*Perspective Chapter: Osteosarcomas of the Head and Neck DOI: http://dx.doi.org/10.5772/intechopen.107456*

On the other hand, while intraoperative determination of resection margins might represent a useful tool in other head and neck malignancies, osteosarcomas do often pose a significant challenge for the surgeon as intraoperative pathological examination does not indeed allow for the assessment of bone margins. Only soft tissue margins can be assessed through the intraoperative consultation, thus the need to wait for final pathology report to assess adequate margins.

Anyhow, surgery should be discussed even though we can only provide a close but negative margin and not a wide free negative margin of safety as desired.

According to Ha et al., a positive margin will mean a drop on overall survival from 75–35% (P = .008) [21]. In a meta-analysis by Smeele et al. [26], in 1998, it was already state clearly that patients benefit on overall and disease-free survival when complete resection was achieved versus incomplete resection (P < .001). The latter group was still better off compared with those who did not undergo resection at all (P < .01). Survival curves show a dramatic drop on overall survival from around 50% at 5 years for complete resection to less that 25% at 3 years for incomplete resection.

When discussing the management of the neck, it is widely agreed that regional spread of osteogenic sarcomas is rare, thus prophylactic dissection of N0 patients is not indicated, regardless of histologic grade or tumor size. Therefore, selective neck dissection is only indicated in patients with clinical/radiologic nodal metastases [5].

Although there is no general consensus, nodal localization should be treated surgically and should be considered an adverse feature when evaluating adjuvant treatments.

Unlike in the management of most other head and neck cancers, prophylactic neck dissection is not advised for high-grade or large osteosarcomas of the head and neck region.

Further research in this regard would be advisable, though, as the only data available on this matter are now old and suggest that prophylactic lymph node dissection has a detrimental effect on patients overall survival [27, 28].

**Figure 7** shows the surgical resection, osteo-integrated implants, and reconstruction of patient presented in **Figure 1**, a 35-year-old female with a maxillary chondroblastic osteosarcoma, and **Figure 8** shows the surgery for patient shown in **Figure 3**, a 27-year-old male patient with osteosarcoma of the left mandible.

### **Figure 7.**

*Surgical resection, osteo-integrated implants and reconstruction of patient presented in* **Figure 1***, a 35-year-old female with a maxillary chondroblastic osteosarcoma.*

### **Figure 8.**

*Surgery for patient shown in* **Figure 3***, a 27-year-old male patient with osteosarcoma of the left mandible. (a) 3D model for preoperative surgical planning. (b) Surgical tumor excised (left mandibulectromy). (c) Mandibule with the cutting guide for medial osteotomy and surgical defect after mandibulectomy. (d) Fibula-free flap harvested for reconstruction according to surgical preoperative planning and flap in-situ on left mandibule defect.*

### **7.2 Chemotherapy**

Surgery still is the main therapeutic modality for cure on HNOS. However, many trials indicate the benefit of adjuvant chemotherapy in improving survival of patients with extremity OS. Treatment approach for this disease had a major shift when several studies evidenced that chemotherapy improved significantly overall and diseasefree survival [29]. Link et al. evidenced an improvement on 2 years of disease-free survival from 17 to 66% with the addition of chemotherapy to the treatment of long bones OS [30]. After that, implementation of standardized treatment protocols involving both neoadjuvant and adjuvant chemotherapy has resulted in significantly improved overall survival up to 60–80% for extremity osteosarcomas, compared with 10–20% with surgery alone [31, 32]. Multimodal treatment has also shown to improve disease-free survival, and some trials on the role of neoadjuvant chemotherapy were even successful on facilitating limb preservation in selected patients [33].

However, these trials repeatedly avoided enrolment of head and neck cases because of significant difference in clinical presentation, course of disease, prognosis, and the need for multidisciplinary treatment.

There are few retrospective studies, meta-analyses, or reviews that assess the role of chemotherapy specifically in HNOS; however, they have shown conflicting results [26, 32, 34–38]. In addition, these studies have small samples and use different chemotherapeutic agents or their combinations, which limits the evaluation of chemotherapy as an independent factor impacting treatment outcomes and prognosis. As a result, the benefit of chemotherapy remains unclear.

Guadagnolo et al. studied 119 patients with HNOS and failed to find a survival benefit in patients who received chemotherapy plus surgery versus surgery alone [10]. Chen et al. reported comparable findings in their study of 160 patients with HNOS [39].

### *Perspective Chapter: Osteosarcomas of the Head and Neck DOI: http://dx.doi.org/10.5772/intechopen.107456*

On the contrary, Smeele et al. published on 201 patients with HNOS treated between 1974 and 1994 and did found a statistically significant survival benefit in patients who underwent chemotherapy and surgery versus surgery alone, on overall survival and disease-free survival. Moreover, chemotherapy was found to increase survival even in those cases of incomplete surgical resection [26].

