J Oral Maxillofac 40367472,
Surg
1990
Treatment of Oral Squamous Cell Carcinoma With Simultaneous Chemotherapy and Radiation: Results and Surgical Implications A. SCOTT EARLE, MD,* DAVID J. ADELSTEIN, MD,t CATHERINE VLASTOU, VISHWA M. SHARAN, MD,5 AND A. THOMAS INDRESANO, DMD”
MD,*
Thirty-seven patients with oral squamous cell carcinoma, many with advanced disease, were treated initially with a protocol using simultaneous intravenous Sfluorouracil (5FU) cis-platinum, and radiation. Twenty-two patients (62%) experienced complete remission after one cycle of therapy. Fifteen patients (38%) demonstrated an incomplete response; surgical resection was possible in 14 of these 15 patients. A second cyle of chemoradiotherapy was administered to all 37 patients. After this treatment resection is possible for some patients who are intially inoperable, and surgery is necessary only for those patients (38%) who show an incomplete remission after the first cycle of therapy and for those who present initially with bony invasion. Furthermore, the treatment of cervical nodes and intraoral disease may be divorced and the extent of surgery may be reduced for many patients. A 5-year survival of 76% is predicted for this group of patients. The described protocol shows promise for treatment of oral squamous cell carcinoma.
In the past, radiation and surgery, either alone or in combination, were the preferred treatments for squamous cell carcinoma of the oral cavity. Although chemotherapy was initially thought to be useful only for palliation, its value in presurgical induction therapy has been increasingly explored. ‘s Recent studies suggest that chemotherapy combined with simultaneous radiation may have even
greater value as induction treatment in this disease, as has been shown also for squamous cell carcinoma of the anus.6-8 As a result of these findings, combinations of chemotherapy, surgery, and radiation (combined modality therapy) are emerging as effective means of treating squamous cell carcinoma of the head and neck. This is a trend that may, in time, affect all surgeons who perform any volume of head and neck surgery. During the course of our studies with combined modality treatment we have had difficulty in defining what the indications and extent of surgery should be.9 We believe that others will also have this problem as treatment modalities change. Our previous reports’*6.9 included squamous cell carcinoma arising from any site within the head and neck. The present article reviews only patients with intraoral squamous cell carcinoma treated with a single protocol of combined therapy, with special emphasis on the indications for surgical intervention as they have evolved on our services during the past 5 years. We hoped, in reviewing this series of patients, to find answers to the following questions:
* Director, Division of Plastic Surgery, MetroHealth Medical Center, Cleveland, OH. I Staff Physician, Cleveland Clinic Foundation; formerly, Department of Medicine, MetroHealth Medical Center, Cleveland, OH. $ Plastic Surgeon, Athens, Greece; formerly, Division of Plastic Surgery, MetroHealth Medical Center, Cleveland, OH. § Staff Radiologist, Department of Radiology, MetroHealth Medical Center, Cleveland, OH. 11 Director, Division of Oral Surgery, MetroHealth Medical Center, Cleveland, OH. Address correspondence and reprint requests to Dr Earle: Division of Plastic Surgery, Cleveland MetroHealth Medical Center, 3395 Sc:ranton Rd. Cleveland OH, 44109. 0 1990 geons
American
Association
of Oral
and Maxillofacial
Sur-
0276-2391/9014604-0006$3.00/O
367
368
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
1) What percentage of patients with intraoral squamous cell carcinoma are cured of their disease when our protocol of combined modality (chemotherapy, radiation, and surgery) is used? 2) What, precisely, should the role of surgery be-including not only indications, but also scope, extent, and timing. Methods A11patients were treated according to the protocol outlined below using the most promising of several plans of treatment that have been or are presently being evaluated in our hospital.‘~6~‘0~‘2The senior author directly supervised all surgical procedures in this group of patients. There were four separate treatment steps: 1. Endoscopy to rule out other primary foci was performed on each patient, usually under general anesthesia. Lesions were measured and staged, margins were tattooed with India ink for future reference, and biopsy was performed on the lesion. 2. Treatment was then started immediately; this induction (the first cycle) included: I) cisplatin 75 mg/m2 given intravenously (IV) on the first day; 2) Sfluorouracil (5FU) 1,000 mg/m*/d as a continuous IV infusion over 4 days beginning on the first day; 3) radiation, 30 Gy in 1.5 fractions over 3 weeks delivered concurrently; and 4) an identical course of 5-FU and cisplatin without concurrent radiation administered 1 to 3 weeks after completion of radiotherapy. Figure 1 schematically indicates this treatment plan. 3. A minimum of 8 weeks after beginning the induction therapy, patients were evaluated for response. Careful examination of the original primary site was performed, under anesthesia if necessary, with multiple biopsies taken as appropriate. Radiographic studies were repeated, as indicated, to confirm clinical assessment . A complete response was defined as disappearance of all radiographic, clinical and, when applicable, histologic evidence of disease. Partial response
FIGURE 1. Diagrammatic depiction of the protocol used
