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Cancer of the Head and Neck with Special Reference to Perfusion with Anticancer Agents*
Cancer of the Head and Neck with Special Reference to Perfusion with Anticancer Agents* From the Divisions of Plastic Surgery and Neurosurgery, Duke University Medical Center, Durham, North Carolina
KENNETH PICKRELL, M.D., F.A.C.S. BARNES WOODHALL, M.D., F.A.C.S. N. G. GEORGIADE, M.D., F.A.C.S. GUIDO MATTON, M.D.;t M.S. MAHALEY, JR., M.D.
AccoRDING to the natural history of malignant diseas~_:, some cases are incurable from the onset, or from the time of their first discovery~ Some instances progress to incurability by the patient's neglect of the symptoms. Others reach inoperability by ill-timed, inadequate or injudicious use of the modalities of therapy. Other instances occur when, despite the most prompt and best treatment known, the disease advances and progresses by local, regional or distant spread to an inoperable or incurable state. The great majority of primary tumors arising in the head and neck are readily accessible and should lend themselves to early diagnosis and treatment. However, contrary to these potentially favorable factors, much is yet to be desired and learned in the control of cancer in these locations. THE PRIMARY LESION
The treatment of the primary lesion is of greatest importance. The successful treatment of a cancer requires detailed and explicit information *Supported by grants from the National Institutes of Health, Bethesda, Maryland, including that designated for the support of the Center fqr Study of Aging. t Present address: University of Ghent, Ghent, Belgium.
469
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PICKRELL,
WooDHALL,
GEoRGIADE,
MATTON,
MAHALEY
r .. ,.,.,,,,J lymphatic trunk Fig. 1. Schematic drawing of the deep cervidallymph nodes. All of the lymphatics of the face and oral cavity find their way into the deep cervical chains. The lymphatics from the"posterior cheek pass to the parotid group; those from the anterior cheek, side of the nose, upper lip, and the lateral portions of the lower lip empty into the submaxillary glands. Those from the central part of the lower lip run into the submentals. All three groups then pass to the deep chain. Those from the tongue drain directly to the deep chain. The jugular trunk on the left side drains into the thoracic duct. On the right side, the collecting trunk empties into the subclavian vein at its angle of junction with the internal jugular. This highly concentrated network of lymphatics offers an anatomic basis for complete excision of involved nodes and metastases from cancers originating in the head.
regarding the biologic characteristics of each tumor. Such knowledge includes: variation in cell morphology, rapidity of growth, predictable spread to regional lymph nodes or contiguous tissues, and incidence of extension by hematogenous route. With this information in the surgeon's cerebral armamentarium, the selection of the operation or treatment of choice will assert itself. There is a striking difference in the treatment between a mucoepidermoid carcinoma of the parotid and a highly neoplastic adenocarcinoma. The former will require a subtotal or a total conservative parotidectomy with preservation of the facial nerve, while the latter demands a total radical parotidectomy and neck dissection. The modalities and potentialities of each lesion are of far greater importance to the surgeon, and to his patient, than the extent or array of his instrument or operating room armamentarium. With this knowledge,
Cancer of the Head and Neck
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the surgeon's viewpoint can be flexible to select the operation or treatment which is indicated on the basis of all factors related to the lesion. The golden opportunity to cure the patient who has a lesion in this area, or in any other region, is at the first operation, well planned and executed perfectly. METHOD OF SPREAD
Since death from cancer arising in the head and neck ordinarily occurs with the lesion and metastases still confined above the clavicles, extended, in-continuity or en bloc radical operations have been developed not only to circumscribe widely the primary lesion, but also to remove the paths of lymphatic spread; for example, composite radical jaw-neck resections for intraoral cancers. 24 • 33 • 40 • 42 • 43 • 44 While there has been marked lowering of the mortality rates in some instances, there has been limited success in others, even when the primary lesion appears to be localized and operable. 4 Although recurrence at the primary site is of great importance, it does not account for the death of the patient in the majority of instances. Mortality rates are generally influenced by uncontrolled cervical or regional metastases and by the incidence of hematogenous spread. These factors are of paramount importance in evaluating our present concept of therapy. Cancer of the head and neck spreads mainly through the lymphatic paths (Fig. 1); exceptions are melanomas (Fig. 2) and thyroid carcinomas which have a high incidence of vascular metastases. Malignant tumor cells enter lymphatic vessels by direct invasion. Accumulations of these cells are then carried to regional lymph nodes, which act as a filter and as a nidus for further growth. As the node is replaced by tumor, a block to lymphatic flow occurs. Collateral spread of tumor cells may produce the same picture in groups or echelons of regional lymph nodes as described by Martin and associates, 29 • 31 Rouviere 36 and others. Most malignant tumors arising in the head and neck tend to unilateral spread through tumor emboli to the regional lymph nodes. These nodes become involved before they are noted clinically. Bilateral metastases are predictable if the primary tumor is located near the midline, or if sufficient lymphatic blockage occurs on one side of the neck to accelerate retrograde extension across the neck. The cervical lymphatics are divided into the superficial and deep chains of nodes. The superficial lymphatics drain the skin and its appendages, then perforate the cervical fascia to enter the deep cervical lymph channels (see Fig. 1). They are usually involved late in the disease by retrograde metastases, unless the primary lesion is located in the skin. Secondary involvement of the superficial lymphatics usually connotes inoperability. The deep cervical lymphatics receive the collecting lymph vessels from the skin of the face, oral cavity mucous membranes, tongue,
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WooDHALL,
GEORGIADE,
MATTON,
MAHALEY
Fig. 2. A, A 26 year old man with a primary melanoma of the left temporal region (white arrow) and proven cervical metastases (black arrow). B, Patient was perfused with A139 following which the primary lesion was excised widely and a radical ·neck dissection was performed. Two of 35 lymph nodes were involved. 1, Hypoglossal nerve; 2, internal carotid artery; 3, external carotid artery ligated; 4, common carotid artery and vagus nerve. C, Photo one month following perfusion showing unilateral alopecia and edema of scalp, face and neck, indicative of good distribution of the anticancer agent. D, Four months postperfusion shows regeneration of hair and complete disappearance of perfusion reaction.
