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© 2001 American Society for Clinical Oncology High-Dose Intra-Arterial Cisplatin Boost With Hyperfractionated Radiation Therapy for Advanced Squamous Cell Carcinoma of the Head and NeckByFrom the Departments of Radiation Medicine, Surgery, Otolaryngology, Medical Oncology, and Radiology, University of Kentucky, Lexington, KY. Address reprint requests to William F. Regine, MD, University of Kentucky Medical Center, 800 Rose St, Lexington, KY 40536-0293; email: wilregi{at}pop.uky.edu
PURPOSE: To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m2 received at the start of and during RT boost treatment). RESULTS: Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months. CONCLUSION: In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.
TWO MODALITIES of therapy have well-established roles in the treatment of squamous cell carcinoma of the head and neck (SCCHN): surgery and radiation therapy (RT). In general, smaller lesions (stage T1 to T2) are effectively treated by either excision or RT, whereas patients with more advanced disease (eg, stage T3 to T4/III/IV) are treated with combined surgery and RT. However, even when surgery, which typically involves organ (eg, larynx) loss and/or dysfunction, and RT are used together, only a small fraction of patients with advanced locoregional disease are cured. Historically, those found to have unresectable disease have received primary RT alone, with 5-year survival rates of approximately 10% to 20% and the majority of patients dying from secondary causes other than local disease progression.1 The use of altered fractionation RT was found to be superior to once-a-day RT for SCCHN in a randomized trial of over 1,000 patients conducted by the Radiation Therapy Oncology Group.2 Further improvement in the treatment of SCCHN cancer may be seen with the addition of chemotherapy to RT and/or surgery. Cisplatin remains one of the most effective chemotherapeutic agents with activity against SCCHN.3,4 Laboratory and clinical evidence suggests that cisplatin enhances the effects of radiation when given concurrently.5-7 Several studies have reported high rates of tumor response, associated organ preservation, and improved survival using cisplatin-based regimens with concurrent standard or altered fractionation RT.6,8-11 Although a substantial proportion of patients selected for this intensive strategy are able to complete therapy, mucositis and other toxicities are common and often severe,7,9-16 restricting the type of patient selected for this combination treatment. The relatively low toxicity and high tumor response rates reported with use of intra-arterial (IA) supradose cisplatin (150 mg/m2) given concurrently with conventional once-a-day or hyperfractionated (HFX) RT for advanced SCCHN may make this an optimized method of combining chemotherapy with radiation.17-20 Our previously reported experience with the use of single-dose IA cisplatin given at the start of the boost phase of HFX-RT suggested that this therapy was well tolerated and associated with a high complete response (CR) rate in a highly unfavorable subset of patients with locally advanced SCCHN.20 Building on this experience, we subsequently evaluated dose intensification of the IA cisplatin used in the current program. This intensification involved the addition of a second dose of IA cisplatin during the boost phase of HFX-RT. The results of these consecutive phase I/II studies evaluating the tolerability and efficacy of high-dose IA cisplatin boost and HFX-RT in patients with locally advanced SCCHN are the subject of this report.
Patient Characteristics From December 1995 to August 1999, 42 patients with locally advanced, primary SCCHN were treated on consecutive University of Kentucky head and neck protocols 95-H&N-07 (N = 18) and 97-H&N-09 (N = 24), which were phase I/II studies of HFX-RT and high-dose IA cisplatin boost received once (95-H&N-07) or twice (97-H&N-09), referred to as HYPERRADPLAT. Before the start of therapy, all patients signed informed consent approved by our institutional review board and according to federal guidelines. All patients were previously untreated and without distant metastases. Enrollment was limited to patients with 1993/1998 American Joint Committee on Cancer stage III or IV disease.21,22 Study procedure required each patient to have a Karnofsky performance status of  60%; WBC count of more than 3,500/mm3, platelet count of more than 100,000/µl, bilirubin  1.5 mg/dL, AST and ALT less than three times the upper limits of normal, albumin 3 g/dL, a creatinine clearance 60 mL/min (calculated or measured), a prothrombin time of less than 16 seconds, and a partial thromboplastin time of less than 35 seconds. In addition, protocol required all patients to have a chest x-ray and other appropriate studies to fully define the extent and severity of existing or suspected malignant and nonmalignant disease, including but not limited to endoscopy, computed tomography (CT) scans, and/or magnetic resonance imaging (MRI) before the start of therapy.
