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Preoperative combination chemotherapy for advanced stage head and neck cancer
Preoperative Combination Chemotherapy for Advanced Stage Head and Neck Cancer Promising Early Results
Merrlll S. Klea, MD, Chicago, Illinois Bemsrd C. Pecaro, DOS, MD, Chicago, Illinois Leo I. Gordon, MD, Chicago, Illinois Walter W. Hawk, PhD, Chicago, Illinois Michael J. Kraut, MD, Chicago, Illinois Yosd Krespl, MD, Chicago, Illinois Robed H. Dssoff, DMD, MD, Chicago, Illinois
Cynlhla Schlff, RN, Chicago, Illinois Ramananda Shetly, MD, Chicago, Illinois George A. Slssm, MD, Chicago, Illinois
Cancer of the head and neck region constitutes about 5 percent of malignant neoplasma in the United States. The majority are squamous cell carcinomas that occur in the oral cavity, pharynx, larynx, and sinuses. Despite the relative infrequency of this neoplasm compared with cancers of the breast, lung, and gastrointestinal tract, high risk populations can be identified because of the known association of this disease with the abuse of alcohol and tobacco. Moreover, squamous cell carcinomas of the head and neck are locally aggressive and, even when detected early, may result in substantial functional as well as cosmetic defects. Patients with Ts or T4 primary lesions have a 3 year disease-free survival rate of only 15 to 40 percent [ 1,2]. Local relapse after surgery or radiation is the most frequent pattern of recurrence, and chemotherapy has been of marginal benefit in this setting [3]. Attempts to improve tumor control rates using radiation therapy with the patient under hyperbaric oxygen [4], hyperfractionation or hypofractionation
vohaln 148, Sopiombu 1984
schemes [5], and sequencing radiation before or after definitive surgery [6-8] have had limited impact on overall survival The role of chemotherapy in the treatment of head and neck cancer has not yet been established. Until recently, systemic chemotherapy has been a palliative maneuver in the treatment of patients with far advanced, locally recurrent disease or metastatic disaase that appears after initial therapy with radiation or surgery. Nonetheless, ample evidence exists that a number of single agents have antitumor activity [3,9,1(J). Among the most active are methotrexate, bleomycin, and cisplatin, with response rates ranging from 20 to 50 percent. Although there have been numerous reports of higher tumor regression rates with drug combinations [3,10,11], no single drug or combination of drugs has gained widespread acceptance as the standard chemotherapeutic approach. It saems clear that response rates improve when drug treatments are given before definitive radiation or surgery [3]. Optimal nutritional and performance status and batter drug delivery because of preservation of tumor vascularity are probably important factors. Thus, in an effort to improve local disease control by reducing tumor bulk with chemotherapy before definitive surgery or radiation and to eradicate regional and distant microscopic metastatic disease,
367
Kies et al
TABLE I
The Chemotherapy Program Day
Cisplatin. 80 mg/m2 Bleomycin, 5 mg/m* Methotrexate. 40 ma/m* l
1
8
15
22
X x ...
‘X’ ...
‘X’ X
‘X’ X
Each cycle is repeated every 28 days.
we have treated previously untreated patients with cisplatin, bleomycin, and methotrexate in combination before surgery and radiation therapy. Herein, we report our results in 19 consecutive patients. Material and Methods Eligibility: To be considered for inclusion, the following criteria were established: (1) Stage 3 or 4 (American Joint Commission for Staging, 1978) squamous cell carcinoma of the oral cavity, pharynx, hypopharynx, larynx, or cervical esophagus; (2) diagnosis histologically confirmed by biopsy, (3) serum creatinine level less than or equal to 1.5 mg/dl, (4) creatinine clearance exceeding 50 ml/min, (5) a white blood cell count exceeding 4,000/mm3 and a platelet count exceeding 106,000/mm3, (6) performance status of at least 70 percent on the Karnofsky scale, (7) forced expiratory volume and vital capacity exceeding 60 percent of predicted, (8) measurable disease, and (9) no previous treatment. Informed consent was obtained from each patient before therapy was initiated. Treatment plan: Patients were jointly evaluated by surgical, medical, and radiation oncology units. The staging workup included panendoscopy and tattooing of all measurable tumor to facilitate later assessment of response and to serve as guideposts for surgery in patients achieving major tumor regression. After the initial evaluations, surgery, or radiation therapy was planned for each patient. All patients then commenced drug therapy, as outlined in Table I. Patients were hospitalized for cisplatin therapy; otherwise the chemotherapy was given in the outpatient clinic. Patients were followed weekly, and those with any clinical or radiographic evidence of disease progression were advanced from chemotherapy to surgery or radiation therapy. No tumor shrinkage after 2 weeks or failure of the response to improve before the start of the next treatment cycle was considered an indication to discontinue chemotherapy and to proceed to surgery or radiation therapy. The drug treatment schema is listed in Table I. Cisplatin was given 4 hours after instituting an intravenous infusion of 5 percent dextrose in 0.5 N saline solution with 10 mEq potassium chloride per 1,000 ml given at a rate of 250 ml/hour. Mannitol (12.5 g) was given intravenously immediately before the cisplatin infusion started. Fluid orders were adjusted over the ensuing I2 hours to ensure a urine output equal to or greater than 150 ml/hour. Before each cycle of therapy, the serum creatinine level and creatinine clearance were determined. If the serum creatinine level increased to 2 mg/lOO ml or the creatinine clearance diminished to less than 50 ml/min, ciaplatin was withheld. Serial audiograms were performed as clinically indicated. Pulmonary function tests were repeated monthly, and bleomycin was discontinued if there was evidence of di-