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major salivary glands, pharynx, larynx and thyroid. They accompany the internal jugular vein and its branches (Fig. 1). Nodes are also found around or embedded in the major salivary glands, submental and paratracheal regions. Practically all lymphatics about the head and neck drain through the deep cervical chain. This is of extreme practical importance since it offers an anatomic basis for complete excision of the paths of lymphatic spread. The injection of a small quantity (0.1 to 0.2 cc) of Sky-Blue Dye (Wyeth) into or adjacent to the primary lesion has been helpful in outlining the paths of lymphatic spread. Our work with vital dyes on patients with cancer of the head and neck and other lesions and abnormalities of the trunk and extremities will be reported later. 34 SELECTION OF TREATMENT
A careful clinical estimate of the extent of cervical lymph node involvement, if any, has a most important bearing on the selection of treatment. Considerable controversy exists as to whether or not to perform a prophylactic neck dissection when there is no clinical evidence of lymph node involvement. Opinions vary between advocating neck dissection as soon as possible, to postponement until regional lymph node metastases are noted clinically. Blair, Brown, Byars and McDowelP· 5 • 6 advocate neck dissection as soon as possible in patients with intraoral or lip cancer, whether or not neck nodes are palpably enlarged. Kennedy17 concurs in this opinion. Martin and associates25 • 26 • 28 • 32 and Copeland 9 advocate neck dissection only in those cases with definite clinical evidence of lymph node involvement. Their statistics suggest that the cure rate in patients without demonstrable metastases is approximately the same whether or not neck dissection is performed. The principle of en bloc removal of the primary tumor and radical neck dissection in continuity has been applied to lesions of the tongue, oral mucous membranes, alveolus, major salivary glands, hypopharynx, larynx, thyroid and other lesions about the head and neck. Notable contributions have been made to the technique by Martin and associates, 27 • 30 Ward and Hendrick, 42 Copeland, 9 Slaughter and Southwick, 88 • 39 Kremen, 21 Carroll, 7 • 8 Greer, Smith and Klopp 13 and others. Operability connotes discrete and movable lymph nodes and the absence of distant metastases. Contraindications to neck dissection include: (a) clinical evidence of distant metastases; (b) fixation of the cervical nodes to underlying structures; (c) evidence of secondary lymphatic skin invasion; or (d) physical disability which precludes carrying out this elective major surgical procedure. The presence of bilateral cervical metastases is far from hopeless. Martin 31 has reported bilateral neck dissection in 50 cases with a five-year cure rate of about
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MATTON,
MAHALEY
30 per cent. The most frequent indications for bilateral neck dissection are metastases from the tongue, laryngeal and thyroid cancer. Let it be said and emphasized here that suprahyoid or dissection of only the upper neck is not founded upon sound surgical principles and should be condemned. The suprahyoid nodes drain directly into the deep cervical chains. HEAD AND NECK PERFUSION CHEMOTHERAPY
It has been only in recent years that any attempt has been made to control the growth of certain forms of cancer by altering its physiological environment or restraining its growth. However, in the past decade, a new phase of cancer therapy has been established, the search for drugs that could control, restrain or destroy the growth of neoplastic cells. The administration of chemotherapeutic cytotoxic agents to a region of the body isolated from its blood supply was performed in 1950 by Calvin Klopp and associates. 18 • 19 Another pioneer was Oscar Creech who, with his associates, developed practical methods of perfusion and intraarterial infusion.l 0 • 11 • 12 Numerous papers have appeared reporting results in the treatment of small and extensive malignant growths by this method by Woodhall and associates, 47 Stehlin and associates, 41 Ausman and Aust,r Shingleton, Parker, Mahaley and associates36 • 37 and others. Physiologic and biochemical alterations have been described by other investigators. 2 • 14 • 20 • 45 • 48 Isolated perfusion or intra-arterial infusion permits the employment of toxic compounds in amounts greater than allowed by the usual systemic applications. It is possible to alter local physiologic conditions in the perfused tissue to accommodate predicted or known factors that make cytotoxic agents more potent. Additional influence can be exercised over the condition of the vascular system in the perfused circuit to produce more complete dissemination of the drug in the target area. The effectiveness of the method is dependent upon absorption of the chemotherapeutic drug in an active form by the tissue. The benefits of isolated organ or regional perfusion are dependent upon the absorption of the agent by the tissues being perfused. The technique permits the surgeon to alter the tissue environment without disturbing the normal physiologic processes of the remainder of the body. It is possible theoretically to create the optimum environment for the absorption of various cytotoxic agents and thus take advantage not only of increased dosage limits permitted by isolated perfusion, but also of greater absorption of the tissues under these altered conditions. In a previous publication, 47 we described our work on the effect of hyperthermia upon cancer chemotherapy and its application to external cancers of the head in 20 patients who were perfused with alkylating agents. All patients had advanced malignancies: of the antrum, orbit,
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nasopharynx, buccal mucosa, alveolar ridge, tongue, floor of the moJ].th, tonsil and soft palate. Three alkylating agents were used-Al39, * nitrogen mustard (HN2) and cyclophosphamide (Cytoxan). Alkylati,ng agents introduce alkyl groups in place of hydrogen into organic mole.o:u._les. With nitrogen mustard (HN2), its two reactive ethyleneimine groups are the basis for its toxicological and tumor-inhibiting activity. It i.~ particularly injurious to cells that divide frequently, both normal and neoplastic. It is presumed that the polyfunctional alkylating groups react with many cell components, including nucleoproteins, that are essential for cell reproduction. However, toxicity to the normal marrow prevents adequate dosage. Many attempts have been made to discover analoguelil that have a more selective action on tumor cells. While many alkylating agents have been tested by Karnofsky15 • 16 and others, there is no satisfactory evidence that one has been found with a broader or different spectrum of therapeutic activity or a more selectiye effect on any particular type of cancer. Bone marrow depression remains the limiting factor in the use of any of the analogues. Forty-three perfusions have been performed on 39~patients, utilizing a mecha~ical pump, a bubble oxygenator, and a heat exchanger in the eJ!.:tra.corporeal circuit. The tumor vascular bed was isolated by unilateral perfusion of the external carotid artery-internal jugular vein in 33 perfusions, bilateral perfusion of the external carotid-internal jugular in ;five perfusions, and unilateral perfusion of the common carotid-internal jugular in five perfusions. Each perfusion was for 20 to 30 minutes, and the perfusate was heated to 42° C. to enhance the anticancer effect. 22 'Anticancer agents used were: nitrogen mustard (0.5 to 2.5 mg./kg.), A139 (0.8 to 3.0 mg./kg.), and Cytoxan (40 mg./kg.). For each perfusion, the drug was dissolved throughout the perfusate. The average per cent "leak" of perfusate, using P 31-albumin as an indicator, into the systemic circulation following perfusion was 47 to 52 per cent. On the other hand, the escape of active a_nticancer agent into the systemic circulation is much less, presumably due to rapid uptake of drug by tissues of the tumor bed. 23 This leak of drug was responsible for a moderate leukopenia and/or thrombocytopenia following 26 perfusions, all of which reverted to normal after 7 to 14 days. Local tissue tolerance was the factor which actually limited drug dosage. Some degree of alopecia occurred following each perfusion (Fig. 2). Nitrogen mustard and A139, in addition, cause<:f erythema and swelling of the facial tissues. A unique neurotoxicity of the cranial nerves occurred with higher dosages following six perfusio..ns, involving most frequently the eighth _and seventh nerves and less frequently the fifth and ·sixth nerves. Cranial nerve dysfunction was temporary, lasting two to four months, and_appears to result from myelin destruction and axis cylinder fragm:entation. 46
* 2,5-Diethylenimino-3, 6-bis (2-methoxyethoxy)-1,4-benzoquinone.
