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Lip and Oral Cavity Cancer Treatment (PDQ®)–Health Professional Version

General Information About Lip and Oral Cavity Cancer

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Anatomy

The oral cavity extends from the skin-vermilion junctions of the anterior lips to the junction of the hard and soft palates above and to the line of circumvallate papillae below and is divided into the following specific areas:

  • Lip.
  • Anterior two thirds of tongue.
  • Buccal mucosa.
  • Floor of mouth.
  • Lower gingiva.
  • Retromolar trigone.
  • Upper gingiva.
  • Hard palate.

Histopathology

The main routes of lymph node drainage are into the first station nodes (i.e., buccinator, jugulodigastric, submandibular, and submental). Sites close to the midline often drain bilaterally. Second station nodes include the parotid, jugular, and the upper and lower posterior cervical nodes.

Precancerous lesions of the oropharynx include leukoplakia, erythroplakia, and mixed erythroleukoplakia.[1] Leukoplakia, the most common of the three conditions, is defined by the World Health Organization as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease.”[2] The diagnosis of leukoplakia is one of exclusion; conditions such as candidiasis, lichen planus, leukoedema, and others must be ruled out before a diagnosis of leukoplakia can be made.[1]

The prevalence of leukoplakia in the United States is decreasing as a result of reduced tobacco consumption.[3] Although erythroplakia is not as common as leukoplakia, it is much more likely to be associated with dysplasia or carcinoma.[1,4]

Prognostic Factors

Early cancers (stage I and stage II) of the lip and oral cavity are highly curable by surgery or radiation therapy. The choice of treatment is dictated by the anticipated functional and cosmetic results of treatment and by the availability of a surgeon or radiation oncologist with the required expertise.[5-7] A positive surgical margin or a tumor depth of more than 5 mm significantly increases the risk of local recurrence.[8,9] The risk of occult nodal metastases increases based on depth of invasion of the primary tumor. Depth of invasion holds prognostic significance and was included in tumor staging definitions in the American Joint Committee on Cancer (AJCC) 8th edition staging classification.[10,11] Extranodal extension in a lymph node is a significant adverse prognostic factor and was incorporated into the 8th edition AJCC staging system.[12,13]

Advanced cancers (stage III and stage IV) of the lip and oral cavity represent a wide spectrum of challenges for the surgeon and radiation oncologist. Most patients with stage III or stage IV tumors are candidates for treatment by a combination of surgery and radiation therapy. The exception is patients with small T3 lesions and no regional lymph node and no distant metastases or who have no lymph nodes larger than 2 cm in diameter, for whom treatment by radiation therapy alone or surgery alone might be appropriate.[6] Furthermore, because local recurrence and/or distant metastases are common in this group of patients, clinical trials can be considered. Such trials evaluate the potential role of radiation modifiers or combination chemotherapy combined with surgery and/or radiation therapy.

Survival

Patients with head and neck cancers have an increased chance of developing a second primary tumor of the upper aerodigestive tract.[14,15] A study has shown that daily treatment with moderate doses of isotretinoin for 1 year can significantly reduce the incidence of second tumors. However, no survival advantage has been demonstrated, in part due to recurrence and death from the primary malignancy. An additional trial showed no benefit of retinyl palmitate or retinyl palmitate plus beta-carotene when compared with isotretinoin alone.[16][Level of evidence B1]

The cure rates of cancers of the lip and oral cavity depend on the stage and specific site. Most patients present with early cancers of the lip, which are highly curable by surgery or by radiation therapy with cure rates of 90% to 100%. Small cancers of the retromolar trigone, hard palate, and upper gingiva are highly curable by either radiation therapy or surgery with survival rates of as high as 100%. Local control rates as high as 90% can be achieved with either radiation therapy or surgery in small cancers of the anterior tongue, the floor of the mouth, and buccal mucosa.[17]

Moderately advanced and advanced cancers of the lip also can be controlled effectively by surgery, radiation therapy, or both. The choice of treatment is generally dictated by the anticipated functional and cosmetic results of the treatment. Moderately advanced lesions of the retromolar trigone without evidence of spread to cervical lymph nodes are usually curable and have shown local control rates as high as 90%. Such lesions of the hard palate, upper gingiva, and buccal mucosa have a local control rate of up to 80%. In the absence of clinical evidence of spread to cervical lymph nodes, moderately advanced lesions of the floor of the mouth and anterior tongue are generally curable, with survival rates of as high as 70% and 65%, respectively.[17,18]

References
  1. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]
  2. Kramer IR, Lucas RB, Pindborg JJ, et al.: Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46 (4): 518-39, 1978. [PUBMED Abstract]
  3. Scheifele C, Reichart PA, Dietrich T: Low prevalence of oral leukoplakia in a representative sample of the US population. Oral Oncol 39 (6): 619-25, 2003. [PUBMED Abstract]
  4. Shafer WG, Waldron CA: Erythroplakia of the oral cavity. Cancer 36 (3): 1021-8, 1975. [PUBMED Abstract]
  5. Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology - Head and Neck Surgery. Mosby-Year Book, Inc., 1998.
  6. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  7. Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
  8. Jones KR, Lodge-Rigal RD, Reddick RL, et al.: Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg 118 (5): 483-5, 1992. [PUBMED Abstract]
  9. Po Wing Yuen A, Lam KY, Lam LK, et al.: Prognostic factors of clinically stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 24 (6): 513-20, 2002. [PUBMED Abstract]
  10. Sparano A, Weinstein G, Chalian A, et al.: Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 131 (4): 472-6, 2004. [PUBMED Abstract]
  11. D'Cruz AK, Vaish R, Kapre N, et al.: Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. N Engl J Med 373 (6): 521-9, 2015. [PUBMED Abstract]
  12. Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
  13. Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
  14. Day GL, Blot WJ: Second primary tumors in patients with oral cancer. Cancer 70 (1): 14-9, 1992. [PUBMED Abstract]
  15. van der Tol IG, de Visscher JG, Jovanovic A, et al.: Risk of second primary cancer following treatment of squamous cell carcinoma of the lower lip. Oral Oncol 35 (6): 571-4, 1999. [PUBMED Abstract]
  16. Papadimitrakopoulou VA, Lee JJ, William WN, et al.: Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 27 (4): 599-604, 2009. [PUBMED Abstract]
  17. Wallner PE, Hanks GE, Kramer S, et al.: Patterns of Care Study. Analysis of outcome survey data-anterior two-thirds of tongue and floor of mouth. Am J Clin Oncol 9 (1): 50-7, 1986. [PUBMED Abstract]
  18. Takagi M, Kayano T, Yamamoto H, et al.: Causes of oral tongue cancer treatment failures. Analysis of autopsy cases. Cancer 69 (5): 1081-7, 1992. [PUBMED Abstract]

Cellular Classification of Lip and Oral Cavity Cancer

Most head and neck cancers are of squamous cell histology and may be preceded by various precancerous lesions. Minor salivary gland tumors are not uncommon in these sites. Specimens removed from the lesions may show the carcinomas to be noninvasive, in which case the term carcinoma in situ is applied. An invasive carcinoma will be well differentiated, moderately well differentiated, poorly differentiated, or undifferentiated.