388
minishing pulmonary function. Severe skin toxicity, chills and fever, or allergic responses were also considered reasons to discontinue bleomycin therapy. Methotrexate was reduced by 25 percent for patients in whom moderate to severe mucositis developed. Dosage reduction for hematologic toxicity was based on blood count nadirs. Furthermore, reduction of creatinine clearance below baseline or elevation of serum creatinine above the upper laboratory limit of normal was considered grounds for discontinuing methotrexate. The response status of the patient was determined weekly. The following terms were used to clinically define tumor response: (1) Complete response: the complete disappearance of all measurable and palpable tumor. A histologic complete response identified patients who, after complete surgical resection of the suspected tumor region, had no histologic evidence of persistent tumor. (2) Partial response: tumor shrinkage of all measurable disease by greater than 50 percent of the product of the perpendicular diameters of the two largest dimensions of each lesion. (3) Disease progression: increase of 25 percent in the size of the measurable disease during therapy. (4) No response: less than a partial response without evidence of disease progression. Response duration was calculated from the time of the earliest recognized response until relapse, and survival time was calculated from the time of diagnosis. Life table analyses used the product-moment method and were performed using BMDPlL on the Northwestern Cancer Center biometry section’s PDP 1l/34.
Results Patient characteristics and tumor sites and stage are listed in Table II. Nineteen consecutive previously untreated patients comprised the study group. All were entered while receiving treatment between August 1980 and September 1981 and were considered evaluable. The median age was 59 years, and 17 patients were male. All patients were ambulatory at diagnosis and capable of traveling to and from the outpatient clinic area for therapy. Three patients with TsNc lesions were included because they had large primary tumors and were estimated to be at high risk (greater than 50 percent) of relapse after standard local therapy. All patients received chemotherapy before definitive local treatment, which consisted of surgery alone in 6 patients, surgery with postoperative radiation in 11 patients, and radiation alone in 2 patients. In practice, chemotherapy treatments were terminated for responding patients at the discretion of the attending surgeon or radiation therapist soon after the initial response to chemotherapy was recognized. The median duration of chemotherapy was 4 weeks. Complete and partial clinical responses occurred in 14 of 19 patients (74 percent) after chemotherapy (Table II). No patient had progressive disease while receiving chemotherapy. Seventeen of 19 patients were rendered free of clinical evidence of disease for at least a month after all treatment. Of the 17 patients who underwent definitive surgical resection, 2 complete response patients had no histologic evi-
The Anwrlcan Journalo( Suqwy
Chemotherapy for Head and Neck Cancer
TABLE II
Patient Characterlstlcs and Response and Survival Data
Patient Age
Duration of Chemotherapy
WI
8%X
stage
8 site
59. 50, 59, 88, 58, 84. 54, 82, 80, 58, 80,
M M M M F M M M M M M
TaN&, larynx T#l&,, anterior floor of mouth T,N&. floor of mouth TpN&, supraglottic larynx TPNIMO, retromolar trigone T&M,,, floor of mouth T4NIM0, transglottic larynx TsN&, supraglottic larynx Primaty unknown T$l&,, base of tongue T,N&. pyriform sinus
80, 82, 59. 84.
M M M F
TsN&,. T#J&,, T&MO, T3N&,
8 4 5 5
47, 87. 57, 54.
M M M M
TsN&, mandibular-alveolar rktge TsNIMo, retromolar trigone TdNsM,,. retromolar trigone T&M,,. retromolar
l
Response to chemotherapy
Duration (W
@W
Laryngectomy Radiation Composite resection, radiation Hemihyngectomy Composite resection, radiation Composite resection Laryngectomy. radiation Radiation, radical neck dissection Radical neck dissection, radiation Composite resection, radiation Laryngectomy. radical neck dissection. radiation Composite resection Composite resection Laryngectomy. radiation Hemiglossectomy with radical neck dissection Composite resection, radiation Composite resection, radiation Composite resection, radiation Radiation
Clinical CR NR PR Histologic Cr PR NR PR PR PR PR NR
34+
NED 34+ 14 11 27+ 10 19 NED 27+ 8 14 8+’ 10
(W
4 4 4 4 4 8 4 5 4 4 4
tonsillar retromolar trigone postcricoid region anterior tongue
RW+OtlSl3
Definitive Treatment
8 8 3 8
;d 27+ 7 8 28+ 3 11 4
Survival
Histologic CR Clinical CR PR PF!