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GEORGIADE,
MATTON,
MAHALEY
Fig. 3. Hemangiosarcoma perfused with 1 lllg./kg. nitrogen mustard. A, Preperfusion section showing many mitotic figures. B, Nine days postperfusion, showing swelling of nuclei, absence of mitoses and presence of mast cells. C, Sixteen days postperfusion showing lymphocytic response. D, Twenty-four days postperfusion, showing replacement of cancer tissue by scar tissue ( XlOO).
Of the tumors perfused, 28 had advanced or inoperable carcinomas of the'·antrum, nasopharynx, mouth, palate, tongue, tonsil or parotid. The remaining tumor types were melanoma, extensive basal cell carcinoma, adamantine carcinoma, sarcoma, lympho-epitheliGma, meningioma and ependymoblastoma. Twenty-one of the 39 patients perfused are still alive, six showing no evidence of recurrence one to two years later. Of the 18 patients who have died, two succumbed in the immediate postperfusion period of causes not related to perfusion. The average survival time for the remaining 16 patients was seven months. Twenty-one of the 23~.rpatients with pain in the tumor area prior to perfusion had a striking.. 'relief of pain following perfusion, lasting an average of four months. The recurrence of pain coincided in time with gross evidence of recurrence or progression of tumor growth. Only five patients have shown no evidence of even temporary regression of tumor growth. Histological evidence of anticancer drug effect was obtained whenever possible by serial biopsies. The ·most profound histologic changes occurred in sarcomas perfused with nitrogen mustard (Fig. 3). In summary, relief of pain and at least temporary regression of tumor
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growth occurred following most regional chemotherapeutic perfusions. Perfusion seems to be most effective when used as an adjunct to excisional surgery. In this sense, perfusion is employed as a "tumorsterilizing" procedure at the time of, or within a week before radical excision, in an effort to minimize subsequent spread or recurrence of viable tumor cells. While chemotherapeutic perfusion will not supplant surgical extirpation, it may be a valuable adjunct to the head and neck cancer surgeon. CONCLUSIONS
Surgical thought has been widened, deepened and extended to embrace the concept of cancer as a systemic disease, starting initially from a single focus, but unless controlled, it will later radiate and disseminate from many foci or metastases. It is an admissible fact that once this has occurred, all forms of therapy are frequently inadequate to stop this deadly metabolic aggressor, and its inexorable progression is determined largely by the biological characteristics of the disease in relation to the environmental situation of the host. The chemotherapy of cancer will continue to be a major area of medical research until chemicals or tests are found to detect, control or obliterate neoplastic disease. Drugs have now been introduced into clinical practice that exert definite, regular and predictable therapeutic effect on some forms of cancer. They are useful in the management of many patients with inoperable disease. Since chemotherapy is still in its infancy, a great deal of enthusiasm and optimism are necessary to stimulate work in this field against the negativism that pervades any effort to treat inoperable or far-advanced neoplastic disease. There are a number of drugs which have been found to be useful in treating certain forms of neoplastic disease. While they are not curative, they do relieve pain and at least temporarily halt or retard the course of a relentless and otherwise hopeless, fatal disease. REFERENCES 1. Ausman, R. K. and Aust, J. B.: Studies in Isolated Perfusion Chemotherapy. Nitrogen Mustard. Ann. Surg. 153: 527, 1961. 2. Ausman, R. K., Gemmill, S. J., Jernberg, E. J. and Aust, J. B.: Effect of Oxygen on the Uptake of Nitrogen Mustard in Isolated Perfusion. Proc. Am. A. Cancer Res. 3: 92, 1960. 3. Blair, V. P., Brown, J. B. and Byars, L. T.: Our Responsibility Toward Oral Cancer. Ann~ Surg. 106: 568, 1937. 4. Braund, R. R. and Martin, H. E.: Distant Metastases in Cancer of the Upper Respiratory and Alimentary Tracts. Surg. Gynec. & Obst. 73: 63, 1941. 5. Brown, J. B. and McDowell, F.: Neck Dissection for Metastatic Carcinoma. Surg. Gynec. & Obst. 79: 115, 1944. 6. Brown, J. B. and McDowell, F.: Neck Dissections. Springfield, Ill. Charles C Thomas, 1957.
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MATTON,
MAHALEY
7. Carroll, W. W.: Combined Neck and Jaw Resection for Intraoral Carcinoma. Surg. Gynec. & Obst. 94: 1, 1952. 8. Carroll, W. W.: Role of Radical Neck Dissection in Head and Neck Cancer. illinois M. J. 105: 175, 1954. ; 9. Copeland, M. M.: An Evaluation of Neck Dissection Associated with Other Radical Procedures for the Treatment of Cancer in the Head and Neck. Ann. Surg. 141: 910, 1955. 10. Creech, 0., Krementz, E. T., Ryan, R. F. and Winblad, J. N.: Chemotherapy of Cancer: Regional Perfusion Utilizing an Extracorporeal Circuit. Ann. Surg. 148: 616, 1958. 11. Creech, 0., Krementz, E. T., Ryan, R. F., Reemtsma, K. and Winblad, J. N.: Experiences with Isolation-Perfusion Technics in the Treatment of Cancer. Ann. Surg. 149: 627, 1959. 12. Creech, 0., Ryan, R. F. and Krementz, E. T.: Treatment of Melanomas by Isolation Perfusion Technique. J.A.M.A. 169: 339, 1959. 13. Greer, D. B., Smith, R. B. and Klopp, C. T.: A Surgical Method of Treatment of Carcinoma of the Floor of the Mouth. Surgery 34: 279, 1953. 14. Hottinger, G. C., Ryan, R. F., Delgado, J.P. and Reemtsma, K.: Physiology of Extracorporsal Circulation: Studies of Blood Flow, Oxygen Consumption and Metabolism in the Isolated and Perfused Extremity. Surg. Forum 10: 80, 1960. 15. Karnofsky, D. A.: Chemical Agents Used in the Treatment of Inoperable and 16. 17. 18. 19. 20. 21. 22.
