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Management of Oral and Pharyngeal Cancer: A Multidisciplinary Approach
'f Symposium on New Skills in Surgery
Management of Oral and Pharyngeal Cancer A Multidisciplinary Approach
Ali A. El-Domeiri, M.D., M.s., FR.C.s.,* and Prabir Chaudhuri, MD.t
The chances for cure of very early and localized cancer of the oral cavity and pharynx by surgery or irradiation are fairly good. In contrast, the high incidence of local recurrence and persistent disease after radical surgery or radiation therapy for advanced lesions presents a major problem and accounts for the high failure rate. In recent years various regimens of a combined therapeutic approach have been resorted to in an attempt to increase the control rate in patients with advanced carcinoma of the head and neck. It is hoped that through a logical and well planned therapeutic regimen utilizing the various modalities of surgery, radiation therapy, and chemotherapy a significant improvement in the salvage rate in patients with advanced oral and pharyngeal cancer may be obtained.
EXPERIENCE In this article we will discuss our own experience in the treatment of some of the common cancers of the mouth and pharynx to put into perspective the factors that prompted us to apply a more aggressive course of combined therapy. During a period of 4 years, 1909 to 1972 inclusive, 105 patients with carcinoma of the floor of the mouth, tongue, and tonsils were treated at the University of Illinois and West Side Veterans Administration Hospitals in Chicago. Two patients were lost to follow-up soon after treatment and were not included in this study. The remaining 103 patients were followed for a minimum period of 2 years (Tables 1 to 4). *Assistant Professor of Surgery, The Abraham Lincoln School of Medicine, University of Illi· nois at the Medical Center; Associate Chairman, Division of Surgical Oncology, Cook County Hospital, Chicago t Resident, Department of Surgery, The Abraham Lincoln School of Medicine, University of Illinois at the Medical Center, Chicago
Surgical Clinics of North America - Vol. 55, No.1, February 1975
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I
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ALI A. EL-DOMEIRI AND PRABIR CHAUDHURI
Table 1. Results of Surgery-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION
TOTAL
STAGE
Floor of Mouth
Tongue
Tonsil
SURVIVALS
I II III IV
2/3" 2/5 3/7 0/2
3/4 3/4
2/2
7/9 6/10 8/21 0/7 21/47
3/10 0/2
1/1 2/4 0/3
All stages "Number of disease-free 2-year survivals/number of patients.
Surgical Treatment FLOOR OF MOUTH. Of the 17 patients treated by surgery alone, eight were in Stage I and II and nine in Stage III and IV. Two patients with Stage I disease were treated by wide local excision of the primary lesion: one died with recurrent disease at 27 months and the second is living free of disease at 24 months. The remaining 15 patients had a combined surgical procedure (en bloc resection of the primary lesion with radical neck dissection). Three of six patients (Stage I and II) were living free of disease at 24,39, and 41 months, respectively. Of the nine patients (Stage III and IV), only two survived free of disease for 33 and 36 months, respectively. TONGUE. Twenty patients with carcinoma of the tongue were treated by surgery. Four patients (Stage I) treated by partial glossectomy were free of disease at 17,24,26, and 39 months. the remaining 16 patients had a combined surgical procedure. Three of four patients (Stage II) were free of disease at 28, 34, and 38 months and only 3 of 12 patients (Stage III and IV) were living without disease at 42, 44, and 54 months. TONSIL. Ten patients were treated by a combined surgical procedure. Three out of three patients in Stage I and II were living free of disease at 20, 23, and 60 months. Of the seven patients in Stage III and IV, three were living free of disease at 22,32, and 51 months.
Table 2.
Results of Radiation Therapy-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION
STAGE
II III IV
Floor of Mouth
Tongue
1/1 • 0/1 1/1
0/1 1/2 0/5
0/8
o
TOTAL
Tonsil
SURVIVALS
o
1/2 1/6 2/9 0/11 4/28
0/3 1/3 0/3
All stages 'Number of disease-free 2-year survivals/number of patients.
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MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
Table 3. Results of Preoperative Radiation Therapy and SurgeryNumber of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION STAGE
III
IV
TOTAL
Floor of Mouth
Tongue
Tonsil
SURVIVALS
1/2* 0/4
0/1
0/2
o
o
1/5 0/4 1/9
Both stages 'Number of disease-free 2-year survivals/number of patients.
Radiation Therapy FLOOR OF THE MOUTH. External irradiation was utilized in the treatment of 11 patients with carcinoma of the floor of the mouth. A tumor dose ranging between 5000 and 6500 rads was delivered to the primary lesion and neck. One of two patients (Stage I and II) was free of disease for 44 months and one of nine patients (Stage III and IV) was living without disease for 24 months. TONGUE. Eight patients received radiation therapy. One of three patients (Stage I and II) survived without disease for 53 months and all patients with Stage III and IV were dead within 14 months. TONSIL. Of the nine patients with carcinoma of the tonsil treated by irradiation, one patient with Stage III disease was living free of disease at 25 months.
