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Concomitant cisplatin and hyperfractionated external beam irradiation for advanced malignancy of the head and neck
Concomitant Cisplatin and Hyperfractionated External Beam Irradiation for Advanced Malignancy of the Head and Neck James Fontanesi,
MD,
Neal S. Beckford, Terry Eddy,
MD, BS,
Eric P. Lester, MD, Kevin T. Kavanaugh, Larry E. Kun, MD, Memphis. Tennessee
The combination of cisplatin and hyperfractionated external beam irradiation (HEBI) , followed by salvage surgery when indicated, was evaluated in patients with advanced stage squamous cell carcinoma of the head and neck. Thirty patients with stage III (n = 5) or IV (n = 25) disease received intravenous cisplatin 100 mg/m2 by 6-hour continuous infusion on days 1, 21, and 42 of HEBI. Radiation fractions of 110 cGy were given twice daily, separated by 4 to 6 hours, beginning within 12 hours after cisplatin delivery. Doses to the primary site ranged from 60 to 76.35 Gy (median: 72.3 Cy) , with 60 to 74 Gy to nodal sites. Follow-up ranged from 4 to 28 months (median: 19 months). Clinical complete response of the primary site was seen in 27 of 29 patients (93%), and complete clinical clearance of adenopathy in 20 of 26 (76%). A second biopsy 6 to 8 weeks after completion of treatment showed residual disease in both the primary and nodal sites in three patients, and in only the primary site in one patient. Four patients with persistent adenopathy had pathologic confirmation at surgery. Four patients had recurrence after negative biopsy results 6 to 9 months after treatment biopsy. At present, with median follow-up of 19 months, eight patients (26%) have died secondary to uncontrolled primary or nodal disease. Two patients have died of nonrelated causes. Overall, 10 of 30 patients (66%) remain alive with no evidence of disease. Mucositis and weight loss were the most common side effects of treatment. Seven patients developed significant xerostomia, and four have cisplatin-related hearing loss requiring amplification. The early evidence of excellent response (89% pathologic complete response of primary sites; 78% complete response of nodal sites), coupled with acceptable treatment morbidity, warrants further study of this approach.
From the Denartments of Radiation Oncology, University of Tennessee, Memphii, College of Medicine and St. &de Children’s Research Hospital (JF, DT, TE, LEK), and the Departments of Otolaryngology (NSB, KTK) and Medicine (EPL), University of Tennessee, Memphis, Tennessee. Requests for reprints should be addressed to James Fontanesi, MD, Department of Radiation Oncology, St. Jude Children’s Research Hcupital, 332 North Lauderdale, PO Box 318, Memphis, Tennessee 38101. Presented at the 37th Annual Meeting of the Society of Head and Neck Surgeons, Maui, Hawaii, May 1-4, 1991.
MD,
Doug Tai, Pho,
quamous cell carcinoma of the head and neck region S constitutes approximately 5% of all new malignancies diagnosed in the United States, with an estimated 38,000 new cases in 1990 [I]. Early stage lesions are usually treated successfully by surgery or radiation [2]. Unfortunately, a large proportion of patients present with advanced primary disease and/or regional nodal metastases [3]. Combination therapy with surgery and preop erative or postoperative irradiation has produced limited improvement in local control compared with either modality alone. Survival statistics remain discouraging, however, with 3-year survival estimates ranging from 10% to 40% [3-51. Current techniques of surgical extirpation and reconstruction permit removal of massive amounts of involved tissue with good functional results. However, extensive tumor debulking has not significantly affected local control or long-term survival. To improve this situation, several clinical trials have assessed the impact of adjuvant chemotherapy in patients with advanced stage lesions [6,7]. The addition of neoadjuvant chemotherapy often produces dramatic tumor shrinkage but has not been convincingly shown to improve local control or survival duration [8,9]. Recently, the use of specific antineoplastic agents (e.g., cisplatin) as radiosensitizers in combination with simultaneous irradiation has produced a marked clinical response [IO]. However, no significant improvement in overall survival has been reported. Altered radiation fractionation schemes, used in some earlier trials [I 1,121, have been reintroduced as an alternative to conventional once-daily irradiation, with the goal of improving local control rates in advanced stage head and neck cancers. These schemes rely on the differential response of tumor versus normal tissue, theoretically permitting delivery of the same dose or higher doses over an equivalent or even shorter period of time, with less severe late sequelae. To our knowledge, the combination of cisplatin with hyperfractionated external beam irradiation (HEBI) has not been evaluated previously in the treatment of advanced squamous cell carcinoma of the head and neck. We therefore initiated a study of HEBI plus intravenous cisplatin in patients with advanced squamous cell carcinoma. Clinical response rates, results of posttreatment pathologic evaluation, response to salvage surgery, treatment complications, and duration of local control were assessed in this prospective study. PATIENTS
AND METHODS
From July 1988 through January 1,1991,33 patients with previously untreated stage III and IV tumors of the head and neck (excluding the esophagus) were treated on
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TABLE I Response at End of Treatment (Clinical) and at Pathologic Evaluation (n = 30) Pathologic Response
Clinical Response CR Primary disease TX Tl T2 T3 T4
PR
CR
1
-
1
7 19
1 1
6 19
2 4
Positive Disease
2 1
30% of the initial two-dimension tumor measurement on physical examination and/or diagnostic imaging. Six to eight weeks after therapy was completed, panendoscopy was again performed and multiple specimens were taken from the previously noted tumor-bearing areas. (Two patients died of infectious complications before posttreatment panendoscopy and are not included in the analysis of response.) The remaining patients were then followed monthly (median follow-up: 19 months; range: 4 to 31 months). RESULTS Patient