Far-Advanced Neoplastic Disease. In Beam, W. B., Ed.: Monographs in Medicine, Series I. Baltimore, Williams & Wilkins Co., 1952, pp. 582--636. Karnofsky, D. A.: Hormonal and Chemical Methods in the Treatment of Cancer. Postgrad. Med. 17: 514, 1955. Kennedy, R. H.: Epithelioma of the Lower Lip. Ann. Surg. 106: 577, 1937. Klopp, C. T.: Fractional Intra-arterial Cancer Chemotherapy with Methyl Bis Amine Hydrochloride. Ann. Surg. 132: 811, 1950. Klopp, C. T., Bateman, J., Berry, N., Alford, C. and Winship, T.: Fractional Regional Cancer Chemotherapy. Cancer Research 10: 229, 1950. Knock, F. E.: Perfusion of Compounds Potentiating Radiation for the Therapy of Cancer. Surg. Gynec. & Obst. 113: 73, 1961. Kremen, R. J.: Cancer of the Tongue-Surgical Technique for a Primary Combined en bloc Resection of Tongue, Floor of Mouth and Cervical Lymphatics. Surgery 30: 227, 1951. Mahaley, M. S. Jr. and Woodhall, B.: Effect of Temperature Upon In Vitro Action of Anticancer Agents on VX2 Carcinoma. J. Neurosurg. 18: 269-
272, 1961. 23. Mahaley, M.S. Jr. and Woodhall, B.: Evaluation of Plasma Levels of Alkylating
Agents During Regional Chemotherapeutic Perfusions. J. Surg. Research 1: 285, 1961. 24. Martin, Hayes: Surgery of Head and Neck Tumors. New York, Hoeber-Harper, 1957. 25. Martin, H. E.: Five Year End-Results in the Treatment of Cancer of the Tongue, Lip and Cheek. Surg. Gynec. & Obst. 65: 793, 1937. 26. Martin, H. E.: Treatment of Cervical Metastatic Cancer. Ann. Surg. 114: 972, 1941. 27 Martin, H. E.: Operative Removal of Tumors of the Parotid Salivary Gland. Surgery 31: 670, 1952. 28. Martin, H. E. and Morfit, H. M.: Cervical Lymph Node Metastasis as the First Symptom of Cancer. Surg. Gynec. & Obst. 78: 133, 1944. 29. Martin, H. E. and Morfit, H. M.: Cervical Lymph Node Metastasis as the First Symptom of Cancer. Surg. Gynec. & Obst. 78: 133, 1944. 30. Martin, H. E., Munster, H., Sugarbaker, E. L.: Cancer of the Tongue. Arch. Surg. 41: 888, 1940. 31. Martin, H. E., Del Valle, B., Ehrlich, H. and Cahan, W. G.: Neck Cancer. Cancer 4: 441, 1951. 32. Martin, H. E., Del Valle, B., Ehrlich, H. and Cahan, W. G.: Neck Dissection. Cancer 4: 441, 1951.
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33. Morfi.t, M.: Simultaneous Bilateral Radical Neck Dissection. Surgery 31: 216, 1952. 34. Pickrell, K. L. and Matton, G.: Use of Sky-Blue Dye to Identify Lymphatics; Its Application in Patients with Neoplastic Lesions of the Head and Neck. In preparation. 35. Rouvitre, H.: Anatomy of the Human Lymphatic System. Ann Arbor, Mich., Edwards Bros., 1938. 36. Shingleton, W. W., Parker, R. T. and Mahaley, S.: Abdominal Perfusion for Cancer Chemotherapy. Ann. Surg. 152: 583, 1960. Idem, Surgery 50: 260, 1961. 37. Shingleton, W. W., Reeves, J. W., Keppel, R. A., Mahaley, S. and Taylor, H. M.: Studies on Abdominal Organ Perfusion for Cancer Chemotherapy. Ann. Surg. 151: 741, 1960. 38. Slaughter, D.P. and Roeser, E. H.: Recent Advances in the Surgical Treatment of Intraoral Cancer. S. CLIN. NoRTH AMERICA 29: 1317, 1949. 39. Slaughter, D. P. and Southwick, H. W.: En Bloc Resection of Cancer of the Mouth and Cervical Lymphatics with Preservation of the Mandible. Ann. Surg. 136: 957, 1952. 40. Slaughter, D.P., Roeser, E. A. and Smejkal, W. F.: Excision of the Mandible for Neoplastic Disease. Surgery 26: 507, 1949. 41. Stehlin, J. S., Clark, R. L., White, E. C., Smith, J. L. et al.: Regional Chemotherapy for Cancer. Ann. Surg. 151: 605, 1960. 42. Ward, G. E. and Hendrick, J. W.: Diagnosis and Treatment of Tumors of the Head and Neck. Baltimore, Md., Williams & Wilkins Co., 1950. 43. Ward, G. E. and Robin, J. 0.: A Composite Operation for Radical Neck Dissection of Cancer of the Mouth. Cancer 4: 98, 1951. 44. Ward, G. E., Edgerton, M. T., Chambers, R. G. and McKee, D. M.: Cancer of the Oral Cavity and Pharynx and Results of Treatment by Means of the Composite Operation. Ann. Surg. 150: 202, 1959. 45. Woodhall, B., Hall, K., Mahaley, S. and Jackson, J.: Chemotherapy of Brain Cancer: Experimental and Clinical Studies in Localized Hypothermic Cerebral Perfusion. Ann. Surg. 150: 640, 1959. 46. Woodhall, B., Mahaley, M. S. Jr., Boone, S. and Huneycutt, H.: Effect of Chemotherapeutic Agents upon Peripheral Nerves. In press, J. Surg. Research. 47. Woodhall, B., Pickrell, K. L., Georgiade, N. G., Mahaley, M.S. and Dukes, H. T.: Effect of Hyperthermia upon Cancer Chemotherapy: Application to External Cancers of Head and Face Structures. Ann. Surg. 151: 750, 1960. 48. Woodhall, B., Reynolds, D. H., Mahaley, S. and Sanders, A. P.: Physiologic and Pathologic Effects of Localized Cerebral Hypothermia. Ann. Surg. 147: 673,1958.