Treatment and Evaluation
All patients were evaluated for tumor response, which included repeat imaging (CT and/or MRI) and examination under anesthesia at 6 to 9 weeks after completion of the protocol therapy. In patients whose primary tumor site had not achieved obvious clinical CR and who were medically operable, directed biopsies were performed. In only those patients with evidence of persistent disease at the primary site, surgery was planned as a salvage procedure. All patients with unilateral neck disease of stage N2a or greater underwent planned neck dissection. All toxicities encountered during this study were evaluated according to the National Cancer Institute Common Toxicity Criteria. Acute toxicity was scored from the start of protocol therapy to the time of examination under anesthesia and included planned weekly evaluations during therapy and at 1 month after completion of therapy. These evaluations included history and physical examinations along with complete blood cell counts and chemistries at the start of weeks 6 and 7 of therapy and at 1 month after therapy. Audiometry and 24-hour urine were also checked for creatinine clearance at 1 month after therapy.
Statistical Analysis
Patient characteristics according to stage are listed in Table 1. Among the 42 patients, 40 (95%) had stage IV disease. Thirty-seven (88%) had T4 disease, and 28 (67%) had N2/N3 disease. Primary tumor sites included oropharynx (n = 20), hypopharynx (n = 10), oral cavity (n = 7), larynx (n = 3), nasopharynx (n = 1), and maxillary sinus (n = 1). Thirty-nine patients were male. Age ranged from 35 to 76 years (median, 52 years).
Acute Toxicity Eight (33%) of 24 patients entered onto protocol 97-H&N-09 were unable to receive the second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thus, of the 42 patients, 16 received two injections of IA cisplatin boost, and the remaining 26 patients were treated as per protocol 95-H&N-07, receiving one injection of IA cisplatin boost. Overall, 31 patients (69%) experienced grade 3 mucosal toxicity and three patients (7%) experienced grade 4. All grade 3 and 4 mucosal events were limited to areas initially occupied by tumor and encompassed by the reduced RT portals only. There were no toxic deaths, and other grade 3 and 4 toxicities were limited to grade 3 hematologic, infectious, and skin events in one patient each. There were no neurologic toxicities. Weight change during treatment ranged from -16% to +5% (median, -8%). Thirteen patients required feeding tube placement during therapy, and three, after therapy. Nine patients had a feeding tube placed before the start of therapy. Thirty-two patients (76%) completed therapy without interruption, and 10 patients had treatment interruptions in the range of 1 to 4 days (median, 1 day). A comparative summary of grade 3 and 4 acute toxicities according to treatment protocol is listed in Table 2.
Primary and Nodal Response Thirty-seven patients (88%) achieved CR at the primary site. Twenty-one had pathologically verified CR. Among the 34 patients with positive neck disease, 29 (85%) achieved CR in the neck, including 18 (82%) of 22 patients with N2 or N3 disease who underwent planned neck dissection. A comparative summary of response according to treatment protocol is listed in Table 3.
Patient Status Twenty-one patients were alive and without evidence of disease at 14 to 54 months (median follow-up, 30 months). Thirteen patients were dead of disease at 7 to 20 months (median, 11 months). Eight experienced local and/or regional recurrence only, four experienced distant recurrence only, and one experienced local and distance recurrence. One patient was alive with disease at the primary site only at 14 months. Six patients died of intercurrent disease at 4 to 45 months (median, 6 months). The 2-year actuarial locoregional control is 73% (Fig 2). The 2-year actuarial disease-specific and overall survival rates are 63% and 57%, respectively (Fig 3).