27+ 27+ 28+ 10
28+ 27+ 27+ 12
NR PR PR NR
3 18 5
15 23 13 11
..
Patient was lost to follow-up. CR = complete response; NED = no evidence of disease; NR = no response; PR = partial response.
dence of persistent disease and only chronic inflammation and mild dysplasia on pathologic examination. Serial sectioning of resected specimens was not performed. Two additional patients with complete response had only small foci of residual microscopic tumor. One partial responder had no evidence of malignancy at the primary tumor site, although foci of metastatic nodal disease persisted. Necrosis in areas of previous clinical disease was a frequent finding. Median survival for the entire group of patients is 14.4 months (Table II). Six patients continue to be clinically and radiographically disease-free 27 to 34 months after diagnosis. The four patients who achieved complete response had not relapsed at last follow-up. Notably, only these patients had either no identifiable tumor or only microscopic residual disease foci in the resected surgical specimens. In contrast, none of the 5 patients who did not respond to chemotherapy and only 2 of 10 who partially responded (after chemotherapy) continued without evidence of relapse after definitive surgery and radiation therapy at 27 month follow-up. Twelve patients died from progressive local tumor. A single patient was lost to follow-up after 6 months. Figure I depicts survival curves contrasting the patients with a complete response after chemotherapy versus all those with partial response and no response. The difference was statistically significant, p = 0.008 (log rank test). No differences in survival were observed between patients with partial response and those with no response.
vohma
168,
s4Qtombu
1904
Drug related toxicity consisted primarily of mucositis from methotrexate and bleomycin (8 patients), and nausea and vomiting related to cisplatin (11 patients). Toxic effects were considered severe in four and five patients, respectively. No patients required hospitalization for these effects. Severe myelosuppression, defined as the suppression of granulocyte counts below 500/mm3, was seen in one patient who was admitted for the evaluation of fever and was given empiric antibiotic treatment. Three
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Kies et al
patients.had a modest elevation of the inine level. No exacerbation of surgical associated complications was observed. no drug related deaths, and no patient alysis.
serum creator radiation There were required di-
Comments Interpretation of the head and neck cancer chemotherapy literature is difficult. Although numerous drugs, including adriamycin, bleomycin, cisplatin, cyclophosphamide, fluorouracil, methotrexate, and vincristine, have single agent activity with reported response rates in excessof 15 percent, no drug or drug combination has unequivocably been shown to prolong survival [3]. This is probably because responses to single agents are incomplete and typically of short duration, seldom exceeding 6 months. However, we emphasize that there has been reluctance in the past to treat patients until after relapse following surgery and radiation therapy. Poor patient performance status, bulky tumor in an area previously radiated, and multisystem medical problems common to older patients with a history of alcohol and tobacco abuse were factors that undermined early attempts to determine single agent efficacy. Moreover, efforts to move drugs systematically from phase II to phase III trials in head and neck cancer have been limited because of the relative lack of clinically or radiographically measurable disease in many patients after relapse. Unlike lymphomas, breast and lung cancers, and other obviously systemic malignancies in which chemotherapy drug trials have been extensively conducted, head and neck cancers have not traditionally been considered to require systemic therapy. In one recent review [12], only 9 of 198 autopsied subjects died from distant metastases. Thus, the principal failure of current therapy is a lack of regional disease control despite improvements in surgical and radiation techniques. Given the responsiveness of head and neck cancers to drug therapy and the correlation between advanced tumor size and resistance to surgery and radiation for a broad spectrum of malignancies [13,14], the rationale for preoperative or preradiation chemotherapy is to improve surgical or radiation treatment results largely by reducing primary tumor bulk before definitive local therapy. Sterilizing the tumor periphery, diminishing the risk of tumor implantation after surgical manipulation, and eradicating the regional and systemic microscopic disease are other potential benefits. The response and survival data reported herein do not reflect an advance over a number of alternative preoperative regimens [15-201. In our study, 74 percent of patients achieved measurable tumor regression after chemotherapy, and 6 of 19 patients have remained free of relapse with a minimum follow-up time from diagnosis of 27 months (range 27
370