Tumor grading is recommended using Broder classification (Tumor Grade [G]):

  • G1: well differentiated.
  • G2: moderately well differentiated.
  • G3: poorly differentiated.
  • G4: undifferentiated.[1]

No statistically significant correlation between degree of differentiation and the biological behavior of the cancer exists; however, vascular invasion is a negative prognostic factor.[2]

Because leukoplakia, erythroplakia, and mixed erythroleukoplakia are exclusively clinical terms that have no specific histopathologic connotations,[3] the term leukoplakia should be used solely as a clinically descriptive term to mean that the observer sees a white patch that does not rub off, the significance of which depends on histological findings. Leukoplakia can range from hyperkeratosis to an early invasive carcinoma, or it may represent a fungal infection, lichen planus, or other benign oral disease.

References
  1. Bansberg SF, Olsen KD, Gaffey TA: High-grade carcinoma of the oral cavity. Otolaryngol Head Neck Surg 100 (1): 41-8, 1989. [PUBMED Abstract]
  2. Close LG, Brown PM, Vuitch MF, et al.: Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg 115 (11): 1304-9, 1989. [PUBMED Abstract]
  3. Oral cavity and oropharynx. In: Rosai J, ed.: Rosai and Ackerman's Surgical Pathology. Vol. 1. 10th ed. Mosby Elsevier, 2011, pp. 237-264.

Stage Information for Lip and Oral Cavity Cancer

The staging systems for lip and oral cavity cancer are all clinical staging and are based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation when possible and by both indirect mirror examination and direct endoscopy when necessary. The tumor must be confirmed histologically, and any other pathological data obtained on biopsy may be included. The appropriate nodal drainage areas are examined by careful palpation. Information from diagnostic imaging studies may be used in staging. Magnetic resonance imaging offers an advantage over computed tomographic scans in the detection and localization of head and neck tumors and in the distinction of lymph nodes from blood vessels.[1] If a patient's disease relapses, complete restaging must be done to select the appropriate additional therapy.[2,3]

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define lip and oral cavity cancer. The staging system reflects the whole oral cavity, which includes the mucosa of the lip but not the external (dry) lip.[4] The staging described below is used for patients who have not had a lymph node dissection of the neck.

Table 1. Definition of Primary Tumor (T)a
T CategorybT Criteria
DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bClinical and pathological DOI are now used in conjunction with size to determine the T category.
cDOI is depth of invasion and not tumor thickness.
dSuperficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4.
TXPrimary tumor cannot be assessed.
TisCarcinoma in situ.
T1Tumor ≤2 cm with DOIc ≤5 mm.
T2Tumor ≤2 cm with DOIc >5 mm or tumor >2 cm and ≤4 cm with DOIc ≤10 mm.
T3Tumor >2 cm and ≤4 cm with DOIc >10 mm or tumor >4 cm with DOIc ≤10 mm.
T4Moderately advanced or very advanced local disease.
–T4adModerately advanced local disease. Tumor >4 cm with DOIc >10 mm or tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla or involves the maxillary sinus or skin of the face).
–T4bVery advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery.
Table 2. Definition of Regional Lymph Nodes – Pathological (pN)a
N CategoryN Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+).
NXRegional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
N2Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(+) ; or >3 cm but ≤6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension, and ENE(–).
–N2aMetastasis in a single ipsilateral node ≤3 cm in greatest dimension and ENE(+); or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(–).
–N2bMetastases in multiple ipsilateral nodes, none >6 cm in greatest dimension, and ENE(–).
–N2cMetastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension, and ENE(–).
N3Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
–N3aMetastasis in a lymph node >6 cm in greatest dimension and ENE(–).
–N3bMetastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
Table 3. Definition of Distant Metastasis (M)a
M CategoryM Criteria
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
M0No distant metastasis.
M1Distant metastasis.
Table 4. Definition of TNM Stage 0a
StageTNMDescription
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
0Tis, N0, M0 Tis = Carcinoma in situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 5. Definition of TNM Stage Ia
StageTNMDescription
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
IT1, N0, M0T1 = Tumor ≤2 cm with DOIb ≤5 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 6. Definition of TNM Stage IIa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
IIT2, N0, M0T2 = Tumor ≤2 cm with DOIb >5 mm or tumor >2 cm and ≤4 cm with DOIb ≤10 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 7. Definitions of TNM Stage IIIa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion; ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
IIIT3, N0, M0T3 = Tumor >2 cm and ≤4 cm with DOIb >10 mm or tumor >4 cm with DOIb ≤10 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T1, T2, T3, N1, M0T1, T2, T3 = see Table 1.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
M0 = No distant metastasis.
Table 8. Definitions of TNM Stage IVA, IVB, and IVCa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion; ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bSuperficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4.
cDOI is depth of invasion and not tumor thickness.
IVAT4a, N0, N1, M0T4ab = Moderately advanced local disease. Tumor >4 cm with DOIc >10 mm or tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla or involves the maxillary sinus or skin of the face).
N0 = No regional lymph node metastasis.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
M0 = No distant metastasis.
T1, T2, T3, T4a, N2, M0T1, T2, T3, T4a = see Table 1.
N2 = Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(+); or >3 cm but ≤6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension, and ENE(–).
M0 = No distant metastasis.
IVBAny T, N3, M0Any T = See Table 1.
N3 = Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or in a single contralateral node of any size and ENE(+).
M0 = No distant metastasis.
T4b, Any N, M0T4b = Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery.
Any N = See Table 2.
M0 = No distant metastasis.
IVCAny T, Any N, M1Any T = See Table 1.
Any N = See Table 2.
M1 = Distant metastasis.
References
  1. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988. [PUBMED Abstract]
  2. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  3. Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
  4. Oral cavity cancer. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 79–94.

