and chemotherapy were used most often to manage high-grade tumors and metastatic disease. Even in the presence of distant metastases, surgery was included as part of treatment in almost 70% of patients. Margin status The status of surgical margins was reported for 259 of the 391 patients (66.2%) who underwent disease-di-

7 1676 CANCER October 15, 2003 / Volume 98 / Number 8 TABLE 7 Case-Mix Characteristics by Treatment for Patients Receiving Treatment for Osteosarcoma of the Head and Neck a Treatment (%) Characteristic Surgery only Surgery and chemotherapy Surgery and RT Nonsurgical Trimodal Total Count P value All patients Age 30 yrs yrs yrs Skull/facial bones Mandible Other cm cm cm Osteoblastic, NOS Chondroblastic Other Low (1 2) High (3 4) General summary stage Local Regional Distant RT: radiotherapy; NOS: not otherwise specified. a Data are presented as row percentages, which total 100% when added from left to right. rected surgery. Of those 259 patients, 185 (71.4%) had no residual disease, 53 (20.5%) had microscopic residual disease, and 21 (8.1%) had macroscopic residual disease (Table 8). Positive surgical margins were associated with nonmandibular tumor sites, larger primary tumor size, and higher-grade tumors. Outcome: Survival The 5-year, disease-specific survival rate was 59.7% for patients who were diagnosed with HNOS between 1985 and 1991 (Table 9). Multiple patient, tumor, and treatment factors were associated with a significantly worse survival. These risk factors included age older than 60 years; skull or facial bone sites (vs. mandible); tumor size 6 cm; histology of osteoblastic, NOS; higher grade; advanced stage; nonsurgical initial therapy; and the presence of residual disease after surgical resection. The impact of treatment on 5-year, disease-specific survival was dramatic, in that patients who did not undergo surgical therapy had a markedly worse survival. Patients who underwent surgery alone and surgery plus chemotherapy demonstrated similar 5-year survival rates (74.7% and 71.3%, respectively). In comparison, nonsurgical therapy resulted in a 21.7% 5-year survival. Among the limited number of patients with known surgical margin status, a markedly lower rate of survival was noted for those with positive margins. DISCUSSION Although osteosarcoma is the most common primary bone malignancy, it is extremely uncommon in the head and neck; only 496 cases of HNOS were registered with the NCDB over an 11-year time frame. Unfortunately, the NCDB does not capture all cases of malignancy that occur each year, but it is estimated that at least 70% of all malignancies are reported. Using these estimates, fewer than 70 cases of HNOS occur each year in the United States. Like other uncommon tumors of the head and neck, therapy for HNOS often is based on previous case reports or small case series that span several years. This approach may result in propagation of

8 Head and Neck Osteosarcoma/Smith et al TABLE 8 Surgical Margin Status by, Tumor Size, Histologic Type, and for Surgical Patients with Osteosarcoma of the Head and Neck a Characteristic Clear Surgical margin status (%) Residual disease Unknown Count All patients Skull/facial bones Mandible Other cm cm cm Osteoblastic, NOS Chondroblastic Other Low (1 2) High (3 4) Unknown grade NOS: not otherwise specified. a Data are presented as row percentages, which total 100% when added from left to right. therapy that has limited scientific basis. The capability of the NCDB to collect data on a substantially larger number of patients over a shorter period allows a unique opportunity to assess the impact of patient demographics, tumor factors, and treatment on survival. The patient demographics and tumor characteristics in the NCDB are similar to those found in most small series on HNOS. Most patients are Caucasians in their mid-30s, and no gender predilection is noted. 1,3,6,7,27 29 The tumors typically affect the mandible and maxilla. 1,8,28 Previous studies rarely have reported soft tissue HNOS tumors, although this was the site of origin in 4% of patients in the NCDB. Other tumor characteristics, such as size, grade, and histology, have not been reported consistently. Earlier studies reported 5-year survival rates ranging from 35% to 55%. 1,3,6 8,30 Treatment in these studies frequently involved surgery alone; when given, the most common form of adjuvant therapy was radiotherapy. The 5-year disease-specific survival rate for patients in the NCDB was 59.7%. When patients who were not treated surgically were excluded, the 5-year, disease-specific survival rate increased to 70%. In this NCDB study, several patient and tumor characteristics demonstrated prognostic importance for HNOS. Older age at the time of diagnosis was a negative prognostic factor. Patients age 60 years or younger had a 5-year, disease-specific survival rate 60% compared with 34% for patients older than 60 years. In a previous review of HNOS, Smeele et al. noted that diagnosis prior to age 35 years was associated with better long-term survival. 30 Tumor location, histologic type, and stage also were associated with survival in this NCDB study. The 5-year survival rate for patients with mandibular tumors was almost 10 percentage points higher than patients with tumors located in the craniofacial skeleton. The ICD-O 2 coding system combines skull and facial bone tumors, such that maxillary sites are not distinguishable from extragnathic sites. The inability to analyze theses sites separately poses some limitations, because extragnathic sites potentially are more difficult to resect widely as a result of their close proximity to the orbit and intracranial cavities and have been noted by others to have a worse prognosis. 1 As would be expected, patients with local disease had the highest 5-year survival rate, but even those with regional and distant disease had a 5-year survival rate of 42%. has not been noted previously to have an impact on survival; however, in this database, osteoblastic, NOS, cases demonstrated a 5-year survival rate that was 20 percentage points lower than the rate associated with the chondroblastic variant. and grade are two other prognostic factors that have been reported less consistently in previous HNOS studies. Within the NCDB, patients with low-grade HNOS tumors showed a 74% 5-year survival rate, compared with 42% for patients with high-grade tumors. Ha et al. also noted a marked discrepancy in survival for patients with high-grade versus low-grade HNOS tumors, with a difference at 5 years of nearly 60%. 7 In the current study, patients with smaller tumors ( 6 cm) demonstrated a 60% 5-year survival rate, whereas patients with larger tumors had a 5-year survival rate of only 26%. Size and grade data were not available on approximately 50% of the NCDB cases, which may have biased the conclusions drawn from these findings. However, because no differences in survival were found for patients with and without these data, the bias is likely to be minimal. Marked variability has existed in treatment protocols, but most would agree that surgical excision is a critical component in curative therapy. The role and timing of adjuvant therapy is much more controversial. For patients with HNOS, adjuvant chemotherapy and radiotherapy, as well as trimodality therapy, have been used. 1,3,6,8,28 Within the last 15 years, the prospective trials for non head and neck osteosarcoma have demonstrated that surgery with adjuvant chemo-