Radiation Therapy and Surgery Preoperative irradiation was utilized in patients with Stage III and IV disease to reduce the bulk of the lesion prior to surgical excision. Patients received an average preoperative radiation dose of 4000 rads. Of the nine patients included in this group, only one patient with carcinoma of the floor of the mouth (Stage III) is living without disease at 60 months.
Radiation and Chemotherapy Eight patients with advanced disease were treated by combination of intra-arterial infusion of cytotoxic drugs and radiation therapy. The agent used was methotrexate administered through a catheter placed into the
Table 4. Results of Radiation and Chemotherapy-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION STAGE
Floor of Mouth
Tongue
III
0/1* 0/1
IV
TOTAL
Tonsil
SURVIVALS
o
o
0/1
0/2
0/3
0/7
Both stages 'Number of disease-free 2-year survivals/number of patients.
0/8
llO
ALI A.
EL-DoMEIRI AND PRABIR CHAUDHURI
external carotid via the superficial temporal artery. Patients received a daily dose of 30 to 50 mg for a period of 7 to 15 days. This was followed by a course of radiation therapy with a dose range of 3500 to 5000 rads. All patients were dead within 12 months.
GENERAL CONSIDERATIONS Squamous and epidermoid carcinomas constitute the majority of cancers in the oral cavity and pharynx. These tumors originate in the mucous membrane, then progress to infiltrate into the underlying muscles and adjacent structures and spread primarily via lymphatics to the cervical lymph nodes. Extension of tumor below the clavicle and distant metastases are less frequent and occur in the late stage of the disease. The response to therapy, in general, correlates with the extent of tumor. In those cases presented, the results of treatment compare with the longterm results previously reported. In a retrospective study of patients with carcinoma of the floor of the mouth followed for 5 or more years at our institution, the overall 5-year cure rate was 31 per cent.5 Schottenreld,ll in a review of the end results of 2877 patients with cancer of the oral cavity and pharynx seen at the Memorial Sloan-Kettering Cancer Center during a 15-year period, found that the mean 5-year relative survival rate for infiltrating cancers at all stages was 45.2 per cent. Although cancers arising at different sites in the buccal cavity and pharynx have a similar histologic structure, they do not share the same biologic behavior, which is reflected in the marked variation in their response to therapy and prognosis. Patients with carcinoma of the lip and palate do much better than those with lesions of the floor of mouth and tongue. Metastasis to cervical lymph nodes is by far the most important factor that influences the cure rate. Only 10 per cent of patients with carcinoma of the lip have clinically palpable lymph nodes when first seen, whereas with cancer of the tongue the incidence rises to 40 per cent. Cancers arising in adjacent areas may also exhibit variation in behavior and prognosis. Schottenfeldll reported a 5-year survival rate of 57 per cent in patients with localized cancers of the floor of the mouth and 29 per cent with regional metastases, in contrast to 48 per cent and 18 per cent, respectively, for tongue cancer. The principal cause of failure after radical surgery is recurrence in the neck after radical dissection, which has been reported to be as high as 50 per cent when nodes are positive. One of the effective means in reducing the high incidence of local recurrence is preoperative radiation therapy. Preoperative Irradiation The concept of using preoperative radiation therapy is not new. Improvement in local control of advanced oral cancer with combined preoperative irradiation and surgery was noted by Forsell in 1929. 3 In earlier years the use of a low energy radiation source and the lack of precise means to determine the amount of radiation delivered to the tissues accounted for a significant increase in postoperative complications. With
MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
111
the advance in radiation techniques and the use of high energy sources in recent years, there has been a marked reduction of morbidity and local complication. Preoperative irradiation is intended either to eradicate microscopic nests of cells which may exist beyond the margin of surgical resection or to reduce the bulk of tumor and thus facilitate radical surgical extirpation. It is important to realize that whereas a small dose of radiation may be sufficient to control microscopic aggregates of cancer cells and diminish the number of viable cells likely to exist in the surgical area, a much higher dose is required to produce regression of large cancers and grossly palpable nodes. A review of the literature indicates that there has been a wide variation in the dose levels of radiation used by different workers. Doses ranging from 1500 rads - in a span of 3 to 4 days and followed immediately by surgery - to 5000 rads, with operation four to six weeks later, were utilized. In a controlled prospective study of the effect of irradiation with 2000 rads prior to radical neck dissection, Strong et alP noted a significant reduction in the incidence of cervical recurrence in patients with histologically proven node metastases, but no increase in the 5-year survival rate. In contrast, Lawrence et al.,s using 1400-rad preoperative therapy to the primary lesion and neck in two equal doses delivered 24 and 48 hours prior to the surgical procedure, reported no significant difference in the rate of local recurrence between the irradiated and the nonirradiated groups. Fletcher advocates the use of 4000 to 5000 rads delivered to the primary lesion as well as both necks when surgical excision of a large lesion and neck dissection are contemplated. If the primary lesion is treated by irradiation only and radical neck dissection is planned for clinically positive nodes, the primary lesion is irradiated up to 6500 to 7000 rads. There is experimental evidence to suggest that an increase of 10 to 15 per cent in the biologic dose of radiation may raise local control rates from 30 to 70 per cent. 6 To evaluate the effect of a larger dose of preoperative radiation, we are conducting a prospective study using two dose levels in patients with Stage II to IV cancer of the oral cavity and pharynx. Patients are assigned at random to receive: (a) 2000 rads in five treatments and immediate operation; (b) 4000 rads in 20 treatments, with operation 3 to 4 weeks later; or (c) no radiation before surgery. Preliminary evaluation of the results at 18 months showed comparable reduction of local recurrence in the two groups receiving radiation. However, there was a slight increase in postoperative complications, i.e., wound breakage and fistula formation, which led to longer hospitalization, in the group which had received 4000 rads preoperatively. It is hoped that the use of large doses of preoperative radiation will improve the long-term survival in these patients. This information will be available at the conclusion of the study.