a protocol approved by the appropriate institutibnal review boards. Cancer staging was in accordance with the American Joint Committee for Cancer Staging and EndResults Reporting. All patients had diagnostic studies that included a chest radiograph, barium swallow, computed tomographic scan of the upper aerodigestive tract, and routine blood tests including measurement of magnesium levels and 24-hour creatinine clearance. Patients then underwent panendoscopy with multiple biopsies for tumor mapping. After histopathologic confirmation of squamous cell carcinoma and of the absence of distant metastases, patients were told of their eligibility for this protocol and informed consent was obtained. Treatment: Cisplatin, 100 mg/m2, was given by continuous intravenous infusion over 6 hours on days 1, 2 1, and 42 of treatment. Antiemetics and other supportive therapy were used routinely. Radiotherapy, initiated within 12 hours of the first course of cisplatin, was administered twice daily in fractions of 110 cGy separated by 4 to 6 hours. All patients underwent evaluation of tumor reduction after receiving a total radiation dose of 60 to 76.35 Gy. For patients who did not demonstrate a greater than 70% reduction of primary and/or nodal disease, salvage surgery within 4 weeks was recommended. If tumor reduction greater than 70% was obtained, radiation was continued to final doses of 68 to 74 Gy. A minimum dose of 60 Gy was delivered to nodal sites. If no evidence of measurable disease was noted on physical examination or diagnostic imaging after completion of HEBI, a complete clinical response was recorded. Partial clinical response was defined as residual disease measuring greater than
characteristics: Thirty patients were evaluable for toxicity and response to therapy per protocol. Twenty-five patients presented with stage IV disease and 5 with stage III disease. There were 28 men and 2 women; 19 patients were black. Ages ranged from 26 to 74 years old. The most frequent primary sites were the oropharynx (n = 9) and hypopharynx (n = 9), followed by the oral cavity (n = 5), larynx (n = 4), nasopharynx (n = 2), and unknown primary site (n = 1). Response of primary disease: Twenty-nine patients had known primary disease sites and underwent posttreatment evaluation. Two patients had a clinical partial response to HEBI plus cisplatin. One had less than 70% tumor reduction after receiving 60 Gy and underwent salvage surgery. Pathologic evaluation documented persistent primary disease and nodal involvement. The second patient (total radiation dose: 74 Gy) had biopsynegative posttreatment endoscopic findings. The remaining 27 primary sites were clinically rated as complete responses. At posttreatment biopsy, two patients considered to have clinical complete responses were found to have persistent disease in hypopharyngeal primaries. Both patients died. Overall, a pathologic complete response was documented in 26 patients (89%). During follow-up, recurrence was identified in three patients who had negative endoscopic biopsy results at 8 weeks. One of these patients, who presented with a retromolar trigone primary, had a recurrence in the vallecula at 6 months, underwent salvage surgery, and died at 18 months. A second patient had recurrent disease in an oral cavity primary site at 9 months. This patient is alive without evidence of disease 4 months after salvage surgery. The third patient, who had a recurrence of a primary in the base of the tongue, refused surgery and died of progressive disease at 11 months. Thus, 24 of 29 patients (83%) currently have controlled primary disease. Clinical and pathologic responses based on tumor (T) stage, nodal (N) stage, and primary tumor site are reviewed in Table I. Nodal disease: Of the 26 patients who presented with evidence of nodal involvement, 6 had persistent adenop athy 6 to 8 weeks after completion of HEBI. Two patients with pathologic residual primary disease also had residual nodal disease. A single patient had a pathologic complete response of the primary site but biopsy proven persistent nodal involvement. Three patients thought to have had a partial response of nodal disease at completion of therapy underwent radical neck dissection or biopsy; in
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Nodal disease NO Nl N2 N3 Site Oral cavity Oropharynx Hypopharynx larynx Nasophalynx Neck/unknown
4
-
4
-
9 9 2
-
9 0 5
3 1
4 a 6 4
1 1 3 -
2 1
-
5 7 7 4
1 2 2 -
2 -
1
primary
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each case, there was no evidence of nodal disease. One patient rated as having had a partial clinical response of a hypopharyngeal primary and a complete clinical response of nodal sites was eventually found to have residual primary and nodal disease at surgical salvage. One patient developed recurrent disease in the lymph nodes 6 months after pathologic documentation of a complete response. This patient underwent radical neck dissection and further radiotherapy and is alive without evidence of disease 14 months after surgical salvage. Overall, eight patients have undergone radical neck dissection or biopsy for persistent and/or recurrent disease; three were found to have no evidence of disease in nodal sites. Disease in other sites: Two patients died of pulmonary disease. In one case, biopsy examination revealed metastases from a previously treated colon adenccarcinoma that was thought to be in complete remission. The second patient had a single lung lesion that was a biopsy proven squamous cell carcinoma; the primary site remained in control at the patient’s death (11 months posttreatment), with no other evidence of metastatic disease. Toxicity: Treatment-related toxicities for all 33 patients enrolled in the protocol are reviewed. In general, toxicity was considered acceptable. There was one death from acute renal failure 2 months after completion of cisplatin administration. Three patients died of infectious pneumonia while experiencing low absolute neutrophil counts, each with clinical complete response. Five patients had transient hematologic toxicity requiring delays in the delivery of cisplatin. Four of these patients were unable to complete the third cycle of cisplatin because of low absolute neutrophil counts or poor Kamofsky performance status (one patient had delirium tremens secondary to alcohol cessation). Eight of the first 10 patients enrolled had grade IV (Radiation Therapy Oncology Group grading system) mucositis by week 3 of treatment, and 3 required treatment delays of up to 10 days. These patients had all received an investigational antiemetic agent that was thought to have contributed to the severe mucosal toxicity. Although this association is speculative at this point, grade IV mucositis was seen in only 2 of the remaining 20 patients, who received standard antiemetic regimens. There were no additional therapy delays because of mucositis. Severe xerostomia (preventing the placement of dentures) occurred in seven patients. Soft tissue injury was seen in five patients at the completion of therapy. One patient developed laryngeal chondritis 3 months after completion of radiotherapy, which caused severe pain and dysphagia and required a total laryngectomy. A second patient (TX, N3a) with persistent disease after treatment had wound dehiscence 2’S weeks after radical right neck dissection; with aggressive local care, the wound healed in 1 month. In a third patient, a small pharyngocutaneous listula developed after total laryngectomy and resolved with local care and hyperbaric oxygen. The otolaryngologist who performed salvage surgery did not consider the tissue turgor present after hyperfractionated irradiation plus cisplatin to be significantly different from that seen with preoperative irradiation alone. THE AMERICAN