9 1678 CANCER October 15, 2003 / Volume 98 / Number 8 TABLE 9 Five-Year Disease-Specific Survival for Patients with Osteosarcoma of the Head and Neck Diagnosed between 1985 and 1991 a Yrs after diagnosis Characteristic Patients entering P value All patients Observed Disease-specific Age 30 yrs b yrs yrs Skull/facial bones Mandible cm c 3 6 cm cm Osteoblastic, NOS Chondroblastic Low (1 2) High (3 4) General summary stage Local Regional/distant Treatment Surgery only d Surgery and chemotherapy RT, chemotherapy or both Surgical margins e Clear Residual disease NOS: not otherwise specified; RT: radiotherapy. a Categories with too few patients were omitted. b Patients age 61 years or older had significantly lower survival rates compared with patients age 30 years or younger and patients ages years (P ). Patients age 30 years or younger and patients ages years did not have significantly different survival rates. c Patients who had tumors that measured 6 cm had significantly lower survival rates compared with patients who had tumors that measured 3 6cm(P ) and patients who had tumors that measured. 3cm(P ). Patients who had tumors that measured 3 cm were not significantly different from patients who had tumors that measured 3 6cm(P ). d The treatment group that included radiotherapy, chemotherapy, or both was significantly different from the group that included surgery only and the group that included surgery and chemotherapy. The latter two treatment groups were not significantly different (P ). e Analysis of surgical margins included only patients who underwent surgery. therapy has improved survival markedly. 4,5,13,14 Extrapolation of these results to patients with HNOS would seem logical; however, there are significant differences in the natural history of HNOS and non head and neck osteosarcoma that complicate such conclusions. The importance of surgical excision for patients with HNOS was demonstrated well in the NCDB. Patients who had surgical excision incorporated into their treatment plan had 5-year survival rates in the mid-70% range, whereas patients who did not have surgical therapy had survival rates of 22%. The positive impact of negative margins also was noted in the limited number of patients for whom margin status and 5-year survival rates were available. Patients with clear margins had a 75% 5-year survival rate, compared with the 32% rate for patients with residual disease. Smeele et al. also demonstrated the importance of margin status, with a 40% survival advantage noted in patients who had clear margins of resection. 6 Patients with smaller tumors and mandibular tumors were more likely to have clear resection margins. This is logical, because these tumors are more amenable to aggressive wide resection, whereas craniofacial sites are not as amenable because they are adjacent to more critical structures.

10 Head and Neck Osteosarcoma/Smith et al Currently, the most controversial issue related to therapy is the impact of adjuvant chemotherapy on survival. Recent meta-analyses have reported conflicting conclusions regarding the role of chemotherapy for patients with HNOS. 1,6 Although a limited number of small studies addressing chemotherapy have shown promising results, the counts are too small to justify uniform incorporation of adjuvant therapy. 28 Within the NCDB, no difference in the 5-year survival rate was noted between patients who underwent surgery alone and patients treated with surgery and adjuvant chemotherapy. The survival of both groups, however, showed dramatically improved outcomes compared with previous series, with a 5-year survival rate in the 70% range. Equivalent survival rates were found for the surgery-only group and the surgery with adjuvant chemotherapy group, despite the fact that patients treated with surgery and adjuvant chemotherapy were afflicted more frequently with tumors that exhibited poor prognostic factors. Patients with high-grade tumors and patients with metastatic disease were more likely to receive surgery and chemotherapy, whereas patients with smaller tumors were more frequently treated with surgery alone. In contrast, patients older than age 60 years most often received surgery alone or received surgery with postoperative radiotherapy, whereas few received adjuvant chemotherapy. The explanation for this finding is unknown but may be related to the fact that this older population has other significant comorbidities that prohibit the administration of chemotherapy. No differences were noted when these groups were compared for other negative prognostics factors. In conclusion, surgical excision with clear margins remains critical to successful therapy for patients with HNOS. Improved survival has been noted over the last 2 decades compared with historical control patients, with 5-year survival rates near 60%. Patient age older than 60 years and tumor factors (such as histologic subtype of osteoblastic, NOS; larger size; and higher grade) have been identified as negative prognostic factors and should be considered in treatment planning. The role of chemotherapy is not well defined, but evidence suggests that its incorporation may result in a survival benefit for patients with high-risk tumors. REFERENCES 1. Kassir RR, Rassekh CH, Kinsella JB, Segas J, Carrau RL, Hokanson JA. Osteosarcoma of the head and neck: metaanalysis of nonrandomized studies. Laryngoscope. 1997;107: Caron AS, Hajdu SI, Strong EW. Osteogenic sarcoma of the facial and cranial bones. Am J Surg. 1971;122: Garrington GE, Scofield HH, Cornyn J, Hooker SP. 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