Duke University Medical Center Durham, North CaroliRa
KENNETH PICKRELL, M.D., F.A.C.S. BARNES WOODHALL, M.D., F.A.C.S. N. G. GEORGIADE, M.D., F.A.C.S. GUIDO MATTON, M.D.;t M.S. MAHALEY, JR., M.D.
AccoRDING to the natural history of malignant diseas~_:, some cases are incurable from the onset, or from the time of their first discovery~ Some instances progress to incurability by the patient's neglect of the symptoms. Others reach inoperability by ill-timed, inadequate or injudicious use of the modalities of therapy. Other instances occur when, despite the most prompt and best treatment known, the disease advances and progresses by local, regional or distant spread to an inoperable or incurable state. The great majority of primary tumors arising in the head and neck are readily accessible and should lend themselves to early diagnosis and treatment. However, contrary to these potentially favorable factors, much is yet to be desired and learned in the control of cancer in these locations. THE PRIMARY LESION
The treatment of the primary lesion is of greatest importance. The successful treatment of a cancer requires detailed and explicit information *Supported by grants from the National Institutes of Health, Bethesda, Maryland, including that designated for the support of the Center fqr Study of Aging. t Present address: University of Ghent, Ghent, Belgium.
469
470
PICKRELL,
WooDHALL,
GEoRGIADE,
MATTON,
MAHALEY
r .. ,.,.,,,,J lymphatic trunk Fig. 1. Schematic drawing of the deep cervidallymph nodes. All of the lymphatics of the face and oral cavity find their way into the deep cervical chains. The lymphatics from the"posterior cheek pass to the parotid group; those from the anterior cheek, side of the nose, upper lip, and the lateral portions of the lower lip empty into the submaxillary glands. Those from the central part of the lower lip run into the submentals. All three groups then pass to the deep chain. Those from the tongue drain directly to the deep chain. The jugular trunk on the left side drains into the thoracic duct. On the right side, the collecting trunk empties into the subclavian vein at its angle of junction with the internal jugular. This highly concentrated network of lymphatics offers an anatomic basis for complete excision of involved nodes and metastases from cancers originating in the head.
regarding the biologic characteristics of each tumor. Such knowledge includes: variation in cell morphology, rapidity of growth, predictable spread to regional lymph nodes or contiguous tissues, and incidence of extension by hematogenous route. With this information in the surgeon's cerebral armamentarium, the selection of the operation or treatment of choice will assert itself. There is a striking difference in the treatment between a mucoepidermoid carcinoma of the parotid and a highly neoplastic adenocarcinoma. The former will require a subtotal or a total conservative parotidectomy with preservation of the facial nerve, while the latter demands a total radical parotidectomy and neck dissection. The modalities and potentialities of each lesion are of far greater importance to the surgeon, and to his patient, than the extent or array of his instrument or operating room armamentarium. With this knowledge,
Cancer of the Head and Neck
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the surgeon's viewpoint can be flexible to select the operation or treatment which is indicated on the basis of all factors related to the lesion. The golden opportunity to cure the patient who has a lesion in this area, or in any other region, is at the first operation, well planned and executed perfectly. METHOD OF SPREAD
Since death from cancer arising in the head and neck ordinarily occurs with the lesion and metastases still confined above the clavicles, extended, in-continuity or en bloc radical operations have been developed not only to circumscribe widely the primary lesion, but also to remove the paths of lymphatic spread; for example, composite radical jaw-neck resections for intraoral cancers. 24 • 33 • 40 • 42 • 43 • 44 While there has been marked lowering of the mortality rates in some instances, there has been limited success in others, even when the primary lesion appears to be localized and operable. 4 Although recurrence at the primary site is of great importance, it does not account for the death of the patient in the majority of instances. Mortality rates are generally influenced by uncontrolled cervical or regional metastases and by the incidence of hematogenous spread. These factors are of paramount importance in evaluating our present concept of therapy. Cancer of the head and neck spreads mainly through the lymphatic paths (Fig. 1); exceptions are melanomas (Fig. 2) and thyroid carcinomas which have a high incidence of vascular metastases. Malignant tumor cells enter lymphatic vessels by direct invasion. Accumulations of these cells are then carried to regional lymph nodes, which act as a filter and as a nidus for further growth. As the node is replaced by tumor, a block to lymphatic flow occurs. Collateral spread of tumor cells may produce the same picture in groups or echelons of regional lymph nodes as described by Martin and associates, 29 • 31 Rouviere 36 and others. Most malignant tumors arising in the head and neck tend to unilateral spread through tumor emboli to the regional lymph nodes. These nodes become involved before they are noted clinically. Bilateral metastases are predictable if the primary tumor is located near the midline, or if sufficient lymphatic blockage occurs on one side of the neck to accelerate retrograde extension across the neck. The cervical lymphatics are divided into the superficial and deep chains of nodes. The superficial lymphatics drain the skin and its appendages, then perforate the cervical fascia to enter the deep cervical lymph channels (see Fig. 1). They are usually involved late in the disease by retrograde metastases, unless the primary lesion is located in the skin. Secondary involvement of the superficial lymphatics usually connotes inoperability. The deep cervical lymphatics receive the collecting lymph vessels from the skin of the face, oral cavity mucous membranes, tongue,
472
PrcKRELL,
WooDHALL,
GEORGIADE,
MATTON,
MAHALEY
Fig. 2. A, A 26 year old man with a primary melanoma of the left temporal region (white arrow) and proven cervical metastases (black arrow). B, Patient was perfused with A139 following which the primary lesion was excised widely and a radical ·neck dissection was performed. Two of 35 lymph nodes were involved. 1, Hypoglossal nerve; 2, internal carotid artery; 3, external carotid artery ligated; 4, common carotid artery and vagus nerve. C, Photo one month following perfusion showing unilateral alopecia and edema of scalp, face and neck, indicative of good distribution of the anticancer agent. D, Four months postperfusion shows regeneration of hair and complete disappearance of perfusion reaction.