to 34 months). The number of patients is insufficient to make definitive statements regarding survival or to correlate site and size of the primary cancer with responsiveness to chemotherapy. Our study differs from other recently reported series in that 17 of 19 patients had extensive surgical resection with histopathologic examination immediately after chemotherapy. This practice allowed us to identify the patients with histologically complete response, assess the extent of necrosis and inflammation, and correlate these findings with local and distant control after definitive local therapy. It is striking that the patients with complete response were all free of relapse 27 to 34 months after diagnosis. Two of these patients had no identifiable tumor after histologic examination, and two had only microscopic residual tumor. Not surprisingly, three of these four patients were stage Tz-sNe, suggesting that prospects for a major response to chemotherapy are better for the patient with relatively low tumor bulk at diagnosis. The treatment program proved to be easily tolerable for patients and physicians. Eight patients had at least one episode of severe toxicity, but there were no treatment related fatalities, and in only one instance did a patient require hospitalization because of drug complications. To achieve an improved complete response rate with more durable remissions, the chemotherapy portion of this treatment approach must be critically examined. To date, combination chemotherapy has been given before surgery or radiation therapy in numerous studies [3,15-201. The majority of these treatment programs have consisted of one or two courses of drug therapy delivered before definitive local treatment. Such an approach fails to apply well-known principles of cancer chemotherapy. Currently available drugs kill tumor cells by first order kinetics [21]; we obtain, at best, fractional tumor celI killing with each course of treatment. Even after achievement of complete disease remission, large numbers of malignant cells may persist. In other malignancies where chemotherapy has been found most effective, such as Hodgkin’s disease and childhood leukemia, repeated courses of chemotherapy have been applied at frequent intervals to achieve maximum cell kill. Decker and colleagues [22] have recently reported a much higher complete response rate after three courses of cisplatin and 5fluorouracil chemotherapy compared with one course in advanced head and neck cancer patients. In our current, ongoing studies, we are attempting to deliver three cycles before surgery or radiation therapy and then follow with three more courses in responding patients before discontinuing all therapy. More follow-up time will be needed to determine the ultimate benefit of multimodal treatment programs for patients with head and neck cancer. Our experience, like that of others, is with a relatively
The Anwlcan
Journal 04 Stirgory
Chemotherapy for Head and Neck Cancer
small and heterogeneous patient population, and overall treatment strategy has been individualized as is the usual practice. The achievement of histologically complete responses in patients with large primary tumors after only several weeks of drug therapy is notable, but we cannot assume that a major response to preoperative chemotherapy increases the chance for long-term disease remission or cure. It is not yet clear if tumors responsive to chemotherapy would have been similarly responsive to radiation with no substantive benefit from combining the treatment modalities. Prospective, controlled trials that compare combined modality therapy with standard radiation therapy or surgery are necessary to resolve this issue. Ultimately, effective drug treatment of head and neck malignancies may allow modification of current surgical and radiotherapeutic practices with better functional and cosmetic results. Until the efficacy of chemotherapy is known, however, it would be unwise to compromise established therapeutic approaches. It is important for the general medical practitioner and surgeon to recognize the subset of our population at high risk for head and neck malignancies, the availability of often highly effective surgical and radiotherapeutic treatment options, and the emergence of drug therapy as a potentially integral component of the multidisciplinary management of this group of diseases.
3.
4. 5.
6.
7.
8.
9. 10. 11.
12.
13. 14.
Summary We treated 19 consecutive patients with cisplatin, bleomycin, and methotrexate before definitive surgery or radiation therapy. Fourteen patients (74 percent) had partial or complete tumor regression after chemotherapy. With a minimum follow-up time of 27 months, none of the 4 patients who had a major histologic response relapsed, and only 2 of the remaining 15 patients continued disease-free. The achievement of a complete histologic response after preoperative chemotherapy may correlate with long-term disease-free survival after surgery and radiation therapy for head and neck cancer.
15.
16.
17.
18.
19.
Acknowledgment: We thank Nirsa N. Cortez and Carol Lobbea for help in preparing the manuscript and Christine H. Lamut for assistance with statistical computations. 20.
References 21. 1.
HambergerAD, Fletcher GH, Guillamondegui OM. Byers RM.
Advanced squamous cell carcinoma of the oral cavity and oropharynx treated with lrradlatlon and surgery. Radiology 1976;119:433-8. 2. Perez CA, Lee FA, Ackerman LV. Dgure JH. Powers WE. Not+randomlzed comparison of preoperative Irradiation and
vohns
Ma, 9a@am&r 1904
22.