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Four patients developed high-frequency hearing loss requiring amplification. Weight loss, which ranged from 4 to 25 pounds (4% to 20% of body weight at diagnosis), was a significant side effect of therapy. In all cases, body weight has returned to within 4% of weight at presentation. COMMENTS
Improvements in local control and cure of advanced head and neck squamous cell carcinoma have been elusive. Neoadjuvant chemotherapy has produced high rates of response but has not been conclusively proven superior to conventional therapy in terms of local control and overall survival [6,7,13]. However, a recent report from the Head and Neck Contracts Program reported a significant decrease in distant metastasis among patients who had received adjuvant chemotherapy [14]. Fu et al [9] also reported a trend toward improvement in overall survival with concomitant administration of bleomycin and radiation. The use of chemotherapy to enhance radiobiologic effects holds promise for enhancing locoregional control. In prechnical studies, cisplatin inhibited cell recovery from radiation damage through a number of mechanisms [ 151. This finding may result from effects present at the time of irradiation, including intracellular formation of reactive free radicals or altered binding of platinum complexes to DNA, which has been detected in both oxygenated and hypoxic cells [15,16]. There may also be inhibition of repair of potentially lethal damage [15,17]. The dose of cisplatin used in the present study (100 mg/m*) was determined in part from information documenting drug concentrations of 2 to 10 pg/g in tissue 2 to 10 hours after a similar dose of cisplatin [I8]. These concentrations are similar to those used in laboratory experiments documenting radiation enhancement by cisplatin. Phase II studies of concurrent cisplatin and once-daily radiotherapy have yielded promising early results suggesting improved local and regional responses to therapy. Al-Sarraf et al 1191 used high-dose cisplatin (similar to that used in this study) with conventional daily radiotherapy (66 to 74 Gy) and documented a complete response rate of 69% in 124 patients. Wendt et al [20] reported a complete response rate of 88% in 34 patients who received cisplatin and accelerated fraction radiation. Both cisplatin and radiotherapy were generally well tolerated. Preliminary data from more recent studies (presented at the Third International Head and Neck Oncology Conference) are similar to the aforementioned results. Harrison et al [21] described a protocol using a “field within a field” boosting technique, with cisplatin given on days 1 and 22. Radiation was administered once daily during weeks 1 through 4, delivering 1.8 Gy per fraction to large portals that included gross disease in all areas at risk. During weeks 5 and 6, radiation was given twice daily to overcome the projected accelerated tumor growth, with a morning fraction of 1.8 Gy to the entire area at risk and an afternoon dose of 1.6 Gy limited to the area of gross disease. A total dose of 70 Gy was delivered in 6 weeks. Among 22 patients evaluable for response, 14 (64%) had a complete response and 7 (32%) a partial
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At 1 year, actuarial survival was 69% and local progression-free survival was 56%. Giri et al [22] treated 20 patients with accelerated fraction radiation and concomitant cisplatin. The primary site and all areas at risk for microscopic disease were treated with 1.7 Gy in the morning; 6 hours later, 1.1 Gy was given to a boost volume that included the primary and enlarged nodes with a 2-cm margin. Cisplatin (100 mg/m2) was given as a bolus on days 1,28, and 56. The complete response rate in 19 evaluable patients was 68%. Eighteen patients demonstrated local control of primary sites, with local control of nodal sites achieved in 12 of 15 patients. The clinical complete response rate in this series (primary site 27 of 29 patients; nodal site 20 of 26) compares favorably with other recent studies, although the absence of data on pathologic complete response rates in prior series hinders comparisons. In the current study, biopsies 6 to 8 weeks after completion of therapy showed no evidence of disease in 26 of 29 primary sites; 78% of patients with adenopathy at diagnosis showed no pathologic evidence of tumor at posttreatment biopsy. The decision to use a hyperfractionation technique was based on the difference in response of normal versus malignant tissue and early- versus late-responding tissue to radiation fraction size. The use of multiple small-dose fractions enhances the tolerance of late-reacting tissue. Thus, a similar or larger total dose can be given in a shorter period of time with similar early toxicity and decreased late toxicity. Despite the additional tissue trauma produced by a higher-than-normal radiation dose, patients generally were able to tolerate the protocol. Mucositis was the most common side effect, but it was not markedly more frequent or severe than in other neoadjuvant chemotherapy protocols for squamous cell carcinoma of the head and neck. The precise timing of chemotherapy in this protocol, with the initiation of HEBI immediately after chemo therapy, was dictated by considerations of pharmacologic and radiobiologic efficacy as well as patient and nursing convenience. The protocol presented herein utilized concurrent chemotherapy with hyperfractionated irradiation in order to maximize the potential for tumor cell kill and increased local control. To date, this is the only study of which we are aware that has incorporated a true hyperfractionated radiation technique with concomitant cisplatin. By mandating pathologic evaluation of response and surgical intervention in patients in whom there is an unsatisfactory response to combination therapy, this protocol provides patients with the best possible chance of disease control in the setting of experimental adjuvant therapy. Further evaluation of the treatment of advanced upper aerodigestive tract squamous cell carcinoma with hyperfractionated irradiation and high-dose cisplatin is warranted. response.