was defined as any response that was less than complete, but with more than 50% reduction in the sum of the products of the crossed diameters of all measurable lesions. Patients with less tumor shrinkage were considered to be nonresponders. Progressive disease was defined as a greater than 25% increase in the sum of the products of the crossed diameters of all measurable lesions or the appearance of locally recurrent or metastatic disease. Originally, as this protocol was written, each patient whose lesion was judged initially to be resectable underwent surgery at the end of the first cycle of treatment. We quickly discovered that over half of our patients-all of those who achieved a complete remission after the first cycle, with the exception of one patient-also proved to have no residual microscopic tumor in the surgical specimen. The protocol was then rewritten to modify the surgical indications. The modifications stipulated that all patients would be evaluated at the end of the first cycle and surgery would be performed only in those with clinically evident residual disease (a biopsy was performed if there was any question of persistent disease). It was further stipulated that all patients who presented initially with bone invasion, or who had clinically positive nodes at the end of the first cycle of treatment, were to have appropriate surgical resection. 4. Regardless of whether surgery was performed, every patient was offered a second full course of combined-modality therapy (second cycle), identical to the first, for an overall total of 4 chemotherapy courses and 60 Gy of radiation. After completing treatment, patients rendered free of disease were seen every 2 months and clinically assessed for recurrence. Patients with persistent or recurrent disease were removed from the study and treated at the investigator’s discretion. Patient Data Thirty-seven patients with locally confined squamous cell carcinoma of the oral cavity were treated
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with this protocol during the 4-year period from January 1984 through December 1987. The patient population Twastypical for this disease. Most were in their seventh decade; the youngest was 41 years, the oldest 73 years. There were 24 men and 13 women, in accord with the expected 2:l maleto-female incidence of oral squamous ceil carcinoma. Most of the patients presented with advanced disease, so it was sometimes difficult to determine the exact sites of origin, but these were estimated as listed in Table 1. At the time of diagnosis, 18 patients (49%) had one or more clinically positive cervical lymph nodes. None had evidence of systemic spread at the time of their initial presentation. Most patients presented with advanced disease; 3 1 of the 37 patients (79%) had either stage III or stage IV disease. Figure 2 shows graphically the stage of disease at the time of diagnosis as well as the response after the first cycle of treatment with combined chemotherapy and radiation. The longest follow-up for this group of patients has now been more than 5 years, and the shortest has been 18 months (as of January 1, 1990); the median follow-up is 3% years. Results This protocol, including the rationale for using combined chemotherapy and radiation, details of its administra.tion, toxicity, and results achieved in treating squamous cell carcinoma of the head and neck (all sites) has been described in detail elsewhere.6.10.” The treatment can be summarized briefly by saying that it is difficult for patients and demanding of the professional personnel. It is associated not only with significant toxicity, chiefly, nausea and mucositis that are at times severe enough to require hospitalization, but also with an average 18% loss of body weight. Reversible renal damage and leukopenia occur frequently. Nonetheless, there was only one toxic drug-related death in this series (sepsis, renal failure) in a poor-risk patient during the second postsurgical cycle of chemotherapy and radiation. Table 1.
Sites of Origin
Location
Floor of mouth Tongue Retromolar trigone TonsiVsoft palate Buccal mucosa Alveolar ridge, mandible Alveolar ridge, maxilla Total * One patient had two primary lesions.
No. of Patients II
IO 4 4 4 3 2 38*
0
Part4
Response
rZZZ3 Complete Response
2 5 Z 2 b
10
r-l
Stage II
Stage Ill
Stage IV
FIGURE 2. Stage of disease at the time of entry into the study and response noted at the completion of the first cycle of combined chemotherapy and radiation are shown graphically. Although all patients responded to treatment, the response was proportional to the extent of the disease treated. Thus, whereas 6 stage II patients had full clinical remission, only 7 of 12 stage III and 10 of 19 stage IV patients achieved a complete response.
All 37 patients responded to treatment. Patient responses are shown and correlated with the stage of disease in Fig 2. Not surprisingly, patients with more advanced disease had fewer complete regressions than did those in whom the process was less extensive. Thus, all 6 patients with stage II lesions showed complete clinical remission at the end of the first cycle of treatment, whereas only 10 of 19 (53%) stage IV patients became clinically free of disease after the first cycle. It is convenient to consider these two categories, complete and partial remission, separately. COMPLETE
REMISSION
Twenty-two of the 37 patients (59.5%) had no clinical evidence of residual disease at the completion of the first cycle of chemotherapy and radiation. Early in the series, 8 patients underwent definitive resection (5 composite, 3 local); microscopic tumor was found in only 1 in an area of extensive bone erosion. We subsequently omitted surgery for patients who showed complete clinical remission after the first cycle of combined therapy except for those who had bony involvement at the time of diagnosis. Fourteen patients had no surgical procedure. A typical response is illustrated in Fig 3. There has been only 1 local recurrence among these patients, an inoperable recurrence of a stage IV retromolar lesion at 2 years. There were three other treatment failures in this group. Two patients died of systemic metastases, without evidence of local disease at the time of
370
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
FIGURE 3. A, The appearance of a T2 squamous cell carcinoma of the floor of the mouth and tongue in a 72year-old man photographed prior to treatment at the time of initial staging. B. The same patient following completion of the first cycle of therapy. This is a typical response as seen in all of the patients (58%) who experienced a complete clinical remission during the first treatment cycle.