Irradiation and Chemotherapy Effective control of nonresectable carcinoma of the head and neck by radiation alone may be achieved in a small number of patients. Also, ad-
112
ALI A. EL-DOMEIRI AND PRABIR CHAUDHURI
ministration of chemotherapeutic agents may produce regression of these tumors. In an attempt to promote the response to therapy in patients with advanced disease, various regimens of combined radiotherapy and chemotherapy have been employed. The rationale of using this approach is to obtain maximum local control of the disease, which will result in better palliation and, on rare occasions, a cure. It is important to realize that with this form of therapy there will be an increase in toxic manifestations and complications. Therefore, it is essential to keep these patients under close observation and to obtain relevant laboratory data at regular intervals. Recent reports indicate that a combination of systemic chemotherapy and radiation therapy has produced favorable results in patients with advanced disease. Lipshutz et al. 9 reported marked regression of tumors following the use of 80 mg of hydroxyurea per kg of body weight every third day, one week before and then throughout the period of radiation therapy. Similar results were obtained by Gollin et al. 4 with the concomitant use of systemic 5-fluorouracil (5-FU) and external irradiation. Although the results were encouraging in respect to reduction of tumor size and control of local symptoms, there was no appreciable prolongation of survival in these patients. 2 A combination of systemic therapy with bleomycin and high doses of radiation is currently being used in our institution in the treatment of advanced oral carcinoma. Patients with adequate pulmonary and cardiovascular function are included in this trial. The drug is given intravenously in doses of 20 mg twice a week for 2 weeks prior to irradiation, then continued during the course of radiation to reach a total dose of 200 to 300 mg if no adverse reactions take place. Large doses of radiation are delivered to the primary lesion and the neck. A dose of approximately 6500 rads is given to a large area to include both primary lesion and neck. Radiation is then limited to the primary lesion to reach a dose level of 7500 rads. So far, this form of aggressive therapy has been employed in a small number of patients. The effective control of local disease and the marked regression of tumor noted in some of these patients warrant continuation of this approach. Intra-arterial infusion of cytotoxic agents in conjunction with radiation has also been utilized in the treatment of patients with large cancers of the oral cavity. Regional chemotherapy has been advocated in preference to systemic chemotherapy, because a large concentration of the drug can be directly delivered to the tumor-bearing area. This is accomplished under local anesthesia by retrograde catheterization of the external carotid artery via the superficial temporal artery using a polyvinyl catheter. In some instances catheterization of the superficial temporal artery may not be feasible because of extensive disease or an abnormally tortuous vessel. Under these circumstances, a catheter is introduced through the brachial or femoral artery under x-ray control and placed into the external carotid artery, through which infusion of the cytotoxic agent is carried out (Fig. 1). Because of the higher risk of hematogenous infection, this route can only be used for a short period. Prophylactic antibiotic coverage is mandatory to minimize the risk of spreading infection.
MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
113
Figure 1. Catheter introduced through the femoral artery and placed into the external carotid artery. Distribution of dye indicates proper positioning to infuse a lesion in the floor of the mouth and tongue. Lingual, facial, maxillary, and posterior occipital arteries are visualized.
In order to achieve maximum response to chemotherapy or radiation therapy, a good blood supply and adequate oxygenation of tumor tissue is essential. Following a full course of radiotherapy many of the blood vessels within the tumor become obliterated as a result of radiation reaction. To ensure that an adequate concentration of the chemotherapeutic agent will reach the tumor mass, it is preferable to initiate treatment with intraarterial infusion for a few days prior to irradiation. It has been suggested that intra-arterial infusion of tumors with methotrexate prior to radiation therapy increases tissue oxygenation and potentiates the effectiveness of radiation!O In some instances, in patients with fungating and extensive lesions, initial treatment with radiotherapy is given to reduce the bulk of the tumor and produce alleviation of symptoms. Under these circumstances intra-arterial infusion with cytotoxic agents may be initiated during the course of radiation therapy. This will ensure that an adequate amount of the agent will reach the tumor tissue since radiation fibrosis and impairment of the tumor vasculature become evident a few weeks after radiation therapy (Fig. 2). Antimetabolites have been the principal agents used for intra-arterial infusion of head and neck cancer. Nervi et al.1O advocate the use of a small dose of methotrexate to a total dose of 80 to 100 mg, depending upon individual tolerance. This prolonged infusion presumably produces minimal impairment of the host-tumor relationship and will cover a period equal to that of replicating neoplastic cells. The best results of this treatment, with shrinkage or complete regression in about 75 per cent of
114
ALI A.
