1. DIAGNOSTIC EVALUATION
2. EXAMINATION UNDER ANESTHESIA AND BIOPSY
3. TREATMENT
4. ADJUVANT TREATMENT
5. FOLLOW UP EXAM
6. BIBLIOGRAPHY

I. DIAGNOSTIC EVALUATION:

Clinical Evaluation:

• Complete history and physical examination includes inspection of surface skin of head and neck with particular attention to skin of scalp and to bone and soft tissue component of underlying skull and neck.

• Complete examination of oropharynx and larynx with attention to possible abnormalities of gum and alveolar ridge and associated soft tissues of mandible/maxilla; inspection via telescope of nasal cavity and nasopharynx.

• Careful evaluation of eye movements, facial skin sensitivity and hearing is important in patients with central facial tumors and facial symmetry and function in patients with lateral skull or retro pharyngeal, preauricular or temporal bone tumors.

• Biopsy of obvious tumor by FNA will indicate general tumor class.

• A confirmatory histologic biopsy is necessary. The biopsy report should contain basic information on the histogenetic origin (bone vs. soft tissue) tumor type and grade (high vs. low grade). The ideal report should contain the 6 parameters most often considered including differentiation, cellularity, amount of stroma, vascularity, amount of tumor necrosis and number of mitoses. 

• The pathologist should be given full patient information and be informed about x-ray findings especially for bone tumors. Availability of the pathologist in the OR for special tissue handling may expedite the diagnosis (references 1-8).

Imaging Studies:

• CT scan or MRI - with soft tissue and bone windows of the entire head and neck are obtained with focus on primary tumor (3mm or 5mm cuts); study should include full view of head and neck to determine relation of primary tumor to adjacent sites in skull and to determine presence of clinically occult nodal metastases.

• Chest radiographs, AP and lateral: If any abnormality obtain CT scan.

• Bone scan, chest CT scan and liver CT should be obtained in cases of high grade sarcomas which have high metastatic potential for lung and bone.

• Panorex - Panoramic View.

Laboratory Tests

• Should include alkaline phosphatase, calcium, phosphorus, bilirubin, serum glutamate-oxaloacetic transaminase(SGOT) and aspartate amino transferase (AST), serum glutamate pyruvate transferase (SGPT), alanine amino transferase (ALT), gamma glutamate transferase (GGT), to screen for liver metastases.
  
• Preoperative tests as required by institution and patient's condition.

Consult

• Medical Oncology
  
  Radiation Oncology in all patients with soft tissue sarcomas.
  
• Dental 
  
  If intraoral resection is contemplated especially if the use of radiation is anticipated.
  
• Reconstructive (microvascular) surgery 
  
  When extended resection is planned in oral cavity/oropharynx/paranasal sinus, or a large ablative defect will result after skull base resection.
  
• Internal Medicine/ Cardiology/ Pulmonology or Anesthesiology
  
  As needed to evaluate coexisting conditions that may preclude or increase the risk of general anesthesia, or may influence therapeutic decisions.
  
• Tumor Board
  
  Appropriate high risk patients should be presented to a multidisciplinary head and neck tumor board with representation by oncologists knowledgeable in sarcomas.

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May be necessary in some cases to assess the extent of disease and to obtain an adequate biopsy for detailed histologic study and staging.

Examination under anesthesia permits deep palpation and instrumentation as necessary. Depending upon the location of the tumor, laryngoscopy, esophagoscopy, nasopharyngoscopy or bronchoscopy may be indicated. 

The tumor should be carefully measured and the boundaries tattooed if preoperative radiation or chemotherapy is to be used. The extent of the tumor should be documented with drawings and photographs if possible.

Stage
Soft Tissue Sarcoma Staging (Simplified from American joint Committee on Cancer (AJCC)

Primary Tumor	Regional Nodes (N)
Tx - cannot be assessed	Nx - not assessable
T0 - not evident	N0 - not palpable
T1 <5cm	N1 - palpable node
T1a - superficial tumor*
T1B Deep Tumor	Distant Metastases
T2 >5cm	M0 - none
T2a superficial	M1 - distant metastasis
T2b deep tumor

*Superficial/deep to superficial fascia

Stage Groupings

Stage I

A-low grade, <5cm, superficial, deep (G1-2, T1a-b, N0M0)

B - Low grade, >5 cm superficial(G1-2, T2a,N0M0)

Stage II

A Low grade, large deep(G1-2, T2b, N0M0)

B High grade, small, superficial/deep(G3-4, T1a-b, N0M0)

C High grade, large superficial(G3-4, T2a, N0M0)

Stage III

High grade, large deep(G3-4, T2b, N0M0)

Stage IV

Any mets(Gany, Tany N1M0)(Gany, Tany, Nany, M1) 

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Primary Tumor

Surgical resection is essential for control of primary sarcoma whether of soft tissue or bone. Although combinations of chemotherapy and radiation may markedly reduce the tumor if given preoperatively, it is essential to remove the full volume as it existed and obtain clear margins. If surgical resection is done prior to planned chemoradiation, clear margins must be obtained. Working closely with the pathologist is important to ensure that gross and frozen section margins are clear.