surgery versus irradiation alone in the management of carcinoma of ths tonsil. Am J Roentgenol Radium Ther Nucl Med 1976;126:246-60. Mead GM, Jacobs C. Changing role of chemotherapy in treatment of head and neck cancer. Am J Med 1962;73: 562-95. Wildermuth 0, Warner GA, Marty R. Clinical hybaroxic radiotherapy after five years. Radiology 1969;93:1149-54. COX JD, Byhardt RW, Komaki R, et al. Reduced fractionation and the potential of hypoxic cell sensitizers in irradiation of malignant epithelial tumors. Int J Radiat Oncol Biol Phys 1960;6:37-40. Fletcher GH, Evers WT. Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology 1970;95:165-6. Fletcher GH, Jessee RH. The place of irradiation in the management of the primary lesion in head and neck cancers. Cancer 1977;39:862-7. Snow JB Jr, Kramer S, Marcia1 VA, Galbar RD, Davis LW, Lowry LD. Evaluation of randomized preoperative and postoperative radiation therapy for syxaglottic carcinoma. Ann Dtol Rhino1 Laryngol 1978;87:686-91. Bertino JR, Masher MB, DeConti RC. Chemotherapy of cancer of the head and neck. Cancer 1973;31:1141-9. Carter SK. The chemotherapy of head and neck cancer. Semin Oncol 1977;4:413-24. Muggia FM, Rozencwieg M, Wouie AE. Role of chemotherapy in head and neck cancer: systemic use of single agents and combinations in advanced disease. Head Neck Surg 1980;2:196-205. King Al, Johnson PE. The use of radioisotope scans in the preoperative evaluation of epidenoi carcinoma of the head and neck. Laryngoscope 1981;91:1052-7. Fletcher GH. Clinical dose-response curves of human malignant epithelial tumors. Br J Radio1 1973;46: l-l 2. Hellman S. Improving the therapeutic index in breast cancer treatment. Cancer Res 1980;40:4335-42. Tarpley JL, Chretien PB, Alexander JC Jr, Hoye RC, Block JB, Ketcham AS. High-dose methotrexate as a preoperative adjuvant in the treatment of epldermoid carcinoma of the head and neck: a feasibility study. Am J Surg 1975;130: 481-6. Arlen M. Combined radiation-methotrexate therapy in preoperative management of carcinoma of ths head and neck. Am J Surg 1976;132:536-40. Piiman SW, Miller D, Weichselbaum R. Initial adjuvant therapy in advanced squamous cell carcinoma of the head and neck employing weekly high-dose methotrexate with leucovorin rescue. Laryngoscope 1978;88:632-8. Elias EG. Chretien PB, Monnard E, et al. Chemotherapy prior to local therapy in advanced squamous cell carcinoma of the head and neck: preliminary assessment of an intensive drug regimen. Cancer 1979;43: 1025-31. Glick JH, Marcia1 V. Richter M, Velez-Garcia E. The adjuvant treatment of inoperable stage Ill and IV epidermoid carcinoma of the head.and neck with platinum and bleomycin infusions prior to definitive radiotherapy. Cancer 1980;46: 1919-24. Glick JH, Taylor SG IV. Integration of chemotherapy into a combined modality treatment plan for head and neck cancer: a review. Int J Radiat Oncol Biol Phys 1981;7:229-42. Frei E Ill, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980;69:585-94. Decker DA, Drelichman A, Jacobs J, et al. Adjuvant chemotherapy with high dose bolus cisdiamminodichloroplatinum II (CDD) and 120 hour infusion 5-fluorouracil @-FU) in staga Ill and IV squamous cell carcinoma of the head and neck. Proc Am Sot Clin Oncol 1982;1:C-757.
371
Merrlll S. Klea, MD, Chicago, Illinois Bemsrd C. Pecaro, DOS, MD, Chicago, Illinois Leo I. Gordon, MD, Chicago, Illinois Walter W. Hawk, PhD, Chicago, Illinois Michael J. Kraut, MD, Chicago, Illinois Yosd Krespl, MD, Chicago, Illinois Robed H. Dssoff, DMD, MD, Chicago, Illinois
Cynlhla Schlff, RN, Chicago, Illinois Ramananda Shetly, MD, Chicago, Illinois George A. Slssm, MD, Chicago, Illinois
Cancer of the head and neck region constitutes about 5 percent of malignant neoplasma in the United States. The majority are squamous cell carcinomas that occur in the oral cavity, pharynx, larynx, and sinuses. Despite the relative infrequency of this neoplasm compared with cancers of the breast, lung, and gastrointestinal tract, high risk populations can be identified because of the known association of this disease with the abuse of alcohol and tobacco. Moreover, squamous cell carcinomas of the head and neck are locally aggressive and, even when detected early, may result in substantial functional as well as cosmetic defects. Patients with Ts or T4 primary lesions have a 3 year disease-free survival rate of only 15 to 40 percent [ 1,2]. Local relapse after surgery or radiation is the most frequent pattern of recurrence, and chemotherapy has been of marginal benefit in this setting [3]. Attempts to improve tumor control rates using radiation therapy with the patient under hyperbaric oxygen [4], hyperfractionation or hypofractionation
vohaln 148, Sopiombu 1984
schemes [5], and sequencing radiation before or after definitive surgery [6-8] have had limited impact on overall survival The role of chemotherapy in the treatment of head and neck cancer has not yet been established. Until recently, systemic chemotherapy has been a palliative maneuver in the treatment of patients with far advanced, locally recurrent disease or metastatic disaase that appears after initial therapy with radiation or surgery. Nonetheless, ample evidence exists that a number of single agents have antitumor activity [3,9,1(J). Among the most active are methotrexate, bleomycin, and cisplatin, with response rates ranging from 20 to 50 percent. Although there have been numerous reports of higher tumor regression rates with drug combinations [3,10,11], no single drug or combination of drugs has gained widespread acceptance as the standard chemotherapeutic approach. It saems clear that response rates improve when drug treatments are given before definitive radiation or surgery [3]. Optimal nutritional and performance status and batter drug delivery because of preservation of tumor vascularity are probably important factors. Thus, in an effort to improve local disease control by reducing tumor bulk with chemotherapy before definitive surgery or radiation and to eradicate regional and distant microscopic metastatic disease,
367
Kies et al
TABLE I
The Chemotherapy Program Day
Cisplatin. 80 mg/m2 Bleomycin, 5 mg/m* Methotrexate. 40 ma/m* l
1
8
15
22
X x ...