EL-DOMEIRI AND PRABIR CHAUDHURI
Figure 2. Late phase of arteriogram in a patient with carcinoma of the posterior part of the floor of the mouth and tongue. Tumor blush indicates good blood supply. Patient received 3000 rads prior to insertion of the catheter for infusion.
patients, were obtained in cases which had not been previously treated by surgery or radiotherapy. Lately, we have been using intra-arterial infusion with bleomycin in doses of 10 to 20 mg per square meter per day for a period of 10 to 14 days prior to radiation therapy. This is followed by radiation to the primary lesion and neck, up to a dose of 6500 to 7000 rads. Marked regression of tumor was achieved in two patients thus treated. One of the limitations of intra-arterial infusion via the external carotid artery is that the drug mainly reaches areas supplied by the branches of this vessel. Therefore, lesions in the pharynx which receive most of their blood supply from the subclavian artery are not totally infused. Results of treatment indicated that the best responses to intra-arterial infusion of cytotoxic agents were obtained in patients with carcinoma located in the buccal cavity and nasal sinuses. 7
CONCLUSION Advanced epidermoid carcinoma of the oral cavity and pharynx presents a considerable problem in management. The cure rate of these lesions is very low and effective palliation is difficult to achieve. With the improvement in radiotherapy techniques and the addition of new chemotherapeutic agents, various regimens of aggressive combined therapy have been employed in an attempt to improve the control rate of these lesions. In order to apply these modalities to produce optimum response, the cooperation of physicians in different disciplines, i.e., surgery, radiation therapy, dentistry, and medical oncology, is essential. After' careful evaluation of the individual patients, members of the team will jointly recommend a form of therapy that is most likely to control the disease
MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
115
with a minimum of complications. This, in our experience, has provided a better and more effective means to handle the complex problems encountered in these patients.
REFERENCES 1. Fletcher, G. H.: The combination of radiation and surgery in oropharynx squamous cell carcinoma. Laval Med., 41: 13-17, 1970. 2. Fletcher, G. H., and Jesse, R. H., Jr.: Contribution of supervoltage roentgenotherapy to integration of radiation and surgery in head and neck squamous cell carcinomas. Cancer, 15:566-577,1962. 3. Forsell, G.: Radiotherapy of malignant tumors in Sweden. Br. J. Radiol., 3:198-234,1930. 4. Gollin, F. F., Ansfield, F. J., Brandenburg, J. H., Ramirez, G., and Vermund, H.: Combined therapy in advanced head and neck cancer. A randomized study. Am. J. Roentgen., 114:83-88, 1971. 5. Helfrich, G. B., Nickels, M. E., El-Domeiri, A., and Das Gupta, T. K.: Management of cancer of the floor of the mouth. Am. J. Surg., 124:559-562, 1972. 6. Herring, D. F., and Campton, D.: The Degree of Precision Required in the Radiation Dose Delivered in Cancer Radiotherapy. Report by Enviro-Med., 1970. 7. Jesse, R. H., Goepfert, H., Lindberg, R. D., and Johnson, R. H.: Combined intra-arterial infusion and radiotherapy for the treatment of advanced cancer of the head and neck. Am. J. Roentgen., 105:20-25,1969. 8. Lawrence, W., Jr., Terz, J. J., Rogers, C., King, R. E., Wolf, J. S., and King, E. R.: Pre-operative irradiation for head and neck cancer: A prospective study. Cancer, 33 :318-323, 1974. 9. Lipshutz, H., and Lerner, H. J.: Six year survival in the combined treatment for advanced head and neck cancer under a combined therapy program. Am. J. Surg., 126:519-522, 1973. 10. Nervi, C., Arcangelli, G., Casole, C., Cortese, M., Guadagni, A. and Le Pera, V.: A reappraisal of intra-arterial chemotherapy. Cancer, 26:577-582, 1970. 11. Schottenfeld, D.: Cancer of the buccal cavity and pharynx: A review of end results of primary treatment in 2,877 cases, 1949-1964. Memorial Sloan-Kettering Cancer Center, Clinical Bulletin, 2:51-57,1972. 12. Strong, E. W., Henschke, U. K., Nickson, J. J., Frazell, E. L., Tollefsen, H. R., and Hilaris, B. S.: Pre-operative x-ray therapy as an adjunct to radical neck dissection. Cancer, 19:1509-1516,1966.