Treatment Option Overview for Lip and Oral Cavity Cancer

The selection of treatment for lip and oral cavity cancer depends on the site and extent of the primary tumor and the status of the lymph nodes. Some options for treatment of this cancer include:[1-5]

  • Surgery alone.
  • Radiation therapy alone.
  • A combination of the surgery and radiation therapy.

For lesions of the oral cavity, surgery must adequately encompass all of the gross as well as the presumed microscopic extent of the disease. If regional nodes are positive, cervical node dissection is usually done in continuity. With modern approaches, the surgeon can successfully ablate large posterior oral cavity tumors and with reconstructive methods can achieve satisfactory functional results. Prosthodontic rehabilitation is important, particularly in early-stage cancers, to assure the best quality of life.

Radiation therapy for lip and oral cavity cancers can be given by external-beam radiation therapy (EBRT) or interstitial implantation alone, but for many sites the use of both modalities produces better control and functional results. Small superficial cancers can be very successfully treated by local implantation using any one of several radioactive sources, by intraoral cone radiation therapy, or by electrons. Larger lesions are frequently managed using EBRT to include the primary site and regional lymph nodes, even if they are not clinically involved. Supplementation with interstitial radiation sources may be necessary to achieve adequate doses to large primary tumors and/or bulky nodal metastases. A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control with prolonged radiation therapy; therefore, lengthened standard treatment schedules should be avoided whenever possible.[6,7]

Early cancers (stage I and stage II) of the lip, floor of the mouth, and retromolar trigone are highly curable by surgery or radiation therapy. The choice of treatment is dictated by the anticipated functional and cosmetic results. Availability of a surgeon or radiation oncologist with the required expertise for the individual patient is also a factor in treatment choice.

Advanced cancers (stage III and stage IV) of the lip, floor of the mouth, and retromolar trigone represent a wide spectrum of challenges for the surgeon and radiation oncologists. Most patients with stage III or stage IV tumors are candidates for treatment with a combination of surgery and radiation therapy. The exceptions are patients with small T3 lesions and no regional lymph nodes, and no distant metastases or patients who have no lymph nodes larger than 2 cm in diameter, for whom treatment by radiation therapy alone or surgery alone might be appropriate. Because local recurrence and/or distant metastases are common in this group of patients, clinical trials that are evaluating the following should be considered:

  • The potential role of radiation modifiers to improve local control or decrease morbidity.
  • The role of combinations of chemotherapy with surgery and/or radiation therapy to improve local control and to decrease the frequency of distant metastases.

Early cancers of the buccal mucosa are equally curable by radiation therapy or adequate excision. Patient factors and local expertise influence the choice of treatment. Larger cancers require composite resection with reconstruction of the defect by pedicle flaps.

Early lesions (T1 and T2) of the anterior tongue may be managed by surgery or by radiation therapy alone. Both modalities produce 70% to 85% cure rates in patients with early lesions. Moderate excisions of tongue, even hemiglossectomy, can often result in little speech disability provided the wound closure is such that the tongue is not bound down. However, if the resection is more extensive, problems may include aspiration of liquids and solids, difficulty swallowing, and speech difficulties. Occasionally, patients with tumor of the tongue require almost total glossectomy. Large lesions generally require combined surgical and radiation treatment. The control rates for larger lesions are about 30% to 40%. According to clinical and radiological evidence of involvement, cancers of the lower gingiva that are exophytic and amenable to adequate local excision may be excised to include portions of bone. More advanced lesions require segmental bone resection, hemimandibulectomy, or maxillectomy, depending on the extent of the lesion and its location.

Early lesions of the upper gingiva or hard palate without bone involvement can be treated with equal effectiveness by surgery or radiation therapy alone. Advanced infiltrative and ulcerating lesions should be treated by a combination of radiation therapy and surgery. Most primary cancers of the hard palate are of minor salivary gland origin. Primary squamous cell carcinoma of the hard palate is uncommon, and these tumors generally represent invasion of squamous cell carcinoma arising on the upper gingiva, which is much more common. Management of squamous cell carcinoma of the upper gingiva and hard palate is usually considered together. Surgical treatment of cancer of the hard palate usually requires excision of underlying bone producing an opening into the antrum. This defect can be filled and covered with a dental prosthesis, which is a maneuver that restores satisfactory swallowing and speech.

Patients who smoke while receiving radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[8] therefore, patients should be counseled to stop smoking before beginning radiation therapy. Dental status evaluation should be performed prior to therapy to prevent late sequelae.

Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[9,10] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[9-11] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[12-14] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[15] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[16]

References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  2. Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
  3. Myers EN, Suen MD, Myers J, eds.: Cancer of the Head and Neck. 4th ed. Saunders, 2003.
  4. Freund HR: Principles of Head and Neck Surgery. 2nd ed. Appleton-Century-Crofts, 1979.
  5. Lore JM: An Atlas of Head and Neck Surgery. 3rd ed. Saunders, 1988.
  6. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
  7. Langendijk JA, de Jong MA, Leemans ChR, et al.: Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time. Int J Radiat Oncol Biol Phys 57 (3): 693-700, 2003. [PUBMED Abstract]
  8. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
  9. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  10. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  11. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  12. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  13. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  14. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  15. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  16. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Stage I Lip and Oral Cavity Cancer

Surgery and/or radiation therapy may be used, depending on the exact site.[1,2]

Treatment Options for Small Lesions of the Lip

Treatment options for stage I small lesions of the lip include:

  1. Surgery.
  2. Radiation therapy.

Surgery and radiation therapy produce similar cure rates, and the method of treatment is dictated by the anticipated cosmetic and functional results.

Treatment Options for Small Anterior Tongue Lesions

Treatment options for stage I small anterior tongue lesions include:

  1. Wide local excision is often used for small lesions that can be resected transorally.
  2. For patients with larger T1 lesions, the following standard treatments are used:
    1. Surgery.
    2. Radiation therapy.
    3. Interstitial implantation alone or with external-beam radiation therapy.
    4. Irradiation of the neck.