REFERENCES 1. SilverbergE, Lubera JA. Cancer statistics. CA 1988; 38: S-22. 2. Harwood AR, Hawkins NV, Rider WD, et al. Radiotherapy of
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early glottic cancer-I. Int J Radiat Oncol Biol Phys 1976; 5: 473-6. 3. Gowan GF, Nagy DG. The incidence and sites of distant metastases in head and neck carcinoma. Surg Gynecol Obstet 1953; 116: 603-7. 4. Baker JL, Fletcher GH. Time, dose, and tumor volume relationships in megavoltage irradiation of squamous cell carcinomas of the retromolar trigone and anterior tonsillar pillar. Int J Radiat Oncol Biol Phys 1976; 2: 407-14. 5. Cardinale F, Fisher JJ. Radiation therapy of carcinoma of the tonsil. Cancer 1977; 39: 604-8. 6. Decker DA, Dreilichman A, Jacobs J, et al. Adjuvant chemotherapy with cis-diammincdichloroplatinum II and 120-hour infusion S-fluorouracil in stage III and IV squamous cell carcinoma of the head and neck. Cancer 1983; 51: 1353-S. 7. Rooney M, Kish J, Jacobs J, ef al. Improved complete response rate and survival in advanced head and neck cancer after threecourse induction therapy with 120-hour S-FU infusion and cisplatin. Cancer 1985; 55: 1123-8. 8. Clark JR, Frei E. Chemotherapy for head and neck cancer: progress and controversy in the management of patients with MO disease. Semin Oncol 1989; 16: 4457. 9. Fu KK, Phillips TL, Silverberg IJ, ef al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987; 5: 1410-8. 10. Slotman GJ, Cummings FJ, Glicksman CL, et al. Preoperative simultaneously administered cis-platinum plus radiation therapy for advanced squamous cell carcinoma of the head and neck. Head Neck Surg 1986; 8: 159-64. 11. Wang CC, Blitzer PH, Suit HD. Twice-a-day radiation therapy for cancer of the head and neck Cancer 1985; 55: 2100-4. 12. Withers HR, Peters L, Thames H, et al. Hyperfractionation. Int J Radiat Oncol Biol Phys 1982; 8: 1807-g. 13. Taylor SO, Applebaum E, Showel JL, et al. A randomized trial of adjuvant chemotherapy in head and neck cancer. J Clin Oncol 1985; 3: 672-9. 14. Adjuvant chemotherapy for advanced head and neck squamous carcinoma: a final report of the Head and Neck Contracts Program. Cancer 1987; 60: 301-11. 15. Nias AH. Radiation and platinum drug interaction. Int J Radiat Biol Relat Stud Phys Chem Med 1985; 48: 297-314. 16. Coughclin CT, Richmond RC. Biological and clinical developments of cisplatin combined with radiation: concepts, utility, projections for new trials, and the emergence of carboplatin. Semin Oncol 1989; 16: 31-43. 17. Dritschilo A, Piro AJ, Kellman AD. The effect of cis-platinum on the repair of radiation damage in plateau phase Chinese hamster (V70) cells. Int J Radiat Oncol Biol Phys 1979; 5: 1345-9. 18. Mattox DE, Stemson LA, Von Hoff DD, Kuhn JG, Repta AJ. Tumor concentration of platinum in patients with head and neck cancer. Otolaryngol Head Neck Surg 1983; 91: 271-5. 19. Al-Sarraf M, Pajak TF, Marcia1 VA, et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck an RTOG study. Cancer 1987; 59: 259-65. 20. Wendt TG, Wustrow TPU, Hartenstein RC, Rohloff R, Trott KR. Accelerated split course radiotherapy and simultaneous cisdichlorodiammine-platinum and 5-fluorouracil chemotherapy with folinic acid enhancement for unresectable carcinoma of the head and neck. Radiother Oncol 1987; 10: 277-84. 21. Harrison L, Bcsl G, Fass D, et al. A new chemo-radiation program for advanced unresectable head and neck cancer [abstract 1.41. Presented at the Third International Head and Neck Oncology Research Conference, Las Vegas, September 1990. 22. Giri PG, Taylor S, Gemer L, et al. Accelerated fractionation radiation therapy and concurrent chemotherapy in advanced squamous cell cancers of the head and neck [abstract 1.81. Presented at the Third International Head and Neck Oncology Research Conference, Las Vegas, September 1990.