Department of Surgery The Abraham Lincoln School of Medicine University of Illinois at the Medical Center P.O. Box 6998 Chicago, Illinois 60680
Management of Oral and Pharyngeal Cancer A Multidisciplinary Approach
Ali A. El-Domeiri, M.D., M.s., FR.C.s.,* and Prabir Chaudhuri, MD.t
The chances for cure of very early and localized cancer of the oral cavity and pharynx by surgery or irradiation are fairly good. In contrast, the high incidence of local recurrence and persistent disease after radical surgery or radiation therapy for advanced lesions presents a major problem and accounts for the high failure rate. In recent years various regimens of a combined therapeutic approach have been resorted to in an attempt to increase the control rate in patients with advanced carcinoma of the head and neck. It is hoped that through a logical and well planned therapeutic regimen utilizing the various modalities of surgery, radiation therapy, and chemotherapy a significant improvement in the salvage rate in patients with advanced oral and pharyngeal cancer may be obtained.
EXPERIENCE In this article we will discuss our own experience in the treatment of some of the common cancers of the mouth and pharynx to put into perspective the factors that prompted us to apply a more aggressive course of combined therapy. During a period of 4 years, 1909 to 1972 inclusive, 105 patients with carcinoma of the floor of the mouth, tongue, and tonsils were treated at the University of Illinois and West Side Veterans Administration Hospitals in Chicago. Two patients were lost to follow-up soon after treatment and were not included in this study. The remaining 103 patients were followed for a minimum period of 2 years (Tables 1 to 4). *Assistant Professor of Surgery, The Abraham Lincoln School of Medicine, University of Illi· nois at the Medical Center; Associate Chairman, Division of Surgical Oncology, Cook County Hospital, Chicago t Resident, Department of Surgery, The Abraham Lincoln School of Medicine, University of Illinois at the Medical Center, Chicago
Surgical Clinics of North America - Vol. 55, No.1, February 1975
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I
108
ALI A. EL-DOMEIRI AND PRABIR CHAUDHURI
Table 1. Results of Surgery-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION
TOTAL
STAGE
Floor of Mouth
Tongue
Tonsil
SURVIVALS
I II III IV
2/3" 2/5 3/7 0/2
3/4 3/4
2/2
7/9 6/10 8/21 0/7 21/47
3/10 0/2
1/1 2/4 0/3
All stages "Number of disease-free 2-year survivals/number of patients.
Surgical Treatment FLOOR OF MOUTH. Of the 17 patients treated by surgery alone, eight were in Stage I and II and nine in Stage III and IV. Two patients with Stage I disease were treated by wide local excision of the primary lesion: one died with recurrent disease at 27 months and the second is living free of disease at 24 months. The remaining 15 patients had a combined surgical procedure (en bloc resection of the primary lesion with radical neck dissection). Three of six patients (Stage I and II) were living free of disease at 24,39, and 41 months, respectively. Of the nine patients (Stage III and IV), only two survived free of disease for 33 and 36 months, respectively. TONGUE. Twenty patients with carcinoma of the tongue were treated by surgery. Four patients (Stage I) treated by partial glossectomy were free of disease at 17,24,26, and 39 months. the remaining 16 patients had a combined surgical procedure. Three of four patients (Stage II) were free of disease at 28, 34, and 38 months and only 3 of 12 patients (Stage III and IV) were living without disease at 42, 44, and 54 months. TONSIL. Ten patients were treated by a combined surgical procedure. Three out of three patients in Stage I and II were living free of disease at 20, 23, and 60 months. Of the seven patients in Stage III and IV, three were living free of disease at 22,32, and 51 months.
Table 2.
Results of Radiation Therapy-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION
STAGE
II III IV
Floor of Mouth
Tongue
1/1 • 0/1 1/1
0/1 1/2 0/5
0/8
o
TOTAL
Tonsil
SURVIVALS
o
1/2 1/6 2/9 0/11 4/28
0/3 1/3 0/3
All stages 'Number of disease-free 2-year survivals/number of patients.
r 109
MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
Table 3. Results of Preoperative Radiation Therapy and SurgeryNumber of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION STAGE
III
IV
TOTAL
Floor of Mouth
Tongue
Tonsil
SURVIVALS
1/2* 0/4
0/1
0/2
o
o
1/5 0/4 1/9
Both stages 'Number of disease-free 2-year survivals/number of patients.
Radiation Therapy FLOOR OF THE MOUTH. External irradiation was utilized in the treatment of 11 patients with carcinoma of the floor of the mouth. A tumor dose ranging between 5000 and 6500 rads was delivered to the primary lesion and neck. One of two patients (Stage I and II) was free of disease for 44 months and one of nine patients (Stage III and IV) was living without disease for 24 months. TONGUE. Eight patients received radiation therapy. One of three patients (Stage I and II) survived without disease for 53 months and all patients with Stage III and IV were dead within 14 months. TONSIL. Of the nine patients with carcinoma of the tonsil treated by irradiation, one patient with Stage III disease was living free of disease at 25 months.