death. Another patient died, without evidence of residual disease, of drug-related sepsis during her second cycle of combined therapy. Thus, of the 22 patients achieving a complete remission after the fast cycle of therapy, 19 (86%) remain free of disease. PARTIAL REMISSION Fourteen patients (38%) achieved only a partial remission at the completion of the first cycle of chemotherapy and radiation. We attempted surgical resection in 13 of these patients (the last patient re-
mained inoperable despite a partial response). It should be stressed that tive patients in this group, all with T4 lesions, had been considered inoperable when they entered this study and that 4 of these 5 were rendered resectable after chemoradiotherapy. Three of these 4 have remained free of disease. In 11 of the 13 resected patients, intraoperative surgical margins free of tumor on frozen section. The two patients with tumor at the surgical margins and the single patient who remained inoperable all have died of their local disease, as has one other patient, the youngest in our series, who had exten-
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EARLE ET AL
sive involvement of the tongue. A fifth patient died of systemic metastases, free of local disease. Two other patients died of unrelated causes; both were free of tumor at the time of death. (Of the 37 patients reported here, 2 died of unrelated small cell cancer of the lung. The simultaneous presence, or later appearance, of pathologically separate carcinoma of the lung is seen fairly often.‘3*‘4) Thus, of the 14 partial responders, there were 5 treatment failures and 2 unrelated deaths; 9 of the 14 patients (64%) in this group were disease-free survivors. Neck dissections were performed either as the sole procedure or as part of a composite resection on 12 of these patients. Three of the patients had shown complete regression of the intraoral primary lesion during the first cycle of chemotherapy and radiation with persistence of cervical adenopathy. In these 3 patients modified neck dissection only, without resection of the primary intraoral site of disease, was carried out. The remaining 9 patients had neck dissection combined with excision of the primary intraoral site for persistent tumor. Classical neck dissections were necessary in two patients only; both had extensive nodal involvement with invasion of other structures in the neck. The remaining 7 patients underwent conservative neck dissection, usually consisting only of removal of the jugular nodes and the contents of the submaxillary triangle, ie, a modified supraomohyoid dissection, sparing the sternocleidomastoid muscle, jugular vein, and accessory nerve. It is noteworthy that not a single patient in this series had a recurrence in the neck regardless of the type of neck dissection performed. Evaluation of treated patients, based on the clinical findings at the end of the first treatment cycle, seems to be remarkably accurate. Biopsy is of limited usefulness. We have used it only in seven patients who had equivocal persistent thickening or incomplete healing in the region of the intraoral primary lesion. Negative biopsies mean little and are useful only insofar as they support clinical evaluation. No patient in this series who had a negative biopsy lat,er developed disease. Only one patient had a positive biopsy; microscopic disease was found, and a limited local resection followed by the scheduled second cycle of chemotherapy and radiation successfully eradicated the remaining tumor. At the completion of therapy we felt that 34 of the original 37 patients in this series were disease free (92%); 29 of these 34 patients remained disease free for an apparent overall cure rate of 78%. Finally, subtracting the two patients who died of unrelated disease, 27 patients (73%) of the original cohort of 37, are alive today, all apparently free of disease. Analysis of the entire patient cohort using the
“product limit” method of Kaplan and Meier14a predicts a disease-free survival of 76%, and an overall survival (death from all causes) of 54% with a median follow-up of more than 3 years. Discussion and Conclusions Multimodality therapy is emerging as effective treatment of squamous cell carcinoma of the head and neck, and particularly of the oral cavity.6,10 In our original protocol, all patients were scheduled to undergo surgery at the completion of the first cycle of chemotherapy and radiation. The decision to omit surgery for those patients who showed complete clinical remission at the end of the first cycle of treatment was a difficult one; a departure from established methods of surgical treatment in this disease seemed, at the time, heretical. We were certain that recurrences would surface. This simply has not happened with a follow-up now exceeding 5 years for some patients. Others recently have reached similar conclusions in treating head and neck cancer.‘5-‘7 To date, only one of our patients in whom surgery was omitted, a patient with an extensive, stage IV, retromolar trigone lesion, has had a recurrence. Although surgery was omitted in many of those patients who achieved complete remission after the first cycle of therapy, we felt, until we reviewed this series of patients, that surgery should be carried out on those who presented with clinically positive cervical nodes. However, we now believe the following: 1) dissection is unnecessary in patients who have no adenopathy after the first cycle of treatment, and 2) it is safe to separate the treatment of the primary lesion and of the cervical node-bearing area. Thus, if one or the other area is clinically negative at the end of the first cycle of therapy, surgery is not required for that site. We recognize, of course, that when optimum access to the mouth and jaw is through a neck incision that a limited neck dissection adds little morbidity to the operation. 3) We recommend composite resection for patients who present initially with bone involvement regardless of clinical findings at the completion of the first cycle as we have found localized microscopic disease in more than half of the patients with bony destruction. There may be objection that we have based our conclusions on inadequate follow-up. This does not seem to be a valid objection. Every recurrence in this series was predictable, given the nature of the disease at the time of the initial staging. Recurrences in all but a single case (which recurred at 2 years) appeared very promptly. Kaplan-Meier survival curves for this group of patients project a dis-
372