VOLUME 162 OCTOBER 1991
MD,
Neal S. Beckford, Terry Eddy,
MD, BS,
Eric P. Lester, MD, Kevin T. Kavanaugh, Larry E. Kun, MD, Memphis. Tennessee
The combination of cisplatin and hyperfractionated external beam irradiation (HEBI) , followed by salvage surgery when indicated, was evaluated in patients with advanced stage squamous cell carcinoma of the head and neck. Thirty patients with stage III (n = 5) or IV (n = 25) disease received intravenous cisplatin 100 mg/m2 by 6-hour continuous infusion on days 1, 21, and 42 of HEBI. Radiation fractions of 110 cGy were given twice daily, separated by 4 to 6 hours, beginning within 12 hours after cisplatin delivery. Doses to the primary site ranged from 60 to 76.35 Gy (median: 72.3 Cy) , with 60 to 74 Gy to nodal sites. Follow-up ranged from 4 to 28 months (median: 19 months). Clinical complete response of the primary site was seen in 27 of 29 patients (93%), and complete clinical clearance of adenopathy in 20 of 26 (76%). A second biopsy 6 to 8 weeks after completion of treatment showed residual disease in both the primary and nodal sites in three patients, and in only the primary site in one patient. Four patients with persistent adenopathy had pathologic confirmation at surgery. Four patients had recurrence after negative biopsy results 6 to 9 months after treatment biopsy. At present, with median follow-up of 19 months, eight patients (26%) have died secondary to uncontrolled primary or nodal disease. Two patients have died of nonrelated causes. Overall, 10 of 30 patients (66%) remain alive with no evidence of disease. Mucositis and weight loss were the most common side effects of treatment. Seven patients developed significant xerostomia, and four have cisplatin-related hearing loss requiring amplification. The early evidence of excellent response (89% pathologic complete response of primary sites; 78% complete response of nodal sites), coupled with acceptable treatment morbidity, warrants further study of this approach.
From the Denartments of Radiation Oncology, University of Tennessee, Memphii, College of Medicine and St. &de Children’s Research Hospital (JF, DT, TE, LEK), and the Departments of Otolaryngology (NSB, KTK) and Medicine (EPL), University of Tennessee, Memphis, Tennessee. Requests for reprints should be addressed to James Fontanesi, MD, Department of Radiation Oncology, St. Jude Children’s Research Hcupital, 332 North Lauderdale, PO Box 318, Memphis, Tennessee 38101. Presented at the 37th Annual Meeting of the Society of Head and Neck Surgeons, Maui, Hawaii, May 1-4, 1991.
MD,
Doug Tai, Pho,
quamous cell carcinoma of the head and neck region S constitutes approximately 5% of all new malignancies diagnosed in the United States, with an estimated 38,000 new cases in 1990 [I]. Early stage lesions are usually treated successfully by surgery or radiation [2]. Unfortunately, a large proportion of patients present with advanced primary disease and/or regional nodal metastases [3]. Combination therapy with surgery and preop erative or postoperative irradiation has produced limited improvement in local control compared with either modality alone. Survival statistics remain discouraging, however, with 3-year survival estimates ranging from 10% to 40% [3-51. Current techniques of surgical extirpation and reconstruction permit removal of massive amounts of involved tissue with good functional results. However, extensive tumor debulking has not significantly affected local control or long-term survival. To improve this situation, several clinical trials have assessed the impact of adjuvant chemotherapy in patients with advanced stage lesions [6,7]. The addition of neoadjuvant chemotherapy often produces dramatic tumor shrinkage but has not been convincingly shown to improve local control or survival duration [8,9]. Recently, the use of specific antineoplastic agents (e.g., cisplatin) as radiosensitizers in combination with simultaneous irradiation has produced a marked clinical response [IO]. However, no significant improvement in overall survival has been reported. Altered radiation fractionation schemes, used in some earlier trials [I 1,121, have been reintroduced as an alternative to conventional once-daily irradiation, with the goal of improving local control rates in advanced stage head and neck cancers. These schemes rely on the differential response of tumor versus normal tissue, theoretically permitting delivery of the same dose or higher doses over an equivalent or even shorter period of time, with less severe late sequelae. To our knowledge, the combination of cisplatin with hyperfractionated external beam irradiation (HEBI) has not been evaluated previously in the treatment of advanced squamous cell carcinoma of the head and neck. We therefore initiated a study of HEBI plus intravenous cisplatin in patients with advanced squamous cell carcinoma. Clinical response rates, results of posttreatment pathologic evaluation, response to salvage surgery, treatment complications, and duration of local control were assessed in this prospective study. PATIENTS
AND METHODS
From July 1988 through January 1,1991,33 patients with previously untreated stage III and IV tumors of the head and neck (excluding the esophagus) were treated on
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TABLE I Response at End of Treatment (Clinical) and at Pathologic Evaluation (n = 30) Pathologic Response
Clinical Response CR Primary disease TX Tl T2 T3 T4
PR
CR
1
-
1
7 19
1 1
6 19
2 4
Positive Disease
2 1
30% of the initial two-dimension tumor measurement on physical examination and/or diagnostic imaging. Six to eight weeks after therapy was completed, panendoscopy was again performed and multiple specimens were taken from the previously noted tumor-bearing areas. (Two patients died of infectious complications before posttreatment panendoscopy and are not included in the analysis of response.) The remaining patients were then followed monthly (median follow-up: 19 months; range: 4 to 31 months). RESULTS Patient