The use of altered fractionation RT (eg, twice-a-day radiotherapy) and combined surgery for advanced neck disease has allowed a significantly greater proportion of patients with advanced head and neck tumors to be cured with organ preservation.2,24,25 Yet, even among patients with relatively favorable advanced disease (eg, T3), at least 30% will develop tumor recurrence despite advances in radiation delivery.24,25 Further improvement in the treatment of SCCHN cancer may be seen with the addition of chemotherapy to RT and/or surgery. The rationale behind our study design was two-fold: to improve local control and to reduce toxicity. The unique features and potential advantages associated with this chemoradiation regimen include late treatment intensification with the administration of IA cisplatin at the start of week 6 of therapy (Fig 1) to specifically address accelerated tumor repopulation. This repopulation has been shown to typically occur during the latter part of a course of radiation and is considered to be a major factor for treatment failure in patients with SCCHN.26-28 This late treatment intensification also corresponds to the time at which the initial RT fields are reduced from comprehensive nodal/mucosal irradiation typically encompassing the region between the base of skull and clavicular head to that of the primary tumor itself with a maximum 2-cm margin. This was done with the intent of minimizing extended-volume mucosal toxicity typically seen with chemoradiation for SCCHN. The use of HFX-RT shortens overall treatment time and enables radiation dose escalation with associated improved local tumor control, minimizing potential radiation late effects.24,29,30 Use of thiosulfate enables the delivery of high-dose (ie, 150 mg/m2) IA cisplatin. In covalently bonding and neutralizing the relatively low plasma concentration of cisplatin, thiosulfate reduces cisplatin systemic toxicity without interfering with the antitumor activity of the much higher cisplatin concentration within the arterial circulation supplying the tumor.31,32 Compared with previously reported chemoradiation experiences for SCCHN, our regimen of high-dose IA cisplatin and concurrent HFX-RT was associated with improved patient tolerance. Reported studies have shown grade 3 and 4 acute toxicity rates of more than 50% and mortality rates of as much as 8%.12,15,16 Specific toxicities and rates include (1) grade 4 hematologic, 10% to 55%9,13,15,16; (2) grade 4 mucosal, 13% to 18%9,15,16; (3) grade 3 and 4 renal, 5% to 7%9,14; and (4) grade 3 and 4 neurologic, 2% to 6%.13,14 Acute toxicity in our study was predominantly mucosal; grade 3 and grade 4 toxicity were 69% and 7%, respectively. Two of the three grade 4 mucosal events and the grade 3 hematologic, infectious, and skin events were limited to patients receiving two injections of IA cisplatin boost. High-dose IA cisplatin, as given in combination with HFX-RT in our study, particularly with use of a single dose of IA cisplatin boost, seems to have avoided some of the acute toxicities reported by the University of Tennessee (UT) in 60 patients using the same dose of IA cisplatin repeated weekly for 4 consecutive weeks with the initiation of conventional once-a-day RT.19 Grade 3 and 4 toxicities seen in the UT experience and not similarly observed in this study included hematologic and neurologic, 12% and 7%, respectively. In addition, our CR rates of 88% and 85% at the primary and involved nodal sites, respectively, compared favorably with the UT results of 91% and 67%, respectively. Similar to the UT experience, these results were achieved in a patient cohort made up of the most unfavorable locally advanced SCCHN. Ninety-five percent of patients in our study had stage IV disease, compared with 73% in the UT experience.
Recently reported results of two randomized trials lend further support to our study design with regard to combining cisplatin with concurrent HFX-RT. In a trial conducted by Duke University,10 116 patients with locally advanced SCCHN were randomized to receive continuous course HFX-RT (74 Gy at 1.25 Gy bid) or split-course HFX-RT with concurrent IV cisplatin and fluorouracil given at weeks 1 and 6 of therapy. Treatment outcome was superior for the patients treated with HFX-RT and concurrent cisplatin-based chemotherapy. The actuarial 4-year locoregional control rate for patients receiving HFX-RT and chemotherapy was 70%, versus 44% for those treated with HFX-RT alone (P = .01), with associated trends toward statistically significant improvement in disease-free survival (61% v 41%, P = .08) and overall survival (55% v 34%, P = .07) with use of HFX-RT and cisplatin-based chemotherapy. Patients in the concurrent HFX-RT and chemotherapy group received a planned and necessary 7- to 10-day break approximately midway through therapy to manage treatment-induced mucositis. In a second randomized trial conducted by Jeremic et al,11 130 patients with locally advanced SCCHN were randomized to receive continuous-course HFX-RT (77 Gy at 1.1 Gy bid) with or without IV concurrent low-dose daily cisplatin. Treatment outcome was superior for patients treated with HFX-RT and concurrent cisplatin. The 2- and 5-year survival rates for patients receiving HFX-RT