Squamous cell carcinoma of the oral cavity following breast cancer treatment.

To the Editor: Early diagnosis and combined modality of treatment have significantly improved the survival of breast cancer patients. Most patients will die of etiologies other than breast cancer, which may include second primary malignancies (SPM). We report here two patients who developed squamous cell carcinoma of the oral cavity following treatment of primary breast cancer with chemotherapy and radiotherapy. The possible association of adjuvant therapy with SPM is discussed.

The first patient is a white female who was diagnosed with breast cancer stage I (T1N0M0) in 1995 at the age of 55 years. After lumpectomy, she received adjuvant chemotherapy with doxorubicin 60 mg/[m.sup.2] plus cyclophosphamide 600 mg/[m.sup.2] IV every 3 weeks for four cycles followed by radiotherapy to the breast for a total dose of 5,400 cGy. The treatment was well tolerated without excessive side effects. As her breast cancer was positive for estrogen receptors, she received tamoxifen for 5 years which was completed in May 2001. In January 2000, she was found to have squamous cell carcinoma of the lateral left tongue (stage I) and underwent partial glossectomy.

The second patient is also a white female who had breast cancer, stage IIA (T1cN1M0), and underwent lumpectomy and axillary lymph node dissection in 1991 at age 47. She subsequently received radiotherapy 5,400 cGy to the breast and combined chemotherapy consisting of cyclophosphamide 100 mg/[m.sup.2]/d orally days 1 through 7, doxorubicin 40 mg/[m.sup.2] IV day 1, vincristine 1 mg IV day 1, methotrexate 100 mg/[m.sup.2] IV day 1, 5-fluorouracil 600 mg/[m.sup.2] IV infusion on day 2, and 300 mg/[m.sup.2]/d on days 8 and 9, and leucovorin 10 mg/[m.sup.2] orally every 6 hours for 6 doses starting on day 2. The treatment was given every 14 days for a total of 8 cycles. The patient experienced grade 2 mucositis on one occasion, and with dosing modification, had a repeat episode of grade 1 mucositis. She was found to have squamous cell carcinoma of the buccal mucosa stage I (T1N0M0) in May 1999 and was treated with surgical resection. Both patients have good oral hygiene and never consumed tobacco or alcohol. They had no significant exposure to tobacco or other carcinogens in their living and working environment, and their family histories were unremarkable. On follow-up, they remain free of active breast cancer, oral cancer, and oral mucosal pathology.

The incidence of nonbreast SPM reportedly ranges from 3.6% to 7.8% with a relative risk compared with age and gender-matched population at 1.1 to 1.4 (CI 95%). (1-3) The annual incidence of oral cancer along with pharyngeal cancer in the United States is 9.7, approximately 12.7 per 100,000. (4) Most patients with oral cancer have recognizable risk factors, such as tobacco and alcohol use. In a large cohort study, 11 of 7,711 patients with breast cancer developed SPM originating from the oral cavity, esophagus, or larynx. (1) However, the details relative to other risk factors (tobacco, alcohol, etc.) in these patients are not available. For the two cases described in this report, the association between the oral cancer and the treatment of breast cancer should be considered, as they had no other known risk factors.

The association of SPM and radiotherapy has been extensively studied. Overall, there is a reported 1% absolute excess incidence of nonbreast SPM in patients who received radiation treatment. (2) The effect of radiation was dose related: excessive risk of SPM was 0.2% for a total dose of 100 cGy and 6.7 fold higher for a dose greater than 2,500 cGy. (1) The increased risk of a second primary breast cancer was seen within 5 years after the initial treatment, whereas that of nonbreast SPM became evident after 5 years post treatment. (2) The two cases presented here are consistent with these findings. The link between chemotherapy and SPM in breast cancer patients is not as well defined. Whereas overall there is no definite evidence that chemotherapy for breast cancer is associated with an increased risk of SPM, the National Surgical Adjuvant Breast and Bowel Project trials revealed an increased incidence of acute leukemia or myelodysplastic syndrome. (5) The use of the hormone modifier, tamoxifen, has been linked to SPM; however, this appears to be limited to endometrial cancer. (1)

In conclusion, the adjuvant treatment of breast cancer may contribute to an increased risk of SPM, although this risk is far outweighed by the benefit. The recognition of the potential development of SPM in breast cancer survivors warrants the cautious screening in these patients which should include an oral examination with evaluation of all lesions. This is especially important in oral cancer and its precancerous lesions as early detection and treatment will significantly improve the outcome of these patients.

Gang Ye, MD

Gary V. Burton, MD

Department of Medicine

Feist-Weiller Cancer Center

Louisiana State University Health Science Center, Shreveport

Shreveport, LA

Cherie-Ann O. Nathan, MD

Department of Otolaryngology/Head and Neck Surgery

Feist-Weiller Cancer Center

Louisiana State University Health Science Center, Shreveport

Shreveport, LA

Federico L. Ampil, MD

Department of Radiology

Feist-Weiller Cancer Center

Louisiana State University Health Science Center, Shreveport

Shreveport, LA

References

1. Rubino C, de Vathaire F Shamsaldin A, et al. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer 2003;89:840-846.

2. Galper S, Gelman R, Recht A, et al. Second nonbreast malignancies after conservative surgery and radiation therapy for early-stage breast cancer. Int J Radial Oncol Biol Phys 2002;52:406-414.

3. Tanaka H, Tsukuma H, Koyama H, et al. Second primary cancers following breast cancer in the Japanese female population. Jpn J Cancer Res 2001;92:1-8.

4. Silverman S Jr. Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge. J Am Dent Assoc 2001;132:7S-11S

5. Smith RE, Bryant J, DeCillis A, et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 2003;21:1195-1204.