ease-free survival rate of 76% at 5 years, a rate that compares favorably with traditional treatment using radiation, surgery, or a combination of both. (It is difficult to evaluate and compare results in the treatment of oral squamous cell carcinoma as there are many variables from series to series. Reported 5-year survival using surgery, radiation, or combinations of both, usually is in the vicinity of 65% for stage II, 45% for stage III, and 15% for stage IV disease.‘8T19 Survival rates using combined perioperative radiation and surgery tend to be higher; Silver et al 2o for example, have reported 60% survival for their’patients with stage III and IV disease.) It is too early yet to predict which combination of therapeutic agents will eventually prove to be best for treating squamous cell carcinoma of the head and neck. Nevertheless, protocols that we and others have described do seem effective. Clearly, chemotherapy coupled with radiation, plus surgery whenever it is indicated, is emerging as an acceptable means of treatment. Even though a survival advantage has not yet been conclusively demonstrated for patients treated with combined modalities, there are other evident advantages. For example, it appears that surgery was unnecessary for over half of the patients presented in this series. Our experience, as well as that of others, has shown that we may omit surgery for some patients and modify its scope for others.93’5-17 This is an intriguing possibility, for although we may minimize to some extent the surgical sequelae of ablative head and neck surgery by using modified (conservation, functional) neck dissection and by providing acceptable reconstruction after jaw and intraoral resections, surgery is still associated with cosmetic and functional impairment, a relatively high complication rate, and the inevitable suffering that attends any major surgical procedure. It is important to note that this was a nonrandomized, single-arm, phase II pilot study and that broad extrapolations from this data are difficult. Nonetheless, we believe that our indications for surgery following combined chemotherapy and radiation as outlined in this report are valid. We did not arrive at them lightly. During evolution of this study some patients underwent unnecessary and often extensive surgery. This permitted us, however, to delineate the surgical indications presented when preliminary chemotherapy and radiation are used. We hope that this experience may be useful to others with an interest in using combined modality therapy for intraoral squamous cell carcinoma. References 1. Adelstein DF, Hines JD, Sharan VM, et al: Combination chemotherapy prior to definitive local therapy in squa-
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
mous cell carcinoma of the head and neck. Oncology 42:80, 1985 2. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308:75, 1983 3. Mead GM. Jacobs C: Changing role of chemotherapy in treatment of head and neck cancer. Am J Med 73582, 1982 4. Rooney M, Kish J, Jacobs J, et al: Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120 hour S-FU infusion and cisplatin. Cancer 55:1123, 1985 5. Taylor SG IV: Head and neck cancer, in Pinedo HM, Longo DL, Chabner BA (eds): Cancer Chemotherapy and Biological Response Modifiers (annual 9). New York, NY, Elsevier Science, 1987, chap 15 6. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous radiotherapy and chemotherapy with 5fluorouracil and cisplatin for locally confined squamous cell head and neck cancer. NC1 Monogr 6:347, 1988 7. Leichman L, Nigro N. Vaitkevicius VK, et al: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78:211, 1985 8. Taylor SG IV, Murthy AK, Showel J. et al: Concomitant therapy with infusion or cisplatin and 5-fluorouracil plus radiation in head and neck cancer. NC1 Mongr 6:343,1988 9. Adelstein DJ, Sharan VM, Earle AS: Surgical modification or elimination after chemoradiotherapy for locally confined squamous cell head and neck cancer. Proceedings of the 2nd International Head and Neck Oncologv Research Conference. Arlington, VA, September 10-72, 1987, in Wolf GT, Carey TE (eds): Head and Neck Oncology Research. Amsterdam, The Netherlands, Kugler & Ghedini, 1988, pp 253-259 10. Adelstein DJ, Sharan VM, Earle AS, et al: Chemoradiotherapy as initial management in patients with squamous cell carcinoma of the head and neck. Cancer Treat Rep 70: 761, 1986 11. Adelstein DJ. Sharan VM, Earle AS, et al: Long-term results after chemoradiotherapy for locally confined squamous cell head and neck cancer. Am J Clin Oncol (in press) 12. Adelstein DF, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined modality therapy for squamous cell head and neck cancer. Proceedings of the Second International Conference on Head and Neck Cancer, Boston, MA, July 31-August 5, 1988 (abstr) 13. Lefor AT, Bredenberg CE, Kellman RM, et al: Multiple malignancies of the lung and head and neck. Arch Surg 121:265, 1986 14. Probert JC, Thompson RW. Bagshaw MA: Patterns of spread of distant metastases in head and neck cancer. Cancer 33: 127, 1974 14a. Kaplan EL, Meier P: Non parametric estimation from incomplete observation. J Am Statistical Assoc 53:457, 1958 15. Hong WK, Wolf GT, Fisher S. et al: A new strategy to preserve the larynx in the treatment of advanced laryngeal cancer: Preliminary report Proc. ASCO 6: 130, 1987 (abstr) 16. Haines IE, Bosl GJ, Ptister D, et al: Larynx preservation in patients with advanced squamous cell cancer of head and neck: recommendations for patient selection. Proc Am Sot Clin Oncol 6:133, 1987 (abst) 17. Jacobs C, Gofftnet DR, Gofftnet L, et al: Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer: a report from the Northem California Oncology Group. Cancer 60: 1178, 1987 18. Hirata RM, Jaques DA, Chambers RG, et al: Carcinoma of the oral cavity: An analysis of 478 cases. Ann Surg 182:98, 1975 19. Ildstad ST, Bigelow ME, Remensnyder JP: Intraoral cancer at the Massachusetts General Hospital. Squamous carcinoma of the floor of the mouth. Ann Surg 197:34, 1983 20. Silver CE, Glackin BK, Brauer et al: Surgical treatment of oral cavity carcinoma. Head Neck Surg 9: 13, 1986
Surg
1990
Treatment of Oral Squamous Cell Carcinoma With Simultaneous Chemotherapy and Radiation: Results and Surgical Implications A. SCOTT EARLE, MD,* DAVID J. ADELSTEIN, MD,t CATHERINE VLASTOU, VISHWA M. SHARAN, MD,5 AND A. THOMAS INDRESANO, DMD”
MD,*
Thirty-seven patients with oral squamous cell carcinoma, many with advanced disease, were treated initially with a protocol using simultaneous intravenous Sfluorouracil (5FU) cis-platinum, and radiation. Twenty-two patients (62%) experienced complete remission after one cycle of therapy. Fifteen patients (38%) demonstrated an incomplete response; surgical resection was possible in 14 of these 15 patients. A second cyle of chemoradiotherapy was administered to all 37 patients. After this treatment resection is possible for some patients who are intially inoperable, and surgery is necessary only for those patients (38%) who show an incomplete remission after the first cycle of therapy and for those who present initially with bony invasion. Furthermore, the treatment of cervical nodes and intraoral disease may be divorced and the extent of surgery may be reduced for many patients. A 5-year survival of 76% is predicted for this group of patients. The described protocol shows promise for treatment of oral squamous cell carcinoma.