and cisplatin were 68% and 40% versus 49% and 25%, respectively, for those treated with HFX-RT alone (P = .008). This was also associated with a significant improvement in 5-year locoregional progression-free survival (46% v 25%, P = .007) and distant metastasis-free survival (50% v 36%, P = .04) with use of HFX-RT and cisplatin. Although general toxicities and rates of treatment interruption were comparable between the two arms, those receiving cisplatin had a higher rate of acute high-grade hematologic toxicity (20% v 0%, P Continuous-course HFX-RT with concurrent double-dose IA cisplatin boost as administered in our 97-H&N-09 study design (Fig 1) was an attempt to build on our previously reported experience of single-dose IA cisplatin administered at the start of week 6 (boost phase) of continuous course HFX-RT.20 This approach (ie, single-dose IA cisplatin boost) was found and continues to be well tolerated. Among 26 patients with locally advanced SCCHN, grade 3 to 4 acute toxicity was limited to one grade 4 (4%) and 20 grade 3 (77%) mucosal events limited to the RT boost field site. No grade 3 or 4 hematologic toxicity was observed. In contrast, dose intensification by administering double-dose IA cisplatin does not seem feasible. This is most notably due to the fact that eight (33%) of the 24 patients were unable to receive the second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). In addition, the rate of grade 4 mucosal toxicity increased to 13%, and grade 3 hematologic, infectious, and skin toxicities, not noted with the use of single-dose IA cisplatin boost, also occurred. This apparent increase in toxicity was not associated with any obvious improvement in tumor response rates (Tables 2 and 3). Nevertheless, our overall results in terms of toxicity profile, along with our CR rates of 88% and 85% at the primary and involved nodal sites, respectively, in this highly unfavorable cohort of patients (95% with stage IV disease), compared favorably with recently reported results made up of more favorable cohorts of patients. This is demonstrated in Tables 4 and 5 where, in the context of patient population, toxicity, and patient outcome, our results are summarized comparatively to other chemoradiation experiences previously discussed as well as with recently reported results from M.D. Anderson Cancer Center involving IV-based chemotherapy boost,33 the University of Maryland experience involving a taxol/carboplatin-based regimen,34 and with the results of the HFX-RT arm from the Intergroup/Radiation Therapy Oncology Group Study 9003.
In conclusion, HFX-RT and IA cisplatin boost seem to be associated with improved patient tolerance compared with previously reported chemoradiation experiences. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. Our results seem to be superior to previously reported chemoradiation experiences in more favorable cohorts of patients with SCCHN. This novel treatment strategy allows for an incremental increase in treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT (Intergroup/Radiation Therapy Oncology Group 9003)2 and needs evaluation in a randomized trial.
1. Brizel DM: Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma. Semin Radiat Oncol 8: 237-246, 1998[Medline] 2. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48: 7-16, 2000[Medline] 3. Jacobs C: Adjuvant chemotherapy for head and neck cancer. J Clin Oncol 7: 823-826, 1989[Medline] 4. Vokes EE. Head and neck cancer, in Perry MC (ed), Chemotherapy Source Book. Baltimore, MD, Williams and Wilkins, 1992, pp 918-931 5. Douple E, Richmond RC, Logan ME: Therapeutic potentiation in a mouse mammary tumor and an intracerebral rat brain tumor by combined cisdicholorodiamine-platinum (II) and radiation. J Clin Hematol Oncol 7: 585-603, 1977 6. Al-Sarraf M, Pajak TF, Marcial VA, et al: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck: An RTOG Study. Cancer 59: 259-265, 1987[Medline]
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Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 16: 1310-1317, 1998 8. Pfister DG, Strong E, Harrison L, et al: Larynx preservation with combined chemotherapy and radiation therapy in advanced but resectable head and neck cancer. J Clin Oncol 9: 850-859, 1991[Abstract] 9. Koch WM, Lee DJ, Eisele DW, et al: Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 121: 974-980, 1995
10.
Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338: 1798-1804, 1998
11.
Jeremic B, Shibamoto Y, Milicic B, et al: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: A prospective randomized trial. J Clin Oncol 18: 1458-1464, 2000 12. Vokes EE, Kies M, Haraf DJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: Impact on the natural history of the disease. J Clin Oncol 13: 876-883, 1995[Abstract]
13.
Shin DM, Glisson BS, Khuri FR, et al: Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 16: 1325-1330, 1998
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Colevas AD, Busse PM, Norris CM, et al: Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial. J Clin Oncol 16: 1331-1339, 1998 15. Siu LL, Czaykowski PM, Tannock IF: Phase I/II study of the CAPABLE regimen for patients with poorly differentiated carcinoma of the nasopharynx. J Clin Oncol 16: 2514