‘X’ ...
‘X’ X
‘X’ X
Each cycle is repeated every 28 days.
we have treated previously untreated patients with cisplatin, bleomycin, and methotrexate in combination before surgery and radiation therapy. Herein, we report our results in 19 consecutive patients. Material and Methods Eligibility: To be considered for inclusion, the following criteria were established: (1) Stage 3 or 4 (American Joint Commission for Staging, 1978) squamous cell carcinoma of the oral cavity, pharynx, hypopharynx, larynx, or cervical esophagus; (2) diagnosis histologically confirmed by biopsy, (3) serum creatinine level less than or equal to 1.5 mg/dl, (4) creatinine clearance exceeding 50 ml/min, (5) a white blood cell count exceeding 4,000/mm3 and a platelet count exceeding 106,000/mm3, (6) performance status of at least 70 percent on the Karnofsky scale, (7) forced expiratory volume and vital capacity exceeding 60 percent of predicted, (8) measurable disease, and (9) no previous treatment. Informed consent was obtained from each patient before therapy was initiated. Treatment plan: Patients were jointly evaluated by surgical, medical, and radiation oncology units. The staging workup included panendoscopy and tattooing of all measurable tumor to facilitate later assessment of response and to serve as guideposts for surgery in patients achieving major tumor regression. After the initial evaluations, surgery, or radiation therapy was planned for each patient. All patients then commenced drug therapy, as outlined in Table I. Patients were hospitalized for cisplatin therapy; otherwise the chemotherapy was given in the outpatient clinic. Patients were followed weekly, and those with any clinical or radiographic evidence of disease progression were advanced from chemotherapy to surgery or radiation therapy. No tumor shrinkage after 2 weeks or failure of the response to improve before the start of the next treatment cycle was considered an indication to discontinue chemotherapy and to proceed to surgery or radiation therapy. The drug treatment schema is listed in Table I. Cisplatin was given 4 hours after instituting an intravenous infusion of 5 percent dextrose in 0.5 N saline solution with 10 mEq potassium chloride per 1,000 ml given at a rate of 250 ml/hour. Mannitol (12.5 g) was given intravenously immediately before the cisplatin infusion started. Fluid orders were adjusted over the ensuing I2 hours to ensure a urine output equal to or greater than 150 ml/hour. Before each cycle of therapy, the serum creatinine level and creatinine clearance were determined. If the serum creatinine level increased to 2 mg/lOO ml or the creatinine clearance diminished to less than 50 ml/min, ciaplatin was withheld. Serial audiograms were performed as clinically indicated. Pulmonary function tests were repeated monthly, and bleomycin was discontinued if there was evidence of di-
388
minishing pulmonary function. Severe skin toxicity, chills and fever, or allergic responses were also considered reasons to discontinue bleomycin therapy. Methotrexate was reduced by 25 percent for patients in whom moderate to severe mucositis developed. Dosage reduction for hematologic toxicity was based on blood count nadirs. Furthermore, reduction of creatinine clearance below baseline or elevation of serum creatinine above the upper laboratory limit of normal was considered grounds for discontinuing methotrexate. The response status of the patient was determined weekly. The following terms were used to clinically define tumor response: (1) Complete response: the complete disappearance of all measurable and palpable tumor. A histologic complete response identified patients who, after complete surgical resection of the suspected tumor region, had no histologic evidence of persistent tumor. (2) Partial response: tumor shrinkage of all measurable disease by greater than 50 percent of the product of the perpendicular diameters of the two largest dimensions of each lesion. (3) Disease progression: increase of 25 percent in the size of the measurable disease during therapy. (4) No response: less than a partial response without evidence of disease progression. Response duration was calculated from the time of the earliest recognized response until relapse, and survival time was calculated from the time of diagnosis. Life table analyses used the product-moment method and were performed using BMDPlL on the Northwestern Cancer Center biometry section’s PDP 1l/34.
Results Patient characteristics and tumor sites and stage are listed in Table II. Nineteen consecutive previously untreated patients comprised the study group. All were entered while receiving treatment between August 1980 and September 1981 and were considered evaluable. The median age was 59 years, and 17 patients were male. All patients were ambulatory at diagnosis and capable of traveling to and from the outpatient clinic area for therapy. Three patients with TsNc lesions were included because they had large primary tumors and were estimated to be at high risk (greater than 50 percent) of relapse after standard local therapy. All patients received chemotherapy before definitive local treatment, which consisted of surgery alone in 6 patients, surgery with postoperative radiation in 11 patients, and radiation alone in 2 patients. In practice, chemotherapy treatments were terminated for responding patients at the discretion of the attending surgeon or radiation therapist soon after the initial response to chemotherapy was recognized. The median duration of chemotherapy was 4 weeks. Complete and partial clinical responses occurred in 14 of 19 patients (74 percent) after chemotherapy (Table II). No patient had progressive disease while receiving chemotherapy. Seventeen of 19 patients were rendered free of clinical evidence of disease for at least a month after all treatment. Of the 17 patients who underwent definitive surgical resection, 2 complete response patients had no histologic evi-
The Anwrlcan Journalo( Suqwy
Chemotherapy for Head and Neck Cancer
TABLE II
Patient Characterlstlcs and Response and Survival Data
Patient Age
Duration of Chemotherapy
WI
8%X
stage
8 site
59. 50, 59, 88, 58, 84. 54, 82, 80, 58, 80,
M M M M F M M M M M M
TaN&, larynx T#l&,, anterior floor of mouth T,N&. floor of mouth TpN&, supraglottic larynx TPNIMO, retromolar trigone T&M,,, floor of mouth T4NIM0, transglottic larynx TsN&, supraglottic larynx Primaty unknown T$l&,, base of tongue T,N&. pyriform sinus
80, 82, 59. 84.