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major salivary glands, pharynx, larynx and thyroid. They accompany the internal jugular vein and its branches (Fig. 1). Nodes are also found around or embedded in the major salivary glands, submental and paratracheal regions. Practically all lymphatics about the head and neck drain through the deep cervical chain. This is of extreme practical importance since it offers an anatomic basis for complete excision of the paths of lymphatic spread. The injection of a small quantity (0.1 to 0.2 cc) of Sky-Blue Dye (Wyeth) into or adjacent to the primary lesion has been helpful in outlining the paths of lymphatic spread. Our work with vital dyes on patients with cancer of the head and neck and other lesions and abnormalities of the trunk and extremities will be reported later. 34 SELECTION OF TREATMENT
A careful clinical estimate of the extent of cervical lymph node involvement, if any, has a most important bearing on the selection of treatment. Considerable controversy exists as to whether or not to perform a prophylactic neck dissection when there is no clinical evidence of lymph node involvement. Opinions vary between advocating neck dissection as soon as possible, to postponement until regional lymph node metastases are noted clinically. Blair, Brown, Byars and McDowelP· 5 • 6 advocate neck dissection as soon as possible in patients with intraoral or lip cancer, whether or not neck nodes are palpably enlarged. Kennedy17 concurs in this opinion. Martin and associates25 • 26 • 28 • 32 and Copeland 9 advocate neck dissection only in those cases with definite clinical evidence of lymph node involvement. Their statistics suggest that the cure rate in patients without demonstrable metastases is approximately the same whether or not neck dissection is performed. The principle of en bloc removal of the primary tumor and radical neck dissection in continuity has been applied to lesions of the tongue, oral mucous membranes, alveolus, major salivary glands, hypopharynx, larynx, thyroid and other lesions about the head and neck. Notable contributions have been made to the technique by Martin and associates, 27 • 30 Ward and Hendrick, 42 Copeland, 9 Slaughter and Southwick, 88 • 39 Kremen, 21 Carroll, 7 • 8 Greer, Smith and Klopp 13 and others. Operability connotes discrete and movable lymph nodes and the absence of distant metastases. Contraindications to neck dissection include: (a) clinical evidence of distant metastases; (b) fixation of the cervical nodes to underlying structures; (c) evidence of secondary lymphatic skin invasion; or (d) physical disability which precludes carrying out this elective major surgical procedure. The presence of bilateral cervical metastases is far from hopeless. Martin 31 has reported bilateral neck dissection in 50 cases with a five-year cure rate of about
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30 per cent. The most frequent indications for bilateral neck dissection are metastases from the tongue, laryngeal and thyroid cancer. Let it be said and emphasized here that suprahyoid or dissection of only the upper neck is not founded upon sound surgical principles and should be condemned. The suprahyoid nodes drain directly into the deep cervical chains. HEAD AND NECK PERFUSION CHEMOTHERAPY
It has been only in recent years that any attempt has been made to control the growth of certain forms of cancer by altering its physiological environment or restraining its growth. However, in the past decade, a new phase of cancer therapy has been established, the search for drugs that could control, restrain or destroy the growth of neoplastic cells. The administration of chemotherapeutic cytotoxic agents to a region of the body isolated from its blood supply was performed in 1950 by Calvin Klopp and associates. 18 • 19 Another pioneer was Oscar Creech who, with his associates, developed practical methods of perfusion and intraarterial infusion.l 0 • 11 • 12 Numerous papers have appeared reporting results in the treatment of small and extensive malignant growths by this method by Woodhall and associates, 47 Stehlin and associates, 41 Ausman and Aust,r Shingleton, Parker, Mahaley and associates36 • 37 and others. Physiologic and biochemical alterations have been described by other investigators. 2 • 14 • 20 • 45 • 48 Isolated perfusion or intra-arterial infusion permits the employment of toxic compounds in amounts greater than allowed by the usual systemic applications. It is possible to alter local physiologic conditions in the perfused tissue to accommodate predicted or known factors that make cytotoxic agents more potent. Additional influence can be exercised over the condition of the vascular system in the perfused circuit to produce more complete dissemination of the drug in the target area. The effectiveness of the method is dependent upon absorption of the chemotherapeutic drug in an active form by the tissue. The benefits of isolated organ or regional perfusion are dependent upon the absorption of the agent by the tissues being perfused. The technique permits the surgeon to alter the tissue environment without disturbing the normal physiologic processes of the remainder of the body. It is possible theoretically to create the optimum environment for the absorption of various cytotoxic agents and thus take advantage not only of increased dosage limits permitted by isolated perfusion, but also of greater absorption of the tissues under these altered conditions. In a previous publication, 47 we described our work on the effect of hyperthermia upon cancer chemotherapy and its application to external cancers of the head in 20 patients who were perfused with alkylating agents. All patients had advanced malignancies: of the antrum, orbit,
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nasopharynx, buccal mucosa, alveolar ridge, tongue, floor of the moJ].th, tonsil and soft palate. Three alkylating agents were used-Al39, * nitrogen mustard (HN2) and cyclophosphamide (Cytoxan). Alkylati,ng agents introduce alkyl groups in place of hydrogen into organic mole.o:u._les. With nitrogen mustard (HN2), its two reactive ethyleneimine groups are the basis for its toxicological and tumor-inhibiting activity. It i.~ particularly injurious to cells that divide frequently, both normal and neoplastic. It is presumed that the polyfunctional alkylating groups react with many cell components, including nucleoproteins, that are essential for cell reproduction. However, toxicity to the normal marrow prevents adequate dosage. Many attempts have been made to discover analoguelil that have a more selective action on tumor cells. While many alkylating agents have been tested by Karnofsky15 • 16 and others, there is no satisfactory evidence that one has been found with a broader or different spectrum of therapeutic activity or a more selectiye effect on any particular type of cancer. Bone marrow depression remains the limiting factor in the use of any of the analogues. Forty-three perfusions have been performed on 39~patients, utilizing a mecha~ical pump, a bubble oxygenator, and a heat exchanger in the eJ!.:tra.corporeal circuit. The tumor vascular bed was isolated by unilateral perfusion of the external carotid artery-internal jugular vein in 33 perfusions, bilateral perfusion of the external carotid-internal jugular in ;five perfusions, and unilateral perfusion of the common carotid-internal jugular in five perfusions. Each perfusion was for 20 to 30 minutes, and the perfusate was heated to 42° C. to enhance the anticancer effect. 22 'Anticancer agents used were: nitrogen mustard (0.5 to 2.5 mg./kg.), A139 (0.8 to 3.0 mg./kg.), and Cytoxan (40 mg./kg.). For each perfusion, the drug was dissolved throughout the perfusate. The average per cent "leak" of perfusate, using P 31-albumin as an indicator, into the systemic circulation following perfusion was 47 to 52 per cent. On the other hand, the escape of active a_nticancer agent into the systemic circulation is much less, presumably due to rapid uptake of drug by tissues of the tumor bed. 23 This leak of drug was responsible for a moderate leukopenia and/or thrombocytopenia following 26 perfusions, all of which reverted to normal after 7 to 14 days. Local tissue tolerance was the factor which actually limited drug dosage. Some degree of alopecia occurred following each perfusion (Fig. 2). Nitrogen mustard and A139, in addition, cause<:f erythema and swelling of the facial tissues. A unique neurotoxicity of the cranial nerves occurred with higher dosages following six perfusio..ns, involving most frequently the eighth _and seventh nerves and less frequently the fifth and ·sixth nerves. Cranial nerve dysfunction was temporary, lasting two to four months, and_appears to result from myelin destruction and axis cylinder fragm:entation. 46
* 2,5-Diethylenimino-3, 6-bis (2-methoxyethoxy)-1,4-benzoquinone.