In cases with large soft tissue tumors an adequate resection may severely compromise normal anatomy, thus careful reconstruction planning preoperatively may be required. If the maxilla is resected, a temporary prosthesis may be inserted until a finished device has been prepared.

Working closely with the reconstructive surgeon may provide an opportunity for innovative solutions both for upper and lower jaw tumors, as well as, to provide coverage of major skull or soft tissue defects.

If a primary bone tumor involves the mandible (i.e., osteosarcoma), it is important to obtain an adequate resection of the mandible. This may require initial removal of the mandible with temporary splinting using a mandibular plate until the final pathology has been reviewed and it is determined that the lesion has been adequately removed. Although one can scrape and cut the end of the bone for cytology, at time of resection, this is not sufficiently reliable if one plans to reconstruct with revascularized bone graft. Bone fixation with assessment of marrow and cortical margins are important especially for a primary bone tumor; i.e., osteosarcoma.

If radiation is used preoperatively, approximately 45-50 Gy is given with or without sensitizing chemotherapy. Postoperative radiation is used for low grade sarcomas, when resection with clear margins is not possible, and for intermediate or high grade sarcomas. The usual dose range is 40 - 70 Gy, by external beam radiation, brachytherapy or both. 

Neck

If the neck is not clinically involved, an elective neck dissection is not indicated. Overall, only 8-10% of sarcomas metastasize to nodes. Although certain sarcomas have a higher propensity for nodal metastases such as malignant fibrous histiocytoma, and synovial sarcomas, a neck dissection would not be warranted unless nodes are clinically or radiologically involved. Neck irradiation would have similar considerations.

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There have been over 10 randomized sarcoma trials and only 1 showed a positive effect with adjuvant chemotherapy^7,8. The drugs most commonly used include Adriamycin, Cisplatin, Ifosphamide, Methotrexate. A large number of randomized trials have explored the benefit of adjuvant chemotherapy with or without radiation therapy for soft tissue sarcoma. At least 9 trials have evaluated Adriamycin (doxorubicin) based regimens. Study groups have generally included extremity, head and neck, and retroperitoneal or visceral sarcomas. One well publicized study from the NCI treated patients with extremity sarcomas with monthly doxorubicin and cyclophosphamide to a maximum cumulative dose of doxorubicin 500-550mg/M² and then followed with 6 cycles of high dose methotrexate with leucovorin7 rescue. After a median follow-up of 4.5 years, patients receiving adjuvant chemotherapy had a significantly improved disease-free and overall survival. At 7 year follow-up, there was still significant improved disease-free survival 75% vs. 54%, p = 0.037, but only a trend towards improved survival in the chemotherapy arm p = 0.124. In the randomized trial of head and neck and retroperitoneal sarcomas treated in a similar way (but included only 31 patients), there was no overall survival differences, and only a suggestion of improvement in disease-free survival at 3 years (p = 0.075).

A protocol of high grade extremity sarcomas by Picci, et al, randomized 77 patients to adjuvant Adriamycin (450ng/M²) cumulative dose vs. no chemotherapy after adequate resection +/- radiation and observed a significant difference in disease-free and overall survival (82% vs. 60%)⁷. A similar study by Eilber, et al, demonstrated no survival difference at 30 months⁷. Unfortunately, the other 7 trials which have included head and neck sarcomas have demonstrated no difference in outcome. Unfortunately, the numbers of head and neck patients are too small and the inclusion of sarcomas of trunk and retroperitoneum with these makes comparison essentially impossible.

Certain high grade sarcomas of the head and neck that would appear to benefit from adjuvant therapies, include scalp sarcomas (angiosarcomas which are at high risk for recurrence, high grade large sarcomas >3-5 cm at any site). The use of radiation and sensitizing chemotherapy provides an opportunity for local regional control even though one may not document overall survival benefit.

Radiation given preoperatively or post operatively has been shown to reduce local recurrence. In an older series by Lindberg from M D Anderson, over 300 patients were treated with conservative surgery with removal of gross tumor, but with limited removal of normal tissue (essentially a shell out) and received 60-70Gy⁹. The local failure rate was 22% (vs. an expected failure rate up to 84% if margins are involved). The 5 year disease-free survival was 61% for all primary sites and was 63% for head and neck sarcomas. Radiation including brachytherapy can increase local control.¹³

The optimum therapy should, therefore, include adequate resection with clear microscopic margins and complimentary therapy with radiation with or without sensitizing chemotherapy for high grade sarcomas. It should be noted that the role of "sensitizing" chemotherapy is poorly documented at present.