M M M F
TsN&,. T#J&,, T&MO, T3N&,
8 4 5 5
47, 87. 57, 54.
M M M M
TsN&, mandibular-alveolar rktge TsNIMo, retromolar trigone TdNsM,,. retromolar trigone T&M,,. retromolar
l
Response to chemotherapy
Duration (W
@W
Laryngectomy Radiation Composite resection, radiation Hemihyngectomy Composite resection, radiation Composite resection Laryngectomy. radiation Radiation, radical neck dissection Radical neck dissection, radiation Composite resection, radiation Laryngectomy. radical neck dissection. radiation Composite resection Composite resection Laryngectomy. radiation Hemiglossectomy with radical neck dissection Composite resection, radiation Composite resection, radiation Composite resection, radiation Radiation
Clinical CR NR PR Histologic Cr PR NR PR PR PR PR NR
34+
NED 34+ 14 11 27+ 10 19 NED 27+ 8 14 8+’ 10
(W
4 4 4 4 4 8 4 5 4 4 4
tonsillar retromolar trigone postcricoid region anterior tongue
RW+OtlSl3
Definitive Treatment
8 8 3 8
;d 27+ 7 8 28+ 3 11 4
Survival
Histologic CR Clinical CR PR PF!
27+ 27+ 28+ 10
28+ 27+ 27+ 12
NR PR PR NR
3 18 5
15 23 13 11
..
Patient was lost to follow-up. CR = complete response; NED = no evidence of disease; NR = no response; PR = partial response.
dence of persistent disease and only chronic inflammation and mild dysplasia on pathologic examination. Serial sectioning of resected specimens was not performed. Two additional patients with complete response had only small foci of residual microscopic tumor. One partial responder had no evidence of malignancy at the primary tumor site, although foci of metastatic nodal disease persisted. Necrosis in areas of previous clinical disease was a frequent finding. Median survival for the entire group of patients is 14.4 months (Table II). Six patients continue to be clinically and radiographically disease-free 27 to 34 months after diagnosis. The four patients who achieved complete response had not relapsed at last follow-up. Notably, only these patients had either no identifiable tumor or only microscopic residual disease foci in the resected surgical specimens. In contrast, none of the 5 patients who did not respond to chemotherapy and only 2 of 10 who partially responded (after chemotherapy) continued without evidence of relapse after definitive surgery and radiation therapy at 27 month follow-up. Twelve patients died from progressive local tumor. A single patient was lost to follow-up after 6 months. Figure I depicts survival curves contrasting the patients with a complete response after chemotherapy versus all those with partial response and no response. The difference was statistically significant, p = 0.008 (log rank test). No differences in survival were observed between patients with partial response and those with no response.