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Fig. 3. Hemangiosarcoma perfused with 1 lllg./kg. nitrogen mustard. A, Preperfusion section showing many mitotic figures. B, Nine days postperfusion, showing swelling of nuclei, absence of mitoses and presence of mast cells. C, Sixteen days postperfusion showing lymphocytic response. D, Twenty-four days postperfusion, showing replacement of cancer tissue by scar tissue ( XlOO).
Of the tumors perfused, 28 had advanced or inoperable carcinomas of the'·antrum, nasopharynx, mouth, palate, tongue, tonsil or parotid. The remaining tumor types were melanoma, extensive basal cell carcinoma, adamantine carcinoma, sarcoma, lympho-epitheliGma, meningioma and ependymoblastoma. Twenty-one of the 39 patients perfused are still alive, six showing no evidence of recurrence one to two years later. Of the 18 patients who have died, two succumbed in the immediate postperfusion period of causes not related to perfusion. The average survival time for the remaining 16 patients was seven months. Twenty-one of the 23~.rpatients with pain in the tumor area prior to perfusion had a striking.. 'relief of pain following perfusion, lasting an average of four months. The recurrence of pain coincided in time with gross evidence of recurrence or progression of tumor growth. Only five patients have shown no evidence of even temporary regression of tumor growth. Histological evidence of anticancer drug effect was obtained whenever possible by serial biopsies. The ·most profound histologic changes occurred in sarcomas perfused with nitrogen mustard (Fig. 3). In summary, relief of pain and at least temporary regression of tumor
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growth occurred following most regional chemotherapeutic perfusions. Perfusion seems to be most effective when used as an adjunct to excisional surgery. In this sense, perfusion is employed as a "tumorsterilizing" procedure at the time of, or within a week before radical excision, in an effort to minimize subsequent spread or recurrence of viable tumor cells. While chemotherapeutic perfusion will not supplant surgical extirpation, it may be a valuable adjunct to the head and neck cancer surgeon. CONCLUSIONS
Surgical thought has been widened, deepened and extended to embrace the concept of cancer as a systemic disease, starting initially from a single focus, but unless controlled, it will later radiate and disseminate from many foci or metastases. It is an admissible fact that once this has occurred, all forms of therapy are frequently inadequate to stop this deadly metabolic aggressor, and its inexorable progression is determined largely by the biological characteristics of the disease in relation to the environmental situation of the host. The chemotherapy of cancer will continue to be a major area of medical research until chemicals or tests are found to detect, control or obliterate neoplastic disease. Drugs have now been introduced into clinical practice that exert definite, regular and predictable therapeutic effect on some forms of cancer. They are useful in the management of many patients with inoperable disease. Since chemotherapy is still in its infancy, a great deal of enthusiasm and optimism are necessary to stimulate work in this field against the negativism that pervades any effort to treat inoperable or far-advanced neoplastic disease. There are a number of drugs which have been found to be useful in treating certain forms of neoplastic disease. While they are not curative, they do relieve pain and at least temporarily halt or retard the course of a relentless and otherwise hopeless, fatal disease. REFERENCES 1. Ausman, R. K. and Aust, J. B.: Studies in Isolated Perfusion Chemotherapy. Nitrogen Mustard. Ann. Surg. 153: 527, 1961. 2. Ausman, R. K., Gemmill, S. J., Jernberg, E. J. and Aust, J. B.: Effect of Oxygen on the Uptake of Nitrogen Mustard in Isolated Perfusion. Proc. Am. A. Cancer Res. 3: 92, 1960. 3. Blair, V. P., Brown, J. B. and Byars, L. T.: Our Responsibility Toward Oral Cancer. Ann~ Surg. 106: 568, 1937. 4. Braund, R. R. and Martin, H. E.: Distant Metastases in Cancer of the Upper Respiratory and Alimentary Tracts. Surg. Gynec. & Obst. 73: 63, 1941. 5. Brown, J. B. and McDowell, F.: Neck Dissection for Metastatic Carcinoma. Surg. Gynec. & Obst. 79: 115, 1944. 6. Brown, J. B. and McDowell, F.: Neck Dissections. Springfield, Ill. Charles C Thomas, 1957.
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7. Carroll, W. W.: Combined Neck and Jaw Resection for Intraoral Carcinoma. Surg. Gynec. & Obst. 94: 1, 1952. 8. Carroll, W. W.: Role of Radical Neck Dissection in Head and Neck Cancer. illinois M. J. 105: 175, 1954. ; 9. Copeland, M. M.: An Evaluation of Neck Dissection Associated with Other Radical Procedures for the Treatment of Cancer in the Head and Neck. Ann. Surg. 141: 910, 1955. 10. Creech, 0., Krementz, E. T., Ryan, R. F. and Winblad, J. N.: Chemotherapy of Cancer: Regional Perfusion Utilizing an Extracorporeal Circuit. Ann. Surg. 148: 616, 1958. 11. Creech, 0., Krementz, E. T., Ryan, R. F., Reemtsma, K. and Winblad, J. N.: Experiences with Isolation-Perfusion Technics in the Treatment of Cancer. Ann. Surg. 149: 627, 1959. 12. Creech, 0., Ryan, R. F. and Krementz, E. T.: Treatment of Melanomas by Isolation Perfusion Technique. J.A.M.A. 169: 339, 1959. 13. Greer, D. B., Smith, R. B. and Klopp, C. T.: A Surgical Method of Treatment of Carcinoma of the Floor of the Mouth. Surgery 34: 279, 1953. 14. Hottinger, G. C., Ryan, R. F., Delgado, J.P. and Reemtsma, K.: Physiology of Extracorporsal Circulation: Studies of Blood Flow, Oxygen Consumption and Metabolism in the Isolated and Perfused Extremity. Surg. Forum 10: 80, 1960. 15. Karnofsky, D. A.: Chemical Agents Used in the Treatment of Inoperable and 16. 17. 18. 19. 20. 21. 22.