In the past, radiation and surgery, either alone or in combination, were the preferred treatments for squamous cell carcinoma of the oral cavity. Although chemotherapy was initially thought to be useful only for palliation, its value in presurgical induction therapy has been increasingly explored. ‘s Recent studies suggest that chemotherapy combined with simultaneous radiation may have even
greater value as induction treatment in this disease, as has been shown also for squamous cell carcinoma of the anus.6-8 As a result of these findings, combinations of chemotherapy, surgery, and radiation (combined modality therapy) are emerging as effective means of treating squamous cell carcinoma of the head and neck. This is a trend that may, in time, affect all surgeons who perform any volume of head and neck surgery. During the course of our studies with combined modality treatment we have had difficulty in defining what the indications and extent of surgery should be.9 We believe that others will also have this problem as treatment modalities change. Our previous reports’*6.9 included squamous cell carcinoma arising from any site within the head and neck. The present article reviews only patients with intraoral squamous cell carcinoma treated with a single protocol of combined therapy, with special emphasis on the indications for surgical intervention as they have evolved on our services during the past 5 years. We hoped, in reviewing this series of patients, to find answers to the following questions:
* Director, Division of Plastic Surgery, MetroHealth Medical Center, Cleveland, OH. I Staff Physician, Cleveland Clinic Foundation; formerly, Department of Medicine, MetroHealth Medical Center, Cleveland, OH. $ Plastic Surgeon, Athens, Greece; formerly, Division of Plastic Surgery, MetroHealth Medical Center, Cleveland, OH. § Staff Radiologist, Department of Radiology, MetroHealth Medical Center, Cleveland, OH. 11 Director, Division of Oral Surgery, MetroHealth Medical Center, Cleveland, OH. Address correspondence and reprint requests to Dr Earle: Division of Plastic Surgery, Cleveland MetroHealth Medical Center, 3395 Sc:ranton Rd. Cleveland OH, 44109. 0 1990 geons
American
Association
of Oral
and Maxillofacial
Sur-
0276-2391/9014604-0006$3.00/O
367
368
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
1) What percentage of patients with intraoral squamous cell carcinoma are cured of their disease when our protocol of combined modality (chemotherapy, radiation, and surgery) is used? 2) What, precisely, should the role of surgery be-including not only indications, but also scope, extent, and timing. Methods A11patients were treated according to the protocol outlined below using the most promising of several plans of treatment that have been or are presently being evaluated in our hospital.‘~6~‘0~‘2The senior author directly supervised all surgical procedures in this group of patients. There were four separate treatment steps: 1. Endoscopy to rule out other primary foci was performed on each patient, usually under general anesthesia. Lesions were measured and staged, margins were tattooed with India ink for future reference, and biopsy was performed on the lesion. 2. Treatment was then started immediately; this induction (the first cycle) included: I) cisplatin 75 mg/m2 given intravenously (IV) on the first day; 2) Sfluorouracil (5FU) 1,000 mg/m*/d as a continuous IV infusion over 4 days beginning on the first day; 3) radiation, 30 Gy in 1.5 fractions over 3 weeks delivered concurrently; and 4) an identical course of 5-FU and cisplatin without concurrent radiation administered 1 to 3 weeks after completion of radiotherapy. Figure 1 schematically indicates this treatment plan. 3. A minimum of 8 weeks after beginning the induction therapy, patients were evaluated for response. Careful examination of the original primary site was performed, under anesthesia if necessary, with multiple biopsies taken as appropriate. Radiographic studies were repeated, as indicated, to confirm clinical assessment . A complete response was defined as disappearance of all radiographic, clinical and, when applicable, histologic evidence of disease. Partial response
FIGURE 1. Diagrammatic depiction of the protocol used
was defined as any response that was less than complete, but with more than 50% reduction in the sum of the products of the crossed diameters of all measurable lesions. Patients with less tumor shrinkage were considered to be nonresponders. Progressive disease was defined as a greater than 25% increase in the sum of the products of the crossed diameters of all measurable lesions or the appearance of locally recurrent or metastatic disease. Originally, as this protocol was written, each patient whose lesion was judged initially to be resectable underwent surgery at the end of the first cycle of treatment. We quickly discovered that over half of our patients-all of those who achieved a complete remission after the first cycle, with the exception of one patient-also proved to have no residual microscopic tumor in the surgical specimen. The protocol was then rewritten to modify the surgical indications. The modifications stipulated that all patients would be evaluated at the end of the first cycle and surgery would be performed only in those with clinically evident residual disease (a biopsy was performed if there was any question of persistent disease). It was further stipulated that all patients who presented initially with bone invasion, or who had clinically positive nodes at the end of the first cycle of treatment, were to have appropriate surgical resection. 4. Regardless of whether surgery was performed, every patient was offered a second full course of combined-modality therapy (second cycle), identical to the first, for an overall total of 4 chemotherapy courses and 60 Gy of radiation. After completing treatment, patients rendered free of disease were seen every 2 months and clinically assessed for recurrence. Patients with persistent or recurrent disease were removed from the study and treated at the investigator’s discretion. Patient Data Thirty-seven patients with locally confined squamous cell carcinoma of the oral cavity were treated