Treatment Options for Small Lesions of the Buccal Mucosa

Treatment options for stage I small lesions of the buccal mucosa include:

  1. Surgery alone for patients with lesions smaller than 1 cm in diameter, if the commissure is not involved.
  2. Radiation therapy, including brachytherapy, should be considered to treat lesions smaller than 1 cm in diameter, if the commissure is involved.
  3. Surgical excision with a split-thickness skin graft or radiation therapy is used to treat larger T1 lesions.

Treatment Options for Small Lesions of the Floor of the Mouth

Treatment options for stage I small lesions of the floor of the mouth include:

  1. Surgery for patients with T1 lesions.
  2. Radiation therapy is used to treat T1 lesions.
  3. Excision alone is generally adequate to treat lesions smaller than 0.5 cm if there is a margin of normal mucosa between the lesion and the gingiva.
  4. Surgery is often used if the lesion is attached to the periosteum.
  5. Radiation therapy is often used if the lesion encroaches on the tongue.

Treatment Options for Small Lesions of the Lower Gingiva

Treatment options for stage I small lesions of the lower gingiva include:

  1. Intraoral resection with or without a rim resection of bone and repair with a split-thickness skin graft are used to treat small lesions.
  2. Radiation therapy may be used for small lesions, but results are generally better after surgery alone.

Treatment Options for Small Tumors of the Retromolar Trigone

Treatment options for stage I small tumors of the retromolar trigone include:

  1. Limited resection of the mandible is performed for early lesions without detectable bone invasion.
  2. Radiation therapy may be used initially if limited resection is not feasible, with surgery reserved for radiation failure.

Treatment Options for Small Lesions of the Upper Gingiva and Hard Palate

Treatment options for stage I small lesions of the upper gingiva and hard palate include:

  1. Surgical resection is used to treat most small lesions.
  2. Postoperative radiation therapy may be used if appropriate.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  2. Guerry TL, Silverman S, Dedo HH: Carbon dioxide laser resection of superficial oral carcinoma: indications, technique, and results. Ann Otol Rhinol Laryngol 95 (6 Pt 1): 547-55, 1986 Nov-Dec. [PUBMED Abstract]

Treatment of Stage II Lip and Oral Cavity Cancer

Surgery and/or radiation therapy may be used, depending on the exact site.[1]

Treatment Options for Small Lesions of the Lip

Treatment options for stage II small lesions of the lip include:

  1. Surgery is used for patients with smaller T2 lesions on the lower lip, if simple closure produces an acceptable cosmetic result.
  2. Radiation therapy, which may include external-beam and/or interstitial techniques, as appropriate, has the advantage of producing a relatively better functional and cosmetic result, with intact skin and muscle innervation, if a reconstructive surgical procedure is required.

Treatment Options for Small Anterior Tongue Lesions

Treatment options for stage II small anterior tongue lesions include:

  1. Radiation therapy is usually selected for patients with T2 lesions that have minimal infiltration to preserve speech and swallowing.[2]
  2. Surgery is reserved for patients for whom radiation treatment failed.[2]
  3. Neck dissection may be considered when primary brachytherapy is used.[2]
  4. Surgery, radiation therapy, or a combination of both are used for deeply infiltrative lesions.

Treatment Options for Small Lesions of the Buccal Mucosa

Treatment options for stage II small lesions of the buccal mucosa include:

  1. Radiation therapy is the usual treatment for patients with small T2 lesions (≤3 cm).
  2. Surgery, radiation therapy, or a combination of these are used, if indicated to treat large T2 lesions (>3 cm). Radiation therapy is often used if the lesion involves the commissure. Surgery is often used, if tumor invades the mandible or maxilla.

Treatment Options for Small Lesions of the Floor of the Mouth

Treatment options for stage II small lesions of the floor of the mouth include:

  1. Surgery is often used for patients with small T2 lesions (≤3 cm) if the lesion is attached to the periosteum.
  2. Radiation therapy is often used to treat patients with small T2 lesions (≤3 cm) if the lesion encroaches on the tongue.
  3. Surgery and radiation therapy are alternative methods of treatment for patients with large T2 lesions (>3 cm), the choice of which depends primarily on the expected extent of disability from surgery.
  4. External-beam radiation therapy with or without interstitial radiation therapy should be considered postoperatively for larger lesions.

Treatment Options for Small Lesions of the Lower Gingiva

Treatment options for stage II small lesions of the lower gingiva include:

  1. Intraoral resection with or without a rim resection of bone and repair with a split-thickness skin graft are used to treat patients with small lesions.
  2. Radiation therapy may be used to treat patients with small lesions, but results are generally better after surgery alone.

Treatment Options for Small Tumors of the Retromolar Trigone

Treatment options for stage II small tumors of the retromolar trigone include:

  1. Limited resection of the mandible is performed to treat patients with early lesions that are without detectable bone invasion.
  2. Radiation therapy may be used initially if limited resection is not feasible.
  3. Surgery is reserved for radiation failure.

Treatment Options for Small Lesions of the Upper Gingiva and Hard Palate

Treatment options for stage II small lesions of the upper gingiva and hard palate include:

  1. Surgical resection with postoperative radiation therapy, as appropriate, is used to treat most lesions. A small study showed that radiation therapy may be used effectively as the sole treatment modality.[3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  2. Pernot M, Malissard L, Aletti P, et al.: Iridium-192 brachytherapy in the management of 147 T2N0 oral tongue carcinomas treated with irradiation alone: comparison of two treatment techniques. Radiother Oncol 23 (4): 223-8, 1992. [PUBMED Abstract]
  3. Yorozu A, Sykes AJ, Slevin NJ: Carcinoma of the hard palate treated with radiotherapy: a retrospective review of 31 cases. Oral Oncol 37 (6): 493-7, 2001. [PUBMED Abstract]

Treatment of Stage III Lip and Oral Cavity Cancer

Surgery and/or radiation therapy are used, depending on the exact tumor site.[1,2] Neoadjuvant chemotherapy, as given in clinical trials, has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. Neoadjuvant chemotherapy is given prior to the other modalities, as opposed to standard adjuvant chemotherapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used as neoadjuvant chemotherapy.[3-6] However, randomized, prospective trials have yet to demonstrate a benefit in either disease-free survival or overall survival for patients receiving neoadjuvant chemotherapy.[7]

Treatment Options for Moderately Advanced Lesions of the Lip

These lesions, including those involving bone, nerves, and lymph nodes, generally require a combination of surgery and radiation therapy.