Radiation Therapy and Surgery Preoperative irradiation was utilized in patients with Stage III and IV disease to reduce the bulk of the lesion prior to surgical excision. Patients received an average preoperative radiation dose of 4000 rads. Of the nine patients included in this group, only one patient with carcinoma of the floor of the mouth (Stage III) is living without disease at 60 months.
Radiation and Chemotherapy Eight patients with advanced disease were treated by combination of intra-arterial infusion of cytotoxic drugs and radiation therapy. The agent used was methotrexate administered through a catheter placed into the
Table 4. Results of Radiation and Chemotherapy-Number of Patients Living Free of Disease 2 Years or More SURVIVAL WITH SITE OF PRIMARY LESION STAGE
Floor of Mouth
Tongue
III
0/1* 0/1
IV
TOTAL
Tonsil
SURVIVALS
o
o
0/1
0/2
0/3
0/7
Both stages 'Number of disease-free 2-year survivals/number of patients.
0/8
llO
ALI A.
EL-DoMEIRI AND PRABIR CHAUDHURI
external carotid via the superficial temporal artery. Patients received a daily dose of 30 to 50 mg for a period of 7 to 15 days. This was followed by a course of radiation therapy with a dose range of 3500 to 5000 rads. All patients were dead within 12 months.
GENERAL CONSIDERATIONS Squamous and epidermoid carcinomas constitute the majority of cancers in the oral cavity and pharynx. These tumors originate in the mucous membrane, then progress to infiltrate into the underlying muscles and adjacent structures and spread primarily via lymphatics to the cervical lymph nodes. Extension of tumor below the clavicle and distant metastases are less frequent and occur in the late stage of the disease. The response to therapy, in general, correlates with the extent of tumor. In those cases presented, the results of treatment compare with the longterm results previously reported. In a retrospective study of patients with carcinoma of the floor of the mouth followed for 5 or more years at our institution, the overall 5-year cure rate was 31 per cent.5 Schottenreld,ll in a review of the end results of 2877 patients with cancer of the oral cavity and pharynx seen at the Memorial Sloan-Kettering Cancer Center during a 15-year period, found that the mean 5-year relative survival rate for infiltrating cancers at all stages was 45.2 per cent. Although cancers arising at different sites in the buccal cavity and pharynx have a similar histologic structure, they do not share the same biologic behavior, which is reflected in the marked variation in their response to therapy and prognosis. Patients with carcinoma of the lip and palate do much better than those with lesions of the floor of mouth and tongue. Metastasis to cervical lymph nodes is by far the most important factor that influences the cure rate. Only 10 per cent of patients with carcinoma of the lip have clinically palpable lymph nodes when first seen, whereas with cancer of the tongue the incidence rises to 40 per cent. Cancers arising in adjacent areas may also exhibit variation in behavior and prognosis. Schottenfeldll reported a 5-year survival rate of 57 per cent in patients with localized cancers of the floor of the mouth and 29 per cent with regional metastases, in contrast to 48 per cent and 18 per cent, respectively, for tongue cancer. The principal cause of failure after radical surgery is recurrence in the neck after radical dissection, which has been reported to be as high as 50 per cent when nodes are positive. One of the effective means in reducing the high incidence of local recurrence is preoperative radiation therapy. Preoperative Irradiation The concept of using preoperative radiation therapy is not new. Improvement in local control of advanced oral cancer with combined preoperative irradiation and surgery was noted by Forsell in 1929. 3 In earlier years the use of a low energy radiation source and the lack of precise means to determine the amount of radiation delivered to the tissues accounted for a significant increase in postoperative complications. With
MANAGEMENT OF ORAL AND PHARYNGEAL CANCER
111
the advance in radiation techniques and the use of high energy sources in recent years, there has been a marked reduction of morbidity and local complication. Preoperative irradiation is intended either to eradicate microscopic nests of cells which may exist beyond the margin of surgical resection or to reduce the bulk of tumor and thus facilitate radical surgical extirpation. It is important to realize that whereas a small dose of radiation may be sufficient to control microscopic aggregates of cancer cells and diminish the number of viable cells likely to exist in the surgical area, a much higher dose is required to produce regression of large cancers and grossly palpable nodes. A review of the literature indicates that there has been a wide variation in the dose levels of radiation used by different workers. Doses ranging from 1500 rads - in a span of 3 to 4 days and followed immediately by surgery - to 5000 rads, with operation four to six weeks later, were utilized. In a controlled prospective study of the effect of irradiation with 2000 rads prior to radical neck dissection, Strong et alP noted a significant reduction in the incidence of cervical recurrence in patients with histologically proven node metastases, but no increase in the 5-year survival rate. In contrast, Lawrence et al.,s using 1400-rad preoperative therapy to the primary lesion and neck in two equal doses delivered 24 and 48 hours prior to the surgical procedure, reported no significant difference in the rate of local recurrence between the irradiated and the nonirradiated groups. Fletcher advocates the use of 4000 to 5000 rads delivered to the primary lesion as well as both necks when surgical excision of a large lesion and neck dissection are contemplated. If the primary lesion is treated by irradiation only and radical neck dissection is planned for clinically positive nodes, the primary lesion is irradiated up to 6500 to 7000 rads. There is experimental evidence to suggest that an increase of 10 to 15 per cent in the biologic dose of radiation may raise local control rates from 30 to 70 per cent. 6 To evaluate the effect of a larger dose of preoperative radiation, we are conducting a prospective study using two dose levels in patients with Stage II to IV cancer of the oral cavity and pharynx. Patients are assigned at random to receive: (a) 2000 rads in five treatments and immediate operation; (b) 4000 rads in 20 treatments, with operation 3 to 4 weeks later; or (c) no radiation before surgery. Preliminary evaluation of the results at 18 months showed comparable reduction of local recurrence in the two groups receiving radiation. However, there was a slight increase in postoperative complications, i.e., wound breakage and fistula formation, which led to longer hospitalization, in the group which had received 4000 rads preoperatively. It is hoped that the use of large doses of preoperative radiation will improve the long-term survival in these patients. This information will be available at the conclusion of the study.