a protocol approved by the appropriate institutibnal review boards. Cancer staging was in accordance with the American Joint Committee for Cancer Staging and EndResults Reporting. All patients had diagnostic studies that included a chest radiograph, barium swallow, computed tomographic scan of the upper aerodigestive tract, and routine blood tests including measurement of magnesium levels and 24-hour creatinine clearance. Patients then underwent panendoscopy with multiple biopsies for tumor mapping. After histopathologic confirmation of squamous cell carcinoma and of the absence of distant metastases, patients were told of their eligibility for this protocol and informed consent was obtained. Treatment: Cisplatin, 100 mg/m2, was given by continuous intravenous infusion over 6 hours on days 1, 2 1, and 42 of treatment. Antiemetics and other supportive therapy were used routinely. Radiotherapy, initiated within 12 hours of the first course of cisplatin, was administered twice daily in fractions of 110 cGy separated by 4 to 6 hours. All patients underwent evaluation of tumor reduction after receiving a total radiation dose of 60 to 76.35 Gy. For patients who did not demonstrate a greater than 70% reduction of primary and/or nodal disease, salvage surgery within 4 weeks was recommended. If tumor reduction greater than 70% was obtained, radiation was continued to final doses of 68 to 74 Gy. A minimum dose of 60 Gy was delivered to nodal sites. If no evidence of measurable disease was noted on physical examination or diagnostic imaging after completion of HEBI, a complete clinical response was recorded. Partial clinical response was defined as residual disease measuring greater than
characteristics: Thirty patients were evaluable for toxicity and response to therapy per protocol. Twenty-five patients presented with stage IV disease and 5 with stage III disease. There were 28 men and 2 women; 19 patients were black. Ages ranged from 26 to 74 years old. The most frequent primary sites were the oropharynx (n = 9) and hypopharynx (n = 9), followed by the oral cavity (n = 5), larynx (n = 4), nasopharynx (n = 2), and unknown primary site (n = 1). Response of primary disease: Twenty-nine patients had known primary disease sites and underwent posttreatment evaluation. Two patients had a clinical partial response to HEBI plus cisplatin. One had less than 70% tumor reduction after receiving 60 Gy and underwent salvage surgery. Pathologic evaluation documented persistent primary disease and nodal involvement. The second patient (total radiation dose: 74 Gy) had biopsynegative posttreatment endoscopic findings. The remaining 27 primary sites were clinically rated as complete responses. At posttreatment biopsy, two patients considered to have clinical complete responses were found to have persistent disease in hypopharyngeal primaries. Both patients died. Overall, a pathologic complete response was documented in 26 patients (89%). During follow-up, recurrence was identified in three patients who had negative endoscopic biopsy results at 8 weeks. One of these patients, who presented with a retromolar trigone primary, had a recurrence in the vallecula at 6 months, underwent salvage surgery, and died at 18 months. A second patient had recurrent disease in an oral cavity primary site at 9 months. This patient is alive without evidence of disease 4 months after salvage surgery. The third patient, who had a recurrence of a primary in the base of the tongue, refused surgery and died of progressive disease at 11 months. Thus, 24 of 29 patients (83%) currently have controlled primary disease. Clinical and pathologic responses based on tumor (T) stage, nodal (N) stage, and primary tumor site are reviewed in Table I. Nodal disease: Of the 26 patients who presented with evidence of nodal involvement, 6 had persistent adenop athy 6 to 8 weeks after completion of HEBI. Two patients with pathologic residual primary disease also had residual nodal disease. A single patient had a pathologic complete response of the primary site but biopsy proven persistent nodal involvement. Three patients thought to have had a partial response of nodal disease at completion of therapy underwent radical neck dissection or biopsy; in
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Nodal disease NO Nl N2 N3 Site Oral cavity Oropharynx Hypopharynx larynx Nasophalynx Neck/unknown
4
-
4
-
9 9 2
-
9 0 5
3 1
4 a 6 4
1 1 3 -
2 1
-
5 7 7 4
1 2 2 -
2 -
1
primary
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each case, there was no evidence of nodal disease. One patient rated as having had a partial clinical response of a hypopharyngeal primary and a complete clinical response of nodal sites was eventually found to have residual primary and nodal disease at surgical salvage. One patient developed recurrent disease in the lymph nodes 6 months after pathologic documentation of a complete response. This patient underwent radical neck dissection and further radiotherapy and is alive without evidence of disease 14 months after surgical salvage. Overall, eight patients have undergone radical neck dissection or biopsy for persistent and/or recurrent disease; three were found to have no evidence of disease in nodal sites. Disease in other sites: Two patients died of pulmonary disease. In one case, biopsy examination revealed metastases from a previously treated colon adenccarcinoma that was thought to be in complete remission. The second patient had a single lung lesion that was a biopsy proven squamous cell carcinoma; the primary site remained in control at the patient’s death (11 months posttreatment), with no other evidence of metastatic disease. Toxicity: Treatment-related toxicities for all 33 patients enrolled in the protocol are reviewed. In general, toxicity was considered acceptable. There was one death from acute renal failure 2 months after completion of cisplatin administration. Three patients died of infectious pneumonia while experiencing low absolute neutrophil counts, each with clinical complete response. Five patients had transient hematologic toxicity requiring delays in the delivery of cisplatin. Four of these patients were unable to complete the third cycle of cisplatin because of low absolute neutrophil counts or poor Kamofsky performance status (one patient had delirium tremens secondary to alcohol cessation). Eight of the first 10 patients enrolled had grade IV (Radiation Therapy Oncology Group grading system) mucositis by week 3 of treatment, and 3 required treatment delays of up to 10 days. These patients had all received an investigational antiemetic agent that was thought to have contributed to the severe mucosal toxicity. Although this association is speculative at this point, grade IV mucositis was seen in only 2 of the remaining 20 patients, who received standard antiemetic regimens. There were no additional therapy delays because of mucositis. Severe xerostomia (preventing the placement of dentures) occurred in seven patients. Soft tissue injury was seen in five patients at the completion of therapy. One patient developed laryngeal chondritis 3 months after completion of radiotherapy, which caused severe pain and dysphagia and required a total laryngectomy. A second patient (TX, N3a) with persistent disease after treatment had wound dehiscence 2’S weeks after radical right neck dissection; with aggressive local care, the wound healed in 1 month. In a third patient, a small pharyngocutaneous listula developed after total laryngectomy and resolved with local care and hyperbaric oxygen. The otolaryngologist who performed salvage surgery did not consider the tissue turgor present after hyperfractionated irradiation plus cisplatin to be significantly different from that seen with preoperative irradiation alone. THE AMERICAN