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Drug related toxicity consisted primarily of mucositis from methotrexate and bleomycin (8 patients), and nausea and vomiting related to cisplatin (11 patients). Toxic effects were considered severe in four and five patients, respectively. No patients required hospitalization for these effects. Severe myelosuppression, defined as the suppression of granulocyte counts below 500/mm3, was seen in one patient who was admitted for the evaluation of fever and was given empiric antibiotic treatment. Three
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Comments Interpretation of the head and neck cancer chemotherapy literature is difficult. Although numerous drugs, including adriamycin, bleomycin, cisplatin, cyclophosphamide, fluorouracil, methotrexate, and vincristine, have single agent activity with reported response rates in excessof 15 percent, no drug or drug combination has unequivocably been shown to prolong survival [3]. This is probably because responses to single agents are incomplete and typically of short duration, seldom exceeding 6 months. However, we emphasize that there has been reluctance in the past to treat patients until after relapse following surgery and radiation therapy. Poor patient performance status, bulky tumor in an area previously radiated, and multisystem medical problems common to older patients with a history of alcohol and tobacco abuse were factors that undermined early attempts to determine single agent efficacy. Moreover, efforts to move drugs systematically from phase II to phase III trials in head and neck cancer have been limited because of the relative lack of clinically or radiographically measurable disease in many patients after relapse. Unlike lymphomas, breast and lung cancers, and other obviously systemic malignancies in which chemotherapy drug trials have been extensively conducted, head and neck cancers have not traditionally been considered to require systemic therapy. In one recent review [12], only 9 of 198 autopsied subjects died from distant metastases. Thus, the principal failure of current therapy is a lack of regional disease control despite improvements in surgical and radiation techniques. Given the responsiveness of head and neck cancers to drug therapy and the correlation between advanced tumor size and resistance to surgery and radiation for a broad spectrum of malignancies [13,14], the rationale for preoperative or preradiation chemotherapy is to improve surgical or radiation treatment results largely by reducing primary tumor bulk before definitive local therapy. Sterilizing the tumor periphery, diminishing the risk of tumor implantation after surgical manipulation, and eradicating the regional and systemic microscopic disease are other potential benefits. The response and survival data reported herein do not reflect an advance over a number of alternative preoperative regimens [15-201. In our study, 74 percent of patients achieved measurable tumor regression after chemotherapy, and 6 of 19 patients have remained free of relapse with a minimum follow-up time from diagnosis of 27 months (range 27
370
to 34 months). The number of patients is insufficient to make definitive statements regarding survival or to correlate site and size of the primary cancer with responsiveness to chemotherapy. Our study differs from other recently reported series in that 17 of 19 patients had extensive surgical resection with histopathologic examination immediately after chemotherapy. This practice allowed us to identify the patients with histologically complete response, assess the extent of necrosis and inflammation, and correlate these findings with local and distant control after definitive local therapy. It is striking that the patients with complete response were all free of relapse 27 to 34 months after diagnosis. Two of these patients had no identifiable tumor after histologic examination, and two had only microscopic residual tumor. Not surprisingly, three of these four patients were stage Tz-sNe, suggesting that prospects for a major response to chemotherapy are better for the patient with relatively low tumor bulk at diagnosis. The treatment program proved to be easily tolerable for patients and physicians. Eight patients had at least one episode of severe toxicity, but there were no treatment related fatalities, and in only one instance did a patient require hospitalization because of drug complications. To achieve an improved complete response rate with more durable remissions, the chemotherapy portion of this treatment approach must be critically examined. To date, combination chemotherapy has been given before surgery or radiation therapy in numerous studies [3,15-201. The majority of these treatment programs have consisted of one or two courses of drug therapy delivered before definitive local treatment. Such an approach fails to apply well-known principles of cancer chemotherapy. Currently available drugs kill tumor cells by first order kinetics [21]; we obtain, at best, fractional tumor celI killing with each course of treatment. Even after achievement of complete disease remission, large numbers of malignant cells may persist. In other malignancies where chemotherapy has been found most effective, such as Hodgkin’s disease and childhood leukemia, repeated courses of chemotherapy have been applied at frequent intervals to achieve maximum cell kill. Decker and colleagues [22] have recently reported a much higher complete response rate after three courses of cisplatin and 5fluorouracil chemotherapy compared with one course in advanced head and neck cancer patients. In our current, ongoing studies, we are attempting to deliver three cycles before surgery or radiation therapy and then follow with three more courses in responding patients before discontinuing all therapy. More follow-up time will be needed to determine the ultimate benefit of multimodal treatment programs for patients with head and neck cancer. Our experience, like that of others, is with a relatively
The Anwlcan
Journal 04 Stirgory
Chemotherapy for Head and Neck Cancer
small and heterogeneous patient population, and overall treatment strategy has been individualized as is the usual practice. The achievement of histologically complete responses in patients with large primary tumors after only several weeks of drug therapy is notable, but we cannot assume that a major response to preoperative chemotherapy increases the chance for long-term disease remission or cure. It is not yet clear if tumors responsive to chemotherapy would have been similarly responsive to radiation with no substantive benefit from combining the treatment modalities. Prospective, controlled trials that compare combined modality therapy with standard radiation therapy or surgery are necessary to resolve this issue. Ultimately, effective drug treatment of head and neck malignancies may allow modification of current surgical and radiotherapeutic practices with better functional and cosmetic results. Until the efficacy of chemotherapy is known, however, it would be unwise to compromise established therapeutic approaches. It is important for the general medical practitioner and surgeon to recognize the subset of our population at high risk for head and neck malignancies, the availability of often highly effective surgical and radiotherapeutic treatment options, and the emergence of drug therapy as a potentially integral component of the multidisciplinary management of this group of diseases.
3.
4. 5.
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9. 10. 11.
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13. 14.
Summary We treated 19 consecutive patients with cisplatin, bleomycin, and methotrexate before definitive surgery or radiation therapy. Fourteen patients (74 percent) had partial or complete tumor regression after chemotherapy. With a minimum follow-up time of 27 months, none of the 4 patients who had a major histologic response relapsed, and only 2 of the remaining 15 patients continued disease-free. The achievement of a complete histologic response after preoperative chemotherapy may correlate with long-term disease-free survival after surgery and radiation therapy for head and neck cancer.
15.
16.
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Acknowledgment: We thank Nirsa N. Cortez and Carol Lobbea for help in preparing the manuscript and Christine H. Lamut for assistance with statistical computations. 20.
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