Irradiation and Chemotherapy Effective control of nonresectable carcinoma of the head and neck by radiation alone may be achieved in a small number of patients. Also, ad-
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ministration of chemotherapeutic agents may produce regression of these tumors. In an attempt to promote the response to therapy in patients with advanced disease, various regimens of combined radiotherapy and chemotherapy have been employed. The rationale of using this approach is to obtain maximum local control of the disease, which will result in better palliation and, on rare occasions, a cure. It is important to realize that with this form of therapy there will be an increase in toxic manifestations and complications. Therefore, it is essential to keep these patients under close observation and to obtain relevant laboratory data at regular intervals. Recent reports indicate that a combination of systemic chemotherapy and radiation therapy has produced favorable results in patients with advanced disease. Lipshutz et al. 9 reported marked regression of tumors following the use of 80 mg of hydroxyurea per kg of body weight every third day, one week before and then throughout the period of radiation therapy. Similar results were obtained by Gollin et al. 4 with the concomitant use of systemic 5-fluorouracil (5-FU) and external irradiation. Although the results were encouraging in respect to reduction of tumor size and control of local symptoms, there was no appreciable prolongation of survival in these patients. 2 A combination of systemic therapy with bleomycin and high doses of radiation is currently being used in our institution in the treatment of advanced oral carcinoma. Patients with adequate pulmonary and cardiovascular function are included in this trial. The drug is given intravenously in doses of 20 mg twice a week for 2 weeks prior to irradiation, then continued during the course of radiation to reach a total dose of 200 to 300 mg if no adverse reactions take place. Large doses of radiation are delivered to the primary lesion and the neck. A dose of approximately 6500 rads is given to a large area to include both primary lesion and neck. Radiation is then limited to the primary lesion to reach a dose level of 7500 rads. So far, this form of aggressive therapy has been employed in a small number of patients. The effective control of local disease and the marked regression of tumor noted in some of these patients warrant continuation of this approach. Intra-arterial infusion of cytotoxic agents in conjunction with radiation has also been utilized in the treatment of patients with large cancers of the oral cavity. Regional chemotherapy has been advocated in preference to systemic chemotherapy, because a large concentration of the drug can be directly delivered to the tumor-bearing area. This is accomplished under local anesthesia by retrograde catheterization of the external carotid artery via the superficial temporal artery using a polyvinyl catheter. In some instances catheterization of the superficial temporal artery may not be feasible because of extensive disease or an abnormally tortuous vessel. Under these circumstances, a catheter is introduced through the brachial or femoral artery under x-ray control and placed into the external carotid artery, through which infusion of the cytotoxic agent is carried out (Fig. 1). Because of the higher risk of hematogenous infection, this route can only be used for a short period. Prophylactic antibiotic coverage is mandatory to minimize the risk of spreading infection.
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Figure 1. Catheter introduced through the femoral artery and placed into the external carotid artery. Distribution of dye indicates proper positioning to infuse a lesion in the floor of the mouth and tongue. Lingual, facial, maxillary, and posterior occipital arteries are visualized.
In order to achieve maximum response to chemotherapy or radiation therapy, a good blood supply and adequate oxygenation of tumor tissue is essential. Following a full course of radiotherapy many of the blood vessels within the tumor become obliterated as a result of radiation reaction. To ensure that an adequate concentration of the chemotherapeutic agent will reach the tumor mass, it is preferable to initiate treatment with intraarterial infusion for a few days prior to irradiation. It has been suggested that intra-arterial infusion of tumors with methotrexate prior to radiation therapy increases tissue oxygenation and potentiates the effectiveness of radiation!O In some instances, in patients with fungating and extensive lesions, initial treatment with radiotherapy is given to reduce the bulk of the tumor and produce alleviation of symptoms. Under these circumstances intra-arterial infusion with cytotoxic agents may be initiated during the course of radiation therapy. This will ensure that an adequate amount of the agent will reach the tumor tissue since radiation fibrosis and impairment of the tumor vasculature become evident a few weeks after radiation therapy (Fig. 2). Antimetabolites have been the principal agents used for intra-arterial infusion of head and neck cancer. Nervi et al.1O advocate the use of a small dose of methotrexate to a total dose of 80 to 100 mg, depending upon individual tolerance. This prolonged infusion presumably produces minimal impairment of the host-tumor relationship and will cover a period equal to that of replicating neoplastic cells. The best results of this treatment, with shrinkage or complete regression in about 75 per cent of
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Figure 2. Late phase of arteriogram in a patient with carcinoma of the posterior part of the floor of the mouth and tongue. Tumor blush indicates good blood supply. Patient received 3000 rads prior to insertion of the catheter for infusion.