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Four patients developed high-frequency hearing loss requiring amplification. Weight loss, which ranged from 4 to 25 pounds (4% to 20% of body weight at diagnosis), was a significant side effect of therapy. In all cases, body weight has returned to within 4% of weight at presentation. COMMENTS
Improvements in local control and cure of advanced head and neck squamous cell carcinoma have been elusive. Neoadjuvant chemotherapy has produced high rates of response but has not been conclusively proven superior to conventional therapy in terms of local control and overall survival [6,7,13]. However, a recent report from the Head and Neck Contracts Program reported a significant decrease in distant metastasis among patients who had received adjuvant chemotherapy [14]. Fu et al [9] also reported a trend toward improvement in overall survival with concomitant administration of bleomycin and radiation. The use of chemotherapy to enhance radiobiologic effects holds promise for enhancing locoregional control. In prechnical studies, cisplatin inhibited cell recovery from radiation damage through a number of mechanisms [ 151. This finding may result from effects present at the time of irradiation, including intracellular formation of reactive free radicals or altered binding of platinum complexes to DNA, which has been detected in both oxygenated and hypoxic cells [15,16]. There may also be inhibition of repair of potentially lethal damage [15,17]. The dose of cisplatin used in the present study (100 mg/m*) was determined in part from information documenting drug concentrations of 2 to 10 pg/g in tissue 2 to 10 hours after a similar dose of cisplatin [I8]. These concentrations are similar to those used in laboratory experiments documenting radiation enhancement by cisplatin. Phase II studies of concurrent cisplatin and once-daily radiotherapy have yielded promising early results suggesting improved local and regional responses to therapy. Al-Sarraf et al 1191 used high-dose cisplatin (similar to that used in this study) with conventional daily radiotherapy (66 to 74 Gy) and documented a complete response rate of 69% in 124 patients. Wendt et al [20] reported a complete response rate of 88% in 34 patients who received cisplatin and accelerated fraction radiation. Both cisplatin and radiotherapy were generally well tolerated. Preliminary data from more recent studies (presented at the Third International Head and Neck Oncology Conference) are similar to the aforementioned results. Harrison et al [21] described a protocol using a “field within a field” boosting technique, with cisplatin given on days 1 and 22. Radiation was administered once daily during weeks 1 through 4, delivering 1.8 Gy per fraction to large portals that included gross disease in all areas at risk. During weeks 5 and 6, radiation was given twice daily to overcome the projected accelerated tumor growth, with a morning fraction of 1.8 Gy to the entire area at risk and an afternoon dose of 1.6 Gy limited to the area of gross disease. A total dose of 70 Gy was delivered in 6 weeks. Among 22 patients evaluable for response, 14 (64%) had a complete response and 7 (32%) a partial
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At 1 year, actuarial survival was 69% and local progression-free survival was 56%. Giri et al [22] treated 20 patients with accelerated fraction radiation and concomitant cisplatin. The primary site and all areas at risk for microscopic disease were treated with 1.7 Gy in the morning; 6 hours later, 1.1 Gy was given to a boost volume that included the primary and enlarged nodes with a 2-cm margin. Cisplatin (100 mg/m2) was given as a bolus on days 1,28, and 56. The complete response rate in 19 evaluable patients was 68%. Eighteen patients demonstrated local control of primary sites, with local control of nodal sites achieved in 12 of 15 patients. The clinical complete response rate in this series (primary site 27 of 29 patients; nodal site 20 of 26) compares favorably with other recent studies, although the absence of data on pathologic complete response rates in prior series hinders comparisons. In the current study, biopsies 6 to 8 weeks after completion of therapy showed no evidence of disease in 26 of 29 primary sites; 78% of patients with adenopathy at diagnosis showed no pathologic evidence of tumor at posttreatment biopsy. The decision to use a hyperfractionation technique was based on the difference in response of normal versus malignant tissue and early- versus late-responding tissue to radiation fraction size. The use of multiple small-dose fractions enhances the tolerance of late-reacting tissue. Thus, a similar or larger total dose can be given in a shorter period of time with similar early toxicity and decreased late toxicity. Despite the additional tissue trauma produced by a higher-than-normal radiation dose, patients generally were able to tolerate the protocol. Mucositis was the most common side effect, but it was not markedly more frequent or severe than in other neoadjuvant chemotherapy protocols for squamous cell carcinoma of the head and neck. The precise timing of chemotherapy in this protocol, with the initiation of HEBI immediately after chemo therapy, was dictated by considerations of pharmacologic and radiobiologic efficacy as well as patient and nursing convenience. The protocol presented herein utilized concurrent chemotherapy with hyperfractionated irradiation in order to maximize the potential for tumor cell kill and increased local control. To date, this is the only study of which we are aware that has incorporated a true hyperfractionated radiation technique with concomitant cisplatin. By mandating pathologic evaluation of response and surgical intervention in patients in whom there is an unsatisfactory response to combination therapy, this protocol provides patients with the best possible chance of disease control in the setting of experimental adjuvant therapy. Further evaluation of the treatment of advanced upper aerodigestive tract squamous cell carcinoma with hyperfractionated irradiation and high-dose cisplatin is warranted. response.