Treatment options for stage III advanced lesions of the lip include:

  1. Surgery using a variety of approaches, the choice of which is dependent on the size and location of the lesion and the need for reconstruction.
  2. Radiation therapy using a variety of techniques, including external-beam radiation therapy (EBRT) with or without brachytherapy, the choice of which is dictated by the size and location of the lesion.
  3. Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3-6,8-10]
  4. Superfractionated radiation therapy (under clinical evaluation).[11]

Treatment Options for Moderately Advanced (Late T2, Small T3) Lesions of the Anterior Tongue

Treatment options for stage III moderately advanced (late T2, small T3) lesions of the anterior tongue include:

  1. EBRT with or without interstitial implant is used to treat minimally infiltrative lesions.
  2. Surgery with postoperative radiation therapy is used to treat deeply infiltrative lesions.[2]

Treatment Options for Moderately Advanced Lesions of the Buccal Mucosa

Treatment options for stage III advanced lesions of the buccal mucosa include:

  1. Radical surgical resection alone.
  2. Radiation therapy alone.
  3. Surgical resection plus radiation therapy, generally postoperative.
  4. Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3-6,8-10,12]

Treatment Options for Moderately Advanced Lesions of the Floor of the Mouth

Treatment options for stage III moderately advanced lesions of the floor of the mouth include:

  1. Surgery using rim resection plus neck dissection or partial mandibulectomy with neck dissection, as appropriate.
  2. Radiation therapy using EBRT alone or EBRT plus an interstitial implant.
  3. Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3-6,8-10,12]
  4. Clinical trials using novel radiation therapy fractionation schemas.[13]

Treatment Options for Moderately Advanced Lesions of the Lower Gingiva

Treatment options for stage III moderately advanced lesions of the lower gingiva include:

  1. Combined radiation therapy and radical resection or radical resection alone are used to treat extensive lesions with moderate bone destruction and/or nodal metastases. Radiation therapy may be administered either preoperatively or postoperatively.

Treatment Options for Moderately Advanced Lesions of the Retromolar Trigone

Treatment options for stage III advanced lesions of the retromolar trigone include:

  1. Surgical composite resection, which may be followed by postoperative radiation therapy.
  2. Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3-6,8-10,12]
  3. Clinical trials using novel radiation therapy fractionation schemas.[13]

Treatment Options for Moderately Advanced Lesions of the Upper Gingiva

Treatment options for stage III moderately advanced lesions of the upper gingiva include:

  1. Radiation therapy alone is used to treat superficial lesions with extensive involvement of the gingiva, hard palate, or soft palate.
  2. A combination of surgery and radiation therapy is used to treat deeply invasive lesions involving bone.

Treatment Options for Moderately Advanced Lesions of the Hard Palate

Treatment options for stage III moderately advanced lesions of the hard palate include:

  1. Radiation therapy alone is used to treat superficial lesions with extensive involvement of the gingiva, hard palate, or soft palate.
  2. A combination of surgery and radiation therapy or surgery alone is used to treat deeply invasive lesions involving bone.

Treatment Options Under Clinical Evaluation for All Stage III Lip and Oral Cavity Cancers

  1. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[8,10,14,15]

    A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients who received concurrent chemotherapy and radiation therapy.[16][Level of evidence B4] Patients who received adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data were not available. No standard regimen existed, and the trials were felt to be too heterogenous to provide definitive recommendations. The results of 18 ongoing trials may further clarify the role of concurrent chemotherapy and radiation therapy in the management of oral cavity cancer.

    The best chemotherapy to use and the appropriate way to integrate the two modalities is still unresolved.[17]

    Similar approaches in the patient with resectable disease, in whom resection would lead to a major functional deficit, are also being explored in randomized trials but cannot be recommended at this time as standard.

  2. Clinical trials of novel fractionation radiation therapy are under evaluation.[13]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  2. Franceschi D, Gupta R, Spiro RH, et al.: Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 166 (4): 360-5, 1993. [PUBMED Abstract]
  3. Ervin TJ, Clark JR, Weichselbaum RR, et al.: An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 5 (1): 10-20, 1987. [PUBMED Abstract]
  4. Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987. [PUBMED Abstract]
  5. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60 (3): 301-11, 1987. [PUBMED Abstract]
  6. Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986. [PUBMED Abstract]
  7. Mazeron JJ, Martin M, Brun B, et al.: Induction chemotherapy in head and neck cancer: results of a phase III trial. Head Neck 14 (2): 85-91, 1992 Mar-Apr. [PUBMED Abstract]
  8. Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987. [PUBMED Abstract]
  9. Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
  10. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
  11. Johnson CR, Khandelwal SR, Schmidt-Ullrich RK, et al.: The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation. Int J Radiat Oncol Biol Phys 32 (3): 635-41, 1995. [PUBMED Abstract]
  12. Licitra L, Grandi C, Guzzo M, et al.: Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 21 (2): 327-33, 2003. [PUBMED Abstract]
  13. Stuschke M, Thames HD: Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials. Int J Radiat Oncol Biol Phys 37 (2): 259-67, 1997. [PUBMED Abstract]
  14. Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991. [PUBMED Abstract]
  15. Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991. [PUBMED Abstract]
  16. Pignon JP, Bourhis J, Domenge C, et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355 (9208): 949-55, 2000. [PUBMED Abstract]
  17. Taylor SG, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994. [PUBMED Abstract]

Treatment of Stage IV Lip and Oral Cavity Cancer

Randomized prospective trials have yet to demonstrate a benefit in either disease-free survival or overall survival for patients receiving neoadjuvant chemotherapy.[1] The use of isotretinoin daily for 1 year to prevent development of second upper aerodigestive tract primaries is under clinical evaluation.[2]

Treatment Options for Advanced Lesions of the Lip

These lesions, including those involving bone, nerves, and lymph nodes, generally require a combination of surgery and radiation therapy.

Treatment options for stage IV advanced lesions of the lip include:

  1. Surgery using a variety of approaches, the choice of which is dependent on the size and location of the lesion and the need for reconstruction. Treatment of both sides of the neck is indicated for selected patients.
  2. Radiation therapy using a variety of techniques, including external-beam radiation therapy (EBRT) with or without brachytherapy, the choice of which is dictated by the size and location of the lesion.
  3. Superfractionated radiation therapy (under clinical evaluation).[3]

Treatment Options for Advanced Lesions of the Anterior Tongue

Treatment options for stage IV advanced lesions of the anterior tongue include:

  1. Combined surgery (i.e., total glossectomy, sometimes requiring laryngectomy), possibly followed by postoperative radiation therapy, may be used to treat selected patients.[4]
  2. Palliative radiation therapy may be used to treat patients with very advanced lesions.