patients, were obtained in cases which had not been previously treated by surgery or radiotherapy. Lately, we have been using intra-arterial infusion with bleomycin in doses of 10 to 20 mg per square meter per day for a period of 10 to 14 days prior to radiation therapy. This is followed by radiation to the primary lesion and neck, up to a dose of 6500 to 7000 rads. Marked regression of tumor was achieved in two patients thus treated. One of the limitations of intra-arterial infusion via the external carotid artery is that the drug mainly reaches areas supplied by the branches of this vessel. Therefore, lesions in the pharynx which receive most of their blood supply from the subclavian artery are not totally infused. Results of treatment indicated that the best responses to intra-arterial infusion of cytotoxic agents were obtained in patients with carcinoma located in the buccal cavity and nasal sinuses. 7
CONCLUSION Advanced epidermoid carcinoma of the oral cavity and pharynx presents a considerable problem in management. The cure rate of these lesions is very low and effective palliation is difficult to achieve. With the improvement in radiotherapy techniques and the addition of new chemotherapeutic agents, various regimens of aggressive combined therapy have been employed in an attempt to improve the control rate of these lesions. In order to apply these modalities to produce optimum response, the cooperation of physicians in different disciplines, i.e., surgery, radiation therapy, dentistry, and medical oncology, is essential. After' careful evaluation of the individual patients, members of the team will jointly recommend a form of therapy that is most likely to control the disease
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with a minimum of complications. This, in our experience, has provided a better and more effective means to handle the complex problems encountered in these patients.
REFERENCES 1. Fletcher, G. H.: The combination of radiation and surgery in oropharynx squamous cell carcinoma. Laval Med., 41: 13-17, 1970. 2. Fletcher, G. H., and Jesse, R. H., Jr.: Contribution of supervoltage roentgenotherapy to integration of radiation and surgery in head and neck squamous cell carcinomas. Cancer, 15:566-577,1962. 3. Forsell, G.: Radiotherapy of malignant tumors in Sweden. Br. J. Radiol., 3:198-234,1930. 4. Gollin, F. F., Ansfield, F. J., Brandenburg, J. H., Ramirez, G., and Vermund, H.: Combined therapy in advanced head and neck cancer. A randomized study. Am. J. Roentgen., 114:83-88, 1971. 5. Helfrich, G. B., Nickels, M. E., El-Domeiri, A., and Das Gupta, T. K.: Management of cancer of the floor of the mouth. Am. J. Surg., 124:559-562, 1972. 6. Herring, D. F., and Campton, D.: The Degree of Precision Required in the Radiation Dose Delivered in Cancer Radiotherapy. Report by Enviro-Med., 1970. 7. Jesse, R. H., Goepfert, H., Lindberg, R. D., and Johnson, R. H.: Combined intra-arterial infusion and radiotherapy for the treatment of advanced cancer of the head and neck. Am. J. Roentgen., 105:20-25,1969. 8. Lawrence, W., Jr., Terz, J. J., Rogers, C., King, R. E., Wolf, J. S., and King, E. R.: Pre-operative irradiation for head and neck cancer: A prospective study. Cancer, 33 :318-323, 1974. 9. Lipshutz, H., and Lerner, H. J.: Six year survival in the combined treatment for advanced head and neck cancer under a combined therapy program. Am. J. Surg., 126:519-522, 1973. 10. Nervi, C., Arcangelli, G., Casole, C., Cortese, M., Guadagni, A. and Le Pera, V.: A reappraisal of intra-arterial chemotherapy. Cancer, 26:577-582, 1970. 11. Schottenfeld, D.: Cancer of the buccal cavity and pharynx: A review of end results of primary treatment in 2,877 cases, 1949-1964. Memorial Sloan-Kettering Cancer Center, Clinical Bulletin, 2:51-57,1972. 12. Strong, E. W., Henschke, U. K., Nickson, J. J., Frazell, E. L., Tollefsen, H. R., and Hilaris, B. S.: Pre-operative x-ray therapy as an adjunct to radical neck dissection. Cancer, 19:1509-1516,1966.
Department of Surgery The Abraham Lincoln School of Medicine University of Illinois at the Medical Center P.O. Box 6998 Chicago, Illinois 60680