REFERENCES 1. SilverbergE, Lubera JA. Cancer statistics. CA 1988; 38: S-22. 2. Harwood AR, Hawkins NV, Rider WD, et al. Radiotherapy of
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early glottic cancer-I. Int J Radiat Oncol Biol Phys 1976; 5: 473-6. 3. Gowan GF, Nagy DG. The incidence and sites of distant metastases in head and neck carcinoma. Surg Gynecol Obstet 1953; 116: 603-7. 4. Baker JL, Fletcher GH. Time, dose, and tumor volume relationships in megavoltage irradiation of squamous cell carcinomas of the retromolar trigone and anterior tonsillar pillar. Int J Radiat Oncol Biol Phys 1976; 2: 407-14. 5. Cardinale F, Fisher JJ. Radiation therapy of carcinoma of the tonsil. Cancer 1977; 39: 604-8. 6. Decker DA, Dreilichman A, Jacobs J, et al. Adjuvant chemotherapy with cis-diammincdichloroplatinum II and 120-hour infusion S-fluorouracil in stage III and IV squamous cell carcinoma of the head and neck. Cancer 1983; 51: 1353-S. 7. Rooney M, Kish J, Jacobs J, ef al. Improved complete response rate and survival in advanced head and neck cancer after threecourse induction therapy with 120-hour S-FU infusion and cisplatin. Cancer 1985; 55: 1123-8. 8. Clark JR, Frei E. Chemotherapy for head and neck cancer: progress and controversy in the management of patients with MO disease. Semin Oncol 1989; 16: 4457. 9. Fu KK, Phillips TL, Silverberg IJ, ef al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987; 5: 1410-8. 10. Slotman GJ, Cummings FJ, Glicksman CL, et al. Preoperative simultaneously administered cis-platinum plus radiation therapy for advanced squamous cell carcinoma of the head and neck. Head Neck Surg 1986; 8: 159-64. 11. Wang CC, Blitzer PH, Suit HD. Twice-a-day radiation therapy for cancer of the head and neck Cancer 1985; 55: 2100-4. 12. Withers HR, Peters L, Thames H, et al. Hyperfractionation. Int J Radiat Oncol Biol Phys 1982; 8: 1807-g. 13. Taylor SO, Applebaum E, Showel JL, et al. A randomized trial of adjuvant chemotherapy in head and neck cancer. J Clin Oncol 1985; 3: 672-9. 14. Adjuvant chemotherapy for advanced head and neck squamous carcinoma: a final report of the Head and Neck Contracts Program. Cancer 1987; 60: 301-11. 15. Nias AH. Radiation and platinum drug interaction. Int J Radiat Biol Relat Stud Phys Chem Med 1985; 48: 297-314. 16. Coughclin CT, Richmond RC. Biological and clinical developments of cisplatin combined with radiation: concepts, utility, projections for new trials, and the emergence of carboplatin. Semin Oncol 1989; 16: 31-43. 17. Dritschilo A, Piro AJ, Kellman AD. The effect of cis-platinum on the repair of radiation damage in plateau phase Chinese hamster (V70) cells. Int J Radiat Oncol Biol Phys 1979; 5: 1345-9. 18. Mattox DE, Stemson LA, Von Hoff DD, Kuhn JG, Repta AJ. Tumor concentration of platinum in patients with head and neck cancer. Otolaryngol Head Neck Surg 1983; 91: 271-5. 19. Al-Sarraf M, Pajak TF, Marcia1 VA, et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck an RTOG study. Cancer 1987; 59: 259-65. 20. Wendt TG, Wustrow TPU, Hartenstein RC, Rohloff R, Trott KR. Accelerated split course radiotherapy and simultaneous cisdichlorodiammine-platinum and 5-fluorouracil chemotherapy with folinic acid enhancement for unresectable carcinoma of the head and neck. Radiother Oncol 1987; 10: 277-84. 21. Harrison L, Bcsl G, Fass D, et al. A new chemo-radiation program for advanced unresectable head and neck cancer [abstract 1.41. Presented at the Third International Head and Neck Oncology Research Conference, Las Vegas, September 1990. 22. Giri PG, Taylor S, Gemer L, et al. Accelerated fractionation radiation therapy and concurrent chemotherapy in advanced squamous cell cancers of the head and neck [abstract 1.81. Presented at the Third International Head and Neck Oncology Research Conference, Las Vegas, September 1990.
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