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DDP 75 m9/m2 RT 3000
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Day
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2
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EARLE ET AL
with this protocol during the 4-year period from January 1984 through December 1987. The patient population Twastypical for this disease. Most were in their seventh decade; the youngest was 41 years, the oldest 73 years. There were 24 men and 13 women, in accord with the expected 2:l maleto-female incidence of oral squamous ceil carcinoma. Most of the patients presented with advanced disease, so it was sometimes difficult to determine the exact sites of origin, but these were estimated as listed in Table 1. At the time of diagnosis, 18 patients (49%) had one or more clinically positive cervical lymph nodes. None had evidence of systemic spread at the time of their initial presentation. Most patients presented with advanced disease; 3 1 of the 37 patients (79%) had either stage III or stage IV disease. Figure 2 shows graphically the stage of disease at the time of diagnosis as well as the response after the first cycle of treatment with combined chemotherapy and radiation. The longest follow-up for this group of patients has now been more than 5 years, and the shortest has been 18 months (as of January 1, 1990); the median follow-up is 3% years. Results This protocol, including the rationale for using combined chemotherapy and radiation, details of its administra.tion, toxicity, and results achieved in treating squamous cell carcinoma of the head and neck (all sites) has been described in detail elsewhere.6.10.” The treatment can be summarized briefly by saying that it is difficult for patients and demanding of the professional personnel. It is associated not only with significant toxicity, chiefly, nausea and mucositis that are at times severe enough to require hospitalization, but also with an average 18% loss of body weight. Reversible renal damage and leukopenia occur frequently. Nonetheless, there was only one toxic drug-related death in this series (sepsis, renal failure) in a poor-risk patient during the second postsurgical cycle of chemotherapy and radiation. Table 1.
Sites of Origin
Location
Floor of mouth Tongue Retromolar trigone TonsiVsoft palate Buccal mucosa Alveolar ridge, mandible Alveolar ridge, maxilla Total * One patient had two primary lesions.
No. of Patients II
IO 4 4 4 3 2 38*
0
Part4
Response
rZZZ3 Complete Response
2 5 Z 2 b
10
r-l
Stage II
Stage Ill
Stage IV
FIGURE 2. Stage of disease at the time of entry into the study and response noted at the completion of the first cycle of combined chemotherapy and radiation are shown graphically. Although all patients responded to treatment, the response was proportional to the extent of the disease treated. Thus, whereas 6 stage II patients had full clinical remission, only 7 of 12 stage III and 10 of 19 stage IV patients achieved a complete response.
All 37 patients responded to treatment. Patient responses are shown and correlated with the stage of disease in Fig 2. Not surprisingly, patients with more advanced disease had fewer complete regressions than did those in whom the process was less extensive. Thus, all 6 patients with stage II lesions showed complete clinical remission at the end of the first cycle of treatment, whereas only 10 of 19 (53%) stage IV patients became clinically free of disease after the first cycle. It is convenient to consider these two categories, complete and partial remission, separately. COMPLETE
REMISSION
Twenty-two of the 37 patients (59.5%) had no clinical evidence of residual disease at the completion of the first cycle of chemotherapy and radiation. Early in the series, 8 patients underwent definitive resection (5 composite, 3 local); microscopic tumor was found in only 1 in an area of extensive bone erosion. We subsequently omitted surgery for patients who showed complete clinical remission after the first cycle of combined therapy except for those who had bony involvement at the time of diagnosis. Fourteen patients had no surgical procedure. A typical response is illustrated in Fig 3. There has been only 1 local recurrence among these patients, an inoperable recurrence of a stage IV retromolar lesion at 2 years. There were three other treatment failures in this group. Two patients died of systemic metastases, without evidence of local disease at the time of
370
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
FIGURE 3. A, The appearance of a T2 squamous cell carcinoma of the floor of the mouth and tongue in a 72year-old man photographed prior to treatment at the time of initial staging. B. The same patient following completion of the first cycle of therapy. This is a typical response as seen in all of the patients (58%) who experienced a complete clinical remission during the first treatment cycle.