Treatment Options for Advanced Lesions of the Buccal Mucosa

Treatment options for stage IV advanced lesions of the buccal mucosa include:

  1. Radical surgical resection alone.
  2. Radiation therapy alone.
  3. Surgical resection plus radiation therapy, which is generally administered postoperatively.

Treatment Options for Advanced Lesions of the Floor of the Mouth

Treatment options for stage IV advanced lesions of the floor of the mouth include:

  1. A combination of surgery and radiation therapy, which is generally administered postoperatively, is often used.
  2. Preoperative radiation therapy is often used for fixed nodes (≥5 cm).

Treatment Options for Advanced Lesions of the Lower Gingiva

Treatment options for stage IV advanced lesions of the lower gingiva include:

  1. Surgery, radiation therapy, or a combination of both are poor controls for advanced tumors with extensive destruction of the mandible and with nodal metastases.

Treatment Options for Advanced Lesions of the Retromolar Trigone

Treatment options for stage IV advanced lesions of the retromolar trigone include:

  1. Surgical composite resection followed by postoperative radiation therapy.

Treatment Options for Advanced Lesions of the Upper Gingiva

Treatment options for stage IV advanced lesions of the upper gingiva include:

  1. Surgery in combination with radiation therapy is generally used to treat lesions that are extensive and infiltrating.

Treatment Options for Advanced Lesions of the Hard Palate

Treatment options for stage IV advanced lesions of the hard palate include:

  1. Surgery in combination with radiation therapy is generally used to treat lesions that are extensive and infiltrating.

Treatment Options Under Clinical Evaluation for All Stage IV Lip and Oral Cavity Cancers

  1. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[5-8]

    A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients who received concurrent chemotherapy and radiation therapy.[9][Level of evidence B4] Patients who received adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data were not available. No standard regimen existed, and the trials were felt to be too heterogenous to provide definitive recommendations. The results of 18 ongoing trials may further clarify the role of concurrent chemotherapy and radiation therapy in the management of oral cavity cancer.

    The best chemotherapy to use and the appropriate way to integrate the two modalities is still unresolved.[10]

    Similar approaches in the patient with resectable disease, in whom resection would lead to a major functional deficit, are also being explored in randomized trials but cannot be recommended at this time as standard.

  2. Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, or as adjuvant therapy after surgery are appropriate.[5,11-18]
  3. Clinical trials of novel fractionation radiation therapy are under evaluation.[19]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Mazeron JJ, Martin M, Brun B, et al.: Induction chemotherapy in head and neck cancer: results of a phase III trial. Head Neck 14 (2): 85-91, 1992 Mar-Apr. [PUBMED Abstract]
  2. Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323 (12): 795-801, 1990. [PUBMED Abstract]
  3. Johnson CR, Khandelwal SR, Schmidt-Ullrich RK, et al.: The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation. Int J Radiat Oncol Biol Phys 32 (3): 635-41, 1995. [PUBMED Abstract]
  4. Franceschi D, Gupta R, Spiro RH, et al.: Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 166 (4): 360-5, 1993. [PUBMED Abstract]
  5. Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987. [PUBMED Abstract]
  6. Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991. [PUBMED Abstract]
  7. Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991. [PUBMED Abstract]
  8. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
  9. Pignon JP, Bourhis J, Domenge C, et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355 (9208): 949-55, 2000. [PUBMED Abstract]
  10. Taylor SG, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994. [PUBMED Abstract]
  11. Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987. [PUBMED Abstract]
  12. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60 (3): 301-11, 1987. [PUBMED Abstract]
  13. Toohill RJ, Duncavage JA, Grossmam TW, et al.: The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies. Laryngoscope 97 (4): 407-12, 1987. [PUBMED Abstract]
  14. Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986. [PUBMED Abstract]
  15. Fu KK, Phillips TL, Silverberg IJ, et al.: Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 5 (9): 1410-8, 1987. [PUBMED Abstract]
  16. Ryan RF, Krementz ET, Truesdale GL: Salvage of stage IV intraoral squamous cell carcinomas with preoperative 5-fluorouracil. Cancer 57 (4): 699-705, 1986. [PUBMED Abstract]
  17. Ervin TJ, Clark JR, Weichselbaum RR, et al.: An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 5 (1): 10-20, 1987. [PUBMED Abstract]
  18. Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
  19. Stuschke M, Thames HD: Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials. Int J Radiat Oncol Biol Phys 37 (2): 259-67, 1997. [PUBMED Abstract]

Treatment Options for Management of Lymph Node Metastases

Patients with advanced lesions should have elective lymph node radiation therapy or node dissection. The risk of metastases to lymph nodes is increased by high-grade histology, large lesions, spread to involve the wet mucosa of the lip or the buccal mucosa in patients with recurrent disease, and invasion of muscle (i.e., orbicularis oris).[1]

Treatment options for management of lymph node metastases include:

  1. Radiation therapy alone or neck dissection:
    • N1 (0–2 cm).
    • N2b or N3; all nodes smaller than 2 cm. (A combined surgical and radiation therapy approach should also be considered.)
  2. Radiation therapy and neck dissection:
    • N1 (2–3 cm), N2a, N3.
  3. Surgery followed by radiation therapy, indications for which are as follows:
    • Multiple positive nodes.
    • Contralateral subclinical metastases.
    • Invasion of tumor through the capsule of the lymph node.
    • N2b or N3 (one or more nodes in each side of the neck, as appropriate, >2 cm).
  4. Radiation therapy prior to surgery:
    • Large fixed nodes.
References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.

Treatment of Metastatic and Recurrent Lip and Oral Cavity Cancer

For lesions of the lip, anterior tongue, buccal mucosa, floor of the mouth, retromolar trigone, upper gingiva, and hard palate, treatment is dictated by the location and size of the recurrent lesion as well as prior treatment.[1,2]

Treatment Options for Metastatic and Recurrent Lip and Oral Cavity Cancer

Treatment options for metastatic and recurrent lip and oral cavity cancer include:

  1. Surgery is the preferred treatment if radiation therapy was used initially.[3]
  2. Surgery,[3] radiation therapy, or a combination of these treatments may be considered if surgery was used to treat the lesion initially.
  3. Immunotherapy.[4-12]
  4. Although chemotherapy has been shown to induce responses, no increase in survival has been demonstrated.[13]
  5. Clinical trials evaluating new chemotherapy drugs, chemotherapy and re-irradiation, or hyperthermia should be considered because both surgical salvage after primary radiation therapy and radiation therapy after primary surgery give poor results.[14,15]

Immunotherapy

Pembrolizumab

Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death-1 (PD-1) pathway. Studies have evaluated pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (SCC).