Survival after treatment of sarcomas is a function of the risk of hematogenous spread of metastasis, particularly to the lung. Systemic administration of cytotoxic chemotherapy to reduce dissemination of sarcomas has been widely tested with moderate success.

Many sarcoma experts believe that ifosfamide is the most active of the compounds used in the treatment of patients with disseminated soft-tissue sarcomas. The second most active drug is doxorubicin.

A standard chemotherapy approach to patients with disseminated sarcomas often involves one of two regimens: (1) doxorubicin (Adriamycin) with or without dacarbazine (DTIC) which has been a standard for many years; or (2) these same two drugs plus ifosfamide (either as the MAID regimen or as A1). In an Intergroup trial the response rate was clearly better with the three-drug MAID regimen than with the two-drug combination of doxorubicin plus dacarbazine (32% vs. 17%).^10-12

Of concern to many oncologists was the lack of any concomitant increase in overall survival in MAID-treated patients. Thus, the value to the patient of an increased change of objective response (e.g., pain control, better preoperative shrinkage of tumor) would have to be judged against the increased toxicity and morbidity of the more intensive MAID regimen. 

A number of randomized, prospective studies have evaluated the benefit of chemotherapy in the postoperative (adjuvant) setting. All of these trials had sample sizes too small to demonstrate any differences among the treatment groups. It should also be pointed out that none of the published adjuvant studies included the most active antisarcoma drug, ifosfamide.

It is reasonable for the clinician to be very selective in choosing patients who may stand to benefit more from adjuvant therapy. The population most at risk for developing metastasis includes patients with high-grade, deep, large (>5cm) sarcomas. Chemotherapy also contributes to optimizing the local control rate, and therefore may allow the surgeon to perform a function-preserving operation. The goal of chemotherapy is to cure or facilitate cure. Therefore it is important to optimize chemotherapy with acceptable toxicity to maximize response and tumor control.

V. FOLLOW UP EXAM:

Examination every 2 weeks during radiation therapy (if given) or if receiving high dose chemotherapy.

Post therapy follow-up:

Complete head and neck examination every 2-3 months during first 2 years then 3-4 months from year 2 to 4 and then a 6-month spread after 4 years.

Studies

Chest radiographs and liver enzymes 2 x per year/ for the first year and annually thereafter.

Baseline CT or MRI of head and neck, repeated as needed on the basis of clinical findings.

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1. Wanebo HJ, Benjamin RS, Hadju SI, Healey GB, Lindberg, RD, Weber, R: Sarcomas of the head and neck. Head and Neck Cancer, Vol. III Ed. J. Johnson and M. Didolker. Excerpta Medica - Int. Cong Prem 1993.

2. Greager JA, Patel MK, Briele HA, Walker MJ, Das Gupta TK: Cancer 1985; 56:820-824.

3. Freedman AM, Reiman HM, Woods JE. Am J Surg 1986; 158:367-392.

4. Farwood AI, Hajdu SI, Shiu MH, Strong EW. Am J Surg 1990; 160:365-372.

5. Wanebo HJ, Koness RJ, McFarlane JK, Eilber FR, Byers RM, Elias EG, Spiro RH. Head Neck 1992; 14:1-7.

6. Healy GB, Upton J, Black P et al Arch Otolaryngol Head Neck Surg 1991; 117: 1185-1188

7. Sarcomas of the Soft Tissues and Bone, Soft Tissue Sarcoma, Brennan et al. 1738-88 Sarcomas of the Bone, Malauer et al, 1789-1852 In Cancer Principles and Practice of Oncology - ed V. Devita, S. Hellman and S.A. Rosenberg, Publ. J. Lippincott, 1997.

8. Hajdu SI. Differential diagnosis of soft tissue and bone tumors. Philadelphia; Lea and Febiger, 1986.

9. Lindberg R. Treatment of localized soft tissue sarcomas in adults at the M.D. Anderson Hospital and Tumor Institute (1960-1981). Cancer Treatment Symposium 1985; 59-65.

10. Sarcoma Meta-Analysis Collaboration: Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults. Meta-analysis of individual data. Lancet 1997; 350:1647-1654.

11. Antman K, Crowley J, Balcerzak SP et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft-tissue and bone sarcomas. J Clin Oncol 1993; 11:1276-1285.

12. Patel SR, Vadhan-Raj S, Papadoupolous N, Et al: High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies - Dose response and schedule dependence. J Clin Oncol 1997; 15:2378-2384. 

13. Harrison LB, Franzese F, Gaynor T et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft-tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 1993; 27: 259-265.