death. Another patient died, without evidence of residual disease, of drug-related sepsis during her second cycle of combined therapy. Thus, of the 22 patients achieving a complete remission after the fast cycle of therapy, 19 (86%) remain free of disease. PARTIAL REMISSION Fourteen patients (38%) achieved only a partial remission at the completion of the first cycle of chemotherapy and radiation. We attempted surgical resection in 13 of these patients (the last patient re-
mained inoperable despite a partial response). It should be stressed that tive patients in this group, all with T4 lesions, had been considered inoperable when they entered this study and that 4 of these 5 were rendered resectable after chemoradiotherapy. Three of these 4 have remained free of disease. In 11 of the 13 resected patients, intraoperative surgical margins free of tumor on frozen section. The two patients with tumor at the surgical margins and the single patient who remained inoperable all have died of their local disease, as has one other patient, the youngest in our series, who had exten-
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sive involvement of the tongue. A fifth patient died of systemic metastases, free of local disease. Two other patients died of unrelated causes; both were free of tumor at the time of death. (Of the 37 patients reported here, 2 died of unrelated small cell cancer of the lung. The simultaneous presence, or later appearance, of pathologically separate carcinoma of the lung is seen fairly often.‘3*‘4) Thus, of the 14 partial responders, there were 5 treatment failures and 2 unrelated deaths; 9 of the 14 patients (64%) in this group were disease-free survivors. Neck dissections were performed either as the sole procedure or as part of a composite resection on 12 of these patients. Three of the patients had shown complete regression of the intraoral primary lesion during the first cycle of chemotherapy and radiation with persistence of cervical adenopathy. In these 3 patients modified neck dissection only, without resection of the primary intraoral site of disease, was carried out. The remaining 9 patients had neck dissection combined with excision of the primary intraoral site for persistent tumor. Classical neck dissections were necessary in two patients only; both had extensive nodal involvement with invasion of other structures in the neck. The remaining 7 patients underwent conservative neck dissection, usually consisting only of removal of the jugular nodes and the contents of the submaxillary triangle, ie, a modified supraomohyoid dissection, sparing the sternocleidomastoid muscle, jugular vein, and accessory nerve. It is noteworthy that not a single patient in this series had a recurrence in the neck regardless of the type of neck dissection performed. Evaluation of treated patients, based on the clinical findings at the end of the first treatment cycle, seems to be remarkably accurate. Biopsy is of limited usefulness. We have used it only in seven patients who had equivocal persistent thickening or incomplete healing in the region of the intraoral primary lesion. Negative biopsies mean little and are useful only insofar as they support clinical evaluation. No patient in this series who had a negative biopsy lat,er developed disease. Only one patient had a positive biopsy; microscopic disease was found, and a limited local resection followed by the scheduled second cycle of chemotherapy and radiation successfully eradicated the remaining tumor. At the completion of therapy we felt that 34 of the original 37 patients in this series were disease free (92%); 29 of these 34 patients remained disease free for an apparent overall cure rate of 78%. Finally, subtracting the two patients who died of unrelated disease, 27 patients (73%) of the original cohort of 37, are alive today, all apparently free of disease. Analysis of the entire patient cohort using the
“product limit” method of Kaplan and Meier14a predicts a disease-free survival of 76%, and an overall survival (death from all causes) of 54% with a median follow-up of more than 3 years. Discussion and Conclusions Multimodality therapy is emerging as effective treatment of squamous cell carcinoma of the head and neck, and particularly of the oral cavity.6,10 In our original protocol, all patients were scheduled to undergo surgery at the completion of the first cycle of chemotherapy and radiation. The decision to omit surgery for those patients who showed complete clinical remission at the end of the first cycle of treatment was a difficult one; a departure from established methods of surgical treatment in this disease seemed, at the time, heretical. We were certain that recurrences would surface. This simply has not happened with a follow-up now exceeding 5 years for some patients. Others recently have reached similar conclusions in treating head and neck cancer.‘5-‘7 To date, only one of our patients in whom surgery was omitted, a patient with an extensive, stage IV, retromolar trigone lesion, has had a recurrence. Although surgery was omitted in many of those patients who achieved complete remission after the first cycle of therapy, we felt, until we reviewed this series of patients, that surgery should be carried out on those who presented with clinically positive cervical nodes. However, we now believe the following: 1) dissection is unnecessary in patients who have no adenopathy after the first cycle of treatment, and 2) it is safe to separate the treatment of the primary lesion and of the cervical node-bearing area. Thus, if one or the other area is clinically negative at the end of the first cycle of therapy, surgery is not required for that site. We recognize, of course, that when optimum access to the mouth and jaw is through a neck incision that a limited neck dissection adds little morbidity to the operation. 3) We recommend composite resection for patients who present initially with bone involvement regardless of clinical findings at the completion of the first cycle as we have found localized microscopic disease in more than half of the patients with bony destruction. There may be objection that we have based our conclusions on inadequate follow-up. This does not seem to be a valid objection. Every recurrence in this series was predictable, given the nature of the disease at the time of the initial staging. Recurrences in all but a single case (which recurred at 2 years) appeared very promptly. Kaplan-Meier survival curves for this group of patients project a dis-