Evidence (pembrolizumab as first-line therapy):

  1. KEYNOTE-048 (NCT02358031) was a nonblinded, randomized, phase III study of participants with untreated locally incurable metastatic or recurrent head and neck SCC that was performed at 200 sites in 37 countries.[6] A total of 882 patients were randomly assigned in a 1:1:1 ratio to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (5-FU) (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and 5-FU (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the programmed death-ligand 1 (PD-L1) combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.

    The primary end points were overall survival (OS) and progression-free survival (PFS). Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.

    1. At the second interim analysis, pembrolizumab alone showed improved or noninferior OS compared with cetuximab with chemotherapy. The median OS results were reported as follows:[6][Level of evidence A1]
      • Among the population with a CPS of 20 or higher, the median OS was 14.9 months in patients who received pembrolizumab alone and 10.7 months in patients who received cetuximab with chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.45–0.83; P = .0007).
      • Among the population with a CPS of 1 or higher, the median OS was 12.3 months in patients who received pembrolizumab alone and 10.3 months in patients who received cetuximab with chemotherapy (HR, 0.78; 95% CI, 0.64–0.96; P = .0086).
      • Among the total population, patients who received pembrolizumab alone had noninferior OS (11.6 months) compared with patients who received cetuximab with chemotherapy (10.7 months) (HR, 0.85; 95% CI, 0.71–1.03; P = .0456).
    2. Pembrolizumab with chemotherapy showed improved OS versus cetuximab with chemotherapy. The OS results were reported as follows:
      • At the second interim analysis, among the total population, the median OS was 13.0 months in patients who received pembrolizumab with chemotherapy and 10.7 months in patients who received cetuximab with chemotherapy (HR, 0.77; 95% CI, 0.63–0.93; P = .0034).
      • At the final analysis, among the population with a CPS of 20 or higher, the median OS was 14.7 months in patients who received pembrolizumab with chemotherapy and 11.0 months in patients who received cetuximab with chemotherapy (HR, 0.60; 95% CI, 0.45–0.82; P = .0004).
      • At the final analysis, among the population with a CPS of 1 or higher, the median OS was 13.6 months in patients who received pembrolizumab with chemotherapy and 10.4 months in patients who received cetuximab with chemotherapy (HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
    3. At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
    4. At the final analysis, grade 3 or higher all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
    5. Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.

Pembrolizumab plus a platinum and 5-FU is an appropriate first-line treatment for patients with metastatic or recurrent head and neck SCC. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck SCC. These results were confirmed at a longer median follow-up of 45 months (interquartile range, 41.0–49.2).[7]

Evidence (pembrolizumab after progression on platinum-based treatment):

  1. The phase III KEYNOTE-040 (NCT02252042) trial included patients with incurable metastatic or recurrent head and neck SCC who had received platinum-based treatment within 3 to 6 months.[4] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator’s choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
    • The median OS was 8.4 months in the pembrolizumab arm and 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[4][Level of evidence A1]
    • Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
    • In patients who received pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified malignant progression. Two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
    • The PD-L1 CPS was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
    • Compared with patients treated with standard therapy, a reduced HRdeath was noted for patients who received pembrolizumab and had PD-1 expression on their tumors or in the tumor microenvironment as noted by a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014).
Nivolumab

Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody.

Evidence (nivolumab combined with ipilimumab in patients who have not previously received systemic therapy):

  1. The CheckMate 651 trial (NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab, cisplatin/carboplatin, and 5-FU for up to six cycles followed by cetuximab maintenance) in patients with recurrent or metastatic head and neck SCC.[9] The primary end points were OS in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher and PFS, objective response rate, and duration of response in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher.
    • Among all randomly assigned patients, there was no statistically significant difference in OS with nivolumab plus ipilimumab versus EXTREME (median OS, 13.9 vs. 13.5 months; HR, 0.95; 97.9% CI, 0.80–1.13; P = .4951). Among patients with a PD-L1 CPS of 20 or higher, there was also no statistically significant OS difference between the two treatments (median OS, 17.6 vs. 14.6 months; HR, 0.78; 97.51% CI, 0.59–1.03; P = .0469).[9][Level of evidence A1]
    • In patients with a CPS of 1 or higher, the median OS was 15.7 months for patients who received nivolumab plus ipilimumab versus 13.2 months for patients who received EXTREME (HR, 0.82; 95% CI, 0.69–0.97).
    • Among patients with a CPS of 20 or higher, the median PFS was 5.4 months for patients who received nivolumab plus ipilimumab and 7.0 months for patients who received EXTREME. The objective response rate was 34.1% for patients who received nivolumab plus ipilimumab and 36.0% for patients who received EXTREME.
    • Grade 3 or 4 treatment-related adverse events occurred in 28.2% of patients who received nivolumab plus ipilimumab and 70.7% of patients who received EXTREME.
    • CheckMate 651 did not meet its primary end points of OS in the randomly assigned or CPS of 20 or higher populations.

    The absence of a survival benefit for immune checkpoint inhibitors in this trial was an unexpected outcome, given the similarity of nivolumab to pembrolizumab in the studies of patients with cisplatin-refractory disease.[4,5] An editorial accompanying the CheckMate 651 trial analyzed some of the factors that may have contributed to a different result. The editorial suggested that survival in the control group, which was longer than that reported in prior studies, may have been impacted by the greater availability of second-line immunotherapy in the control group (46% in CheckMate 651 compared with 25% in the KEYNOTE-048 trial). The authors also suggested that the coadministration of ipilimumab detracted from the activity of nivolumab, as shown in the CheckMate 714 trial.[8]