In 2017, Boon et al. on a retrospective single-institution study of 77 patients with HNOS, where 30 patients received chemotherapy, reported an improved disease-free survival of 33% vs. 67% with addition of neoadjuvant/adjuvant chemotherapy in HNOS vs. non-chemotherapy treated patients, while the overall survival and diseasefree survival were non-significant when all other cofactors were analyzed [34], a similar observation was made by Thariat et al. [35] in mandibular osteosarcomas. Nonetheless, the study by Boon et al. [34] did demonstrate a significant improvement in local recurrence rates among patients with intermediate or high-grade tumors, aged younger than 75 years, who received chemotherapy, in both univariate and multivariable analyses, postulating that the benefit of chemotherapy is thereby likely to depend on individual tumor characteristics, including grade and the presence of positive surgical margins.

While the Cooperative Osteosarcoma Study Group (COSS) protocols (neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy) have demonstrated significantly better disease-free survival in patients with extremity osteosarcoma, there is no consensus as to whether this treatment approach provides a survival benefit in patients with HNOS and timing of chemotherapy in HNOS continues to be heavily debated [7, 8, 26].

In 2021, a study by Shim et al. [32], using data from the NCDB with HNOS from 2004 to 2016, demonstrated a shift in treatment trends since the last HNOS-specific retrospective NCDB analysis was completed in 2003 [8], which mirrors treatment approach of extremity OS, showing a steady increase in the utilization of neoadjuvant and adjuvant chemotherapy in addition to surgery, with fewer patients being treated with surgery alone. However, interestingly, with no corresponding changes in estimated 2-year and 5-year overall survival, as they did not demonstrate a longterm survival benefit for HNOS patients treated with perioperative chemotherapy or radiation therapy in addition to surgery. Nonetheless, this study, which included 694 HNOS patients for the treatment analysis, found that patients treated with neoadjuvant chemotherapy and surgery plus adjuvant chemotherapy demonstrated significantly improved survival in the first 18 months after treatment compared with patients treated with surgery alone, although there was no difference in OS [32]. This observed trend in early survival could be due, in part, to benefits of neoadjuvant chemotherapy in decreasing the confines of the tumor, allowing for a more complete surgical resection. Anyhow, early increases in survival dissipate beyond 5 years after treatment. This phenomenon is perhaps a result of the tumor's propensity for local recurrence and progression, to which patients eventually succumb.

As explained before, complete resection with negative margins is essential to adequately treating osteosarcoma. While this is relatively straightforward in extremity osteosarcoma, HNOS present unique anatomic challenges to R0 resections. Thus, neoadjuvant chemotherapy could help by shrinking the primary tumor burden, allowing higher rates of negative surgical margins, thereby reducing rates of local recurrence.

On the other hand, for OS, the rationale for adjuvant chemotherapy is treating occult disease and preventing distant metastases, which are common in extremity osteosarcomas (up to 44–49%), 9,15, with pulmonary micro metastases known to be present up to 80%. Unlike long bones OS, HNOS metastasize much less frequently (7–17%), with disease progression or failure more likely due to local recurrence [13].

The study by Shim et al. [32] found only 39 out of 1035 (3.8%) HNOS patients in their cohort with metastatic disease. Given the lower metastases rates in HNOS in comparison to extremity osteosarcoma, caution should be used before extrapolating treatment protocols aimed at preventing distant metastases as adjuvant therapy is associated with several adverse effects, including increased risk of secondary malignancy.

Finally, the moment in which to administer chemotherapy in HNOS remains under discussion. Neoadjuvant chemotherapy reported a poor response (a good response being <10% viable tumor) in the COSS study group in 66% of patients in a subgroup of maxillofacial OS patients (n = 16) [40]. However, it becomes important to assess the results from studies specifically focusing on the use of neoadjuvant chemotherapy on HNOS. Thariat et al. [35] evidenced improvement on disease-free and metastaticfree survival and an increased in clear margins rates from 50% to 68% with the use of neoadjuvant chemotherapy for HNOS. Mücke et al. also evidenced, in 2014, that neoadyuvant chemotherapy improved survival for HNOS versus surgery alone and proved to be an independent factor impacting survival on multivariate analysis [37]. Thus, Neoadyuvante Chemotherapy allows for the determination of percent tumor kill at the time of surgical resection and guides requisite changes in chemotherapeutic regimens after surgery; furthermore, it allows the evaluation of response to chemotherapy, and this may be useful as a prognostic marker or to determine adjuvant treatment [16, 36].

As for the chemotherapeutic agents studied and validated for use, Cisplatin, Doxorubicin, Adriamycin, Ifosfamide, Methotrexate, cyclophosphamide, and leucovorin are described in different combinations and schemes.

In summary, chemotherapy has shown to improve survival when added to surgery as multimodal treatment for selected tumors; however, the moment of administration (adjuvant vs. neoadjuvant) is still debated.

**Figure 9** shows the final appearance, 6 months after surgery and chemotherapy, of patient presented in **Figure 1**.