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ease-free survival rate of 76% at 5 years, a rate that compares favorably with traditional treatment using radiation, surgery, or a combination of both. (It is difficult to evaluate and compare results in the treatment of oral squamous cell carcinoma as there are many variables from series to series. Reported 5-year survival using surgery, radiation, or combinations of both, usually is in the vicinity of 65% for stage II, 45% for stage III, and 15% for stage IV disease.‘8T19 Survival rates using combined perioperative radiation and surgery tend to be higher; Silver et al 2o for example, have reported 60% survival for their’patients with stage III and IV disease.) It is too early yet to predict which combination of therapeutic agents will eventually prove to be best for treating squamous cell carcinoma of the head and neck. Nevertheless, protocols that we and others have described do seem effective. Clearly, chemotherapy coupled with radiation, plus surgery whenever it is indicated, is emerging as an acceptable means of treatment. Even though a survival advantage has not yet been conclusively demonstrated for patients treated with combined modalities, there are other evident advantages. For example, it appears that surgery was unnecessary for over half of the patients presented in this series. Our experience, as well as that of others, has shown that we may omit surgery for some patients and modify its scope for others.93’5-17 This is an intriguing possibility, for although we may minimize to some extent the surgical sequelae of ablative head and neck surgery by using modified (conservation, functional) neck dissection and by providing acceptable reconstruction after jaw and intraoral resections, surgery is still associated with cosmetic and functional impairment, a relatively high complication rate, and the inevitable suffering that attends any major surgical procedure. It is important to note that this was a nonrandomized, single-arm, phase II pilot study and that broad extrapolations from this data are difficult. Nonetheless, we believe that our indications for surgery following combined chemotherapy and radiation as outlined in this report are valid. We did not arrive at them lightly. During evolution of this study some patients underwent unnecessary and often extensive surgery. This permitted us, however, to delineate the surgical indications presented when preliminary chemotherapy and radiation are used. We hope that this experience may be useful to others with an interest in using combined modality therapy for intraoral squamous cell carcinoma. References 1. Adelstein DF, Hines JD, Sharan VM, et al: Combination chemotherapy prior to definitive local therapy in squa-
COMBINED THERAPY IN ORAL SQUAMOUS CARCINOMA
mous cell carcinoma of the head and neck. Oncology 42:80, 1985 2. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308:75, 1983 3. Mead GM. Jacobs C: Changing role of chemotherapy in treatment of head and neck cancer. Am J Med 73582, 1982 4. Rooney M, Kish J, Jacobs J, et al: Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120 hour S-FU infusion and cisplatin. Cancer 55:1123, 1985 5. Taylor SG IV: Head and neck cancer, in Pinedo HM, Longo DL, Chabner BA (eds): Cancer Chemotherapy and Biological Response Modifiers (annual 9). New York, NY, Elsevier Science, 1987, chap 15 6. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous radiotherapy and chemotherapy with 5fluorouracil and cisplatin for locally confined squamous cell head and neck cancer. NC1 Monogr 6:347, 1988 7. Leichman L, Nigro N. Vaitkevicius VK, et al: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78:211, 1985 8. Taylor SG IV, Murthy AK, Showel J. et al: Concomitant therapy with infusion or cisplatin and 5-fluorouracil plus radiation in head and neck cancer. NC1 Mongr 6:343,1988 9. Adelstein DJ, Sharan VM, Earle AS: Surgical modification or elimination after chemoradiotherapy for locally confined squamous cell head and neck cancer. Proceedings of the 2nd International Head and Neck Oncologv Research Conference. Arlington, VA, September 10-72, 1987, in Wolf GT, Carey TE (eds): Head and Neck Oncology Research. Amsterdam, The Netherlands, Kugler & Ghedini, 1988, pp 253-259 10. Adelstein DJ, Sharan VM, Earle AS, et al: Chemoradiotherapy as initial management in patients with squamous cell carcinoma of the head and neck. Cancer Treat Rep 70: 761, 1986 11. Adelstein DJ. Sharan VM, Earle AS, et al: Long-term results after chemoradiotherapy for locally confined squamous cell head and neck cancer. Am J Clin Oncol (in press) 12. Adelstein DF, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined modality therapy for squamous cell head and neck cancer. Proceedings of the Second International Conference on Head and Neck Cancer, Boston, MA, July 31-August 5, 1988 (abstr) 13. Lefor AT, Bredenberg CE, Kellman RM, et al: Multiple malignancies of the lung and head and neck. Arch Surg 121:265, 1986 14. Probert JC, Thompson RW. Bagshaw MA: Patterns of spread of distant metastases in head and neck cancer. Cancer 33: 127, 1974 14a. Kaplan EL, Meier P: Non parametric estimation from incomplete observation. J Am Statistical Assoc 53:457, 1958 15. Hong WK, Wolf GT, Fisher S. et al: A new strategy to preserve the larynx in the treatment of advanced laryngeal cancer: Preliminary report Proc. ASCO 6: 130, 1987 (abstr) 16. Haines IE, Bosl GJ, Ptister D, et al: Larynx preservation in patients with advanced squamous cell cancer of head and neck: recommendations for patient selection. Proc Am Sot Clin Oncol 6:133, 1987 (abst) 17. Jacobs C, Gofftnet DR, Gofftnet L, et al: Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer: a report from the Northem California Oncology Group. Cancer 60: 1178, 1987 18. Hirata RM, Jaques DA, Chambers RG, et al: Carcinoma of the oral cavity: An analysis of 478 cases. Ann Surg 182:98, 1975 19. Ildstad ST, Bigelow ME, Remensnyder JP: Intraoral cancer at the Massachusetts General Hospital. Squamous carcinoma of the floor of the mouth. Ann Surg 197:34, 1983 20. Silver CE, Glackin BK, Brauer et al: Surgical treatment of oral cavity carcinoma. Head Neck Surg 9: 13, 1986