  2. CheckMate 714 (NCT02823574), a double-blind phase II trial, evaluated the clinical benefit of first-line nivolumab plus ipilimumab versus nivolumab alone in 425 patients with recurrent or metastatic head and neck SCC.[10] Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo. Treatment continued for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic disease. These were patients who had recurrent disease less than 6 months after completion of platinum-based chemotherapy (adjuvant or neoadjuvant, or as part of multimodal treatment [chemotherapy, surgery, and/or radiation therapy]). Among the 241 patients (56.7%) with platinum-refractory disease, 159 were assigned to receive nivolumab plus ipilimumab and 82 were assigned to receive nivolumab alone. Among the 184 patients (43.3%) with platinum-eligible disease, 123 were assigned to receive nivolumab plus ipilimumab and 61 were assigned to receive nivolumab alone.[10][Level of evidence B3]
    • At primary database lock, the objective response rate in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%–19.5%) with nivolumab plus ipilimumab and 18.3% (95% CI, 10.6%–28.4%) with nivolumab alone (odds ratio, 0.68; 95.5% CI, 0.33–1.43; P = .29).
    • The median duration of response was not reached (NR) in the nivolumab-plus-ipilimumab group (95% CI, 11.0 months–NR) and was 11.1 months (95% CI, 4.1–NR) in the nivolumab-alone group. In the population with platinum-eligible disease, the objective response rate was 20.3% (95% CI, 13.6%–28.5%) with nivolumab plus ipilimumab and 29.5% (95% CI, 18.5%–42.6%) with nivolumab alone.
    • Among the population with platinum-refractory disease, grade 3 or 4 treatment-related adverse events occurred in 25 of 158 patients (15.8%) who received nivolumab plus ipilimumab and in 12 of 82 patients (14.6%) who received nivolumab alone. Among the population with platinum-eligible disease, grade 3 or 4 treatment-related adverse events occurred in 30 of 122 patients (24.6%) who received nivolumab plus ipilimumab and in 8 of 61 patients (13.1%) who received nivolumab alone.
    • This trial did not meet its primary end point of objective response rate benefit with first-line nivolumab plus ipilimumab versus nivolumab alone in patients with platinum-refractory recurrent or metastatic head and neck SCC.

Evidence (nivolumab after progression on platinum-based treatment):

  1. A phase III open-label trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was OS.[5]
    • The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was statistically significantly longer with nivolumab than with standard therapy (HRdeath, 0.70; 97.73% CI, 0.51–0.96; P = .01). The estimated 1-year survival rate was approximately 19% higher in patients who received nivolumab (36.0%) than in those who received standard therapy (16.6%).[5][Level of evidence A1]
    • There was no statistically significant difference in median PFS between treatment groups. The 6-month PFS rate was 19.7% with nivolumab versus 9.9% with standard therapy.
    • The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
    • Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% of the patients in the standard therapy group.
    • Quality-of-life outcomes—including physical, role, and social functioning and pain, sensory, and social contact problems—were stable in the nivolumab group but worse in the standard therapy group. These outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35).
    • In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HRdeath among patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83). In the subgroup of patients with a PD-L1 expression level lower than 1%, the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).
  2. A randomized, phase III, superiority study in India evaluated the dose of immune checkpoint inhibitors in the setting of palliative care for patients with advanced head and neck cancer. Low-dose IV nivolumab (20 mg every 3 weeks) was added to a triple metronomic chemotherapy regimen of oral methotrexate (9 mg/m2 once weekly), celecoxib (200 mg twice daily), and erlotinib (150 mg once daily). Notably, this nivolumab dose is less than 10% of the dose recommended by the U.S. Food and Drug Administration and the European Medicines Agency. A total of 151 patients were randomly assigned to receive either triple metronomic chemotherapy alone (n = 75) or triple metronomic chemotherapy with nivolumab (n = 76). The primary end point was 1-year OS.[11]
    • The addition of low-dose nivolumab to triple metronomic chemotherapy improved the 1-year OS rate from 16.3% (95% CI, 8.0%–27.4%) to 43.4% (95% CI, 30.8%–55.3%) (HR, 0.545; 95% CI, 0.362–0.820; P = .0036).[11][Level of evidence A1]
    • The median OS was 6.7 months (95% CI, 5.8–8.1) for patients who received triple metronomic chemotherapy alone and 10.1 months (95% CI, 7.4–12.6) for patients who received triple metronomic chemotherapy with nivolumab (P = .0052).
    • The rate of grade 3 or higher adverse events was 50% for patients who received triple metronomic chemotherapy alone and 46.1% for patients who received triple metronomic chemotherapy with nivolumab (P = .744).

    Although the control arm in this study cannot be considered standard care, lower doses of immunotherapy appeared to have some benefit in this setting.[12]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
  2. Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985. [PUBMED Abstract]
  3. Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003. [PUBMED Abstract]
  4. Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019. [PUBMED Abstract]
  5. Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016. [PUBMED Abstract]
  6. Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019. [PUBMED Abstract]
  7. Harrington KJ, Burtness B, Greil R, et al.: Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol 41 (4): 790-802, 2023. [PUBMED Abstract]
  8. Burtness B: First-Line Nivolumab Plus Ipilimumab in Recurrent/Metastatic Head and Neck Cancer-What Happened? J Clin Oncol 41 (12): 2134-2137, 2023. [PUBMED Abstract]
  9. Haddad RI, Harrington K, Tahara M, et al.: Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol 41 (12): 2166-2180, 2023. [PUBMED Abstract]
  10. Harrington KJ, Ferris RL, Gillison M, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 9 (6): 779-789, 2023. [PUBMED Abstract]
  11. Patil VM, Noronha V, Menon N, et al.: Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 41 (2): 222-232, 2023. [PUBMED Abstract]
  12. Mitchell AP, Goldstein DA: Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy. J Clin Oncol 41 (2): 170-172, 2023. [PUBMED Abstract]
  13. Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992. [PUBMED Abstract]
  14. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308 (2): 75-9, 1983. [PUBMED Abstract]
  15. Vokes EE, Athanasiadis I: Chemotherapy of squamous cell carcinoma of head and neck: the future is now. Ann Oncol 7 (1): 15-29, 1996. [PUBMED Abstract]

Latest Updates to This Summary (11/25/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Metastatic and Recurrent Lip and Oral Cavity Cancer

Revised the list of treatment options for recurrent lip and oral cavity cancer to include immunotherapy with pembrolizumab or nivolumab.

Added Immunotherapy as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult lip and oral cavity cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
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  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Lip and Oral Cavity Cancer Treatment are:

  • Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)
  • Monaliben Patel, MD (University of Rochester Medical Center)
  • Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Lip and Oral Cavity Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/adult/lip-mouth-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389262]

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