Far-Advanced Neoplastic Disease. In Beam, W. B., Ed.: Monographs in Medicine, Series I. Baltimore, Williams & Wilkins Co., 1952, pp. 582--636. Karnofsky, D. A.: Hormonal and Chemical Methods in the Treatment of Cancer. Postgrad. Med. 17: 514, 1955. Kennedy, R. H.: Epithelioma of the Lower Lip. Ann. Surg. 106: 577, 1937. Klopp, C. T.: Fractional Intra-arterial Cancer Chemotherapy with Methyl Bis Amine Hydrochloride. Ann. Surg. 132: 811, 1950. Klopp, C. T., Bateman, J., Berry, N., Alford, C. and Winship, T.: Fractional Regional Cancer Chemotherapy. Cancer Research 10: 229, 1950. Knock, F. E.: Perfusion of Compounds Potentiating Radiation for the Therapy of Cancer. Surg. Gynec. & Obst. 113: 73, 1961. Kremen, R. J.: Cancer of the Tongue-Surgical Technique for a Primary Combined en bloc Resection of Tongue, Floor of Mouth and Cervical Lymphatics. Surgery 30: 227, 1951. Mahaley, M. S. Jr. and Woodhall, B.: Effect of Temperature Upon In Vitro Action of Anticancer Agents on VX2 Carcinoma. J. Neurosurg. 18: 269-
272, 1961. 23. Mahaley, M.S. Jr. and Woodhall, B.: Evaluation of Plasma Levels of Alkylating
Agents During Regional Chemotherapeutic Perfusions. J. Surg. Research 1: 285, 1961. 24. Martin, Hayes: Surgery of Head and Neck Tumors. New York, Hoeber-Harper, 1957. 25. Martin, H. E.: Five Year End-Results in the Treatment of Cancer of the Tongue, Lip and Cheek. Surg. Gynec. & Obst. 65: 793, 1937. 26. Martin, H. E.: Treatment of Cervical Metastatic Cancer. Ann. Surg. 114: 972, 1941. 27 Martin, H. E.: Operative Removal of Tumors of the Parotid Salivary Gland. Surgery 31: 670, 1952. 28. Martin, H. E. and Morfit, H. M.: Cervical Lymph Node Metastasis as the First Symptom of Cancer. Surg. Gynec. & Obst. 78: 133, 1944. 29. Martin, H. E. and Morfit, H. M.: Cervical Lymph Node Metastasis as the First Symptom of Cancer. Surg. Gynec. & Obst. 78: 133, 1944. 30. Martin, H. E., Munster, H., Sugarbaker, E. L.: Cancer of the Tongue. Arch. Surg. 41: 888, 1940. 31. Martin, H. E., Del Valle, B., Ehrlich, H. and Cahan, W. G.: Neck Cancer. Cancer 4: 441, 1951. 32. Martin, H. E., Del Valle, B., Ehrlich, H. and Cahan, W. G.: Neck Dissection. Cancer 4: 441, 1951.
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33. Morfi.t, M.: Simultaneous Bilateral Radical Neck Dissection. Surgery 31: 216, 1952. 34. Pickrell, K. L. and Matton, G.: Use of Sky-Blue Dye to Identify Lymphatics; Its Application in Patients with Neoplastic Lesions of the Head and Neck. In preparation. 35. Rouvitre, H.: Anatomy of the Human Lymphatic System. Ann Arbor, Mich., Edwards Bros., 1938. 36. Shingleton, W. W., Parker, R. T. and Mahaley, S.: Abdominal Perfusion for Cancer Chemotherapy. Ann. Surg. 152: 583, 1960. Idem, Surgery 50: 260, 1961. 37. Shingleton, W. W., Reeves, J. W., Keppel, R. A., Mahaley, S. and Taylor, H. M.: Studies on Abdominal Organ Perfusion for Cancer Chemotherapy. Ann. Surg. 151: 741, 1960. 38. Slaughter, D.P. and Roeser, E. H.: Recent Advances in the Surgical Treatment of Intraoral Cancer. S. CLIN. NoRTH AMERICA 29: 1317, 1949. 39. Slaughter, D. P. and Southwick, H. W.: En Bloc Resection of Cancer of the Mouth and Cervical Lymphatics with Preservation of the Mandible. Ann. Surg. 136: 957, 1952. 40. Slaughter, D.P., Roeser, E. A. and Smejkal, W. F.: Excision of the Mandible for Neoplastic Disease. Surgery 26: 507, 1949. 41. Stehlin, J. S., Clark, R. L., White, E. C., Smith, J. L. et al.: Regional Chemotherapy for Cancer. Ann. Surg. 151: 605, 1960. 42. Ward, G. E. and Hendrick, J. W.: Diagnosis and Treatment of Tumors of the Head and Neck. Baltimore, Md., Williams & Wilkins Co., 1950. 43. Ward, G. E. and Robin, J. 0.: A Composite Operation for Radical Neck Dissection of Cancer of the Mouth. Cancer 4: 98, 1951. 44. Ward, G. E., Edgerton, M. T., Chambers, R. G. and McKee, D. M.: Cancer of the Oral Cavity and Pharynx and Results of Treatment by Means of the Composite Operation. Ann. Surg. 150: 202, 1959. 45. Woodhall, B., Hall, K., Mahaley, S. and Jackson, J.: Chemotherapy of Brain Cancer: Experimental and Clinical Studies in Localized Hypothermic Cerebral Perfusion. Ann. Surg. 150: 640, 1959. 46. Woodhall, B., Mahaley, M. S. Jr., Boone, S. and Huneycutt, H.: Effect of Chemotherapeutic Agents upon Peripheral Nerves. In press, J. Surg. Research. 47. Woodhall, B., Pickrell, K. L., Georgiade, N. G., Mahaley, M.S. and Dukes, H. T.: Effect of Hyperthermia upon Cancer Chemotherapy: Application to External Cancers of Head and Face Structures. Ann. Surg. 151: 750, 1960. 48. Woodhall, B., Reynolds, D. H., Mahaley, S. and Sanders, A. P.: Physiologic and Pathologic Effects of Localized Cerebral Hypothermia. Ann. Surg. 147: 673,1958.
Duke University Medical Center Durham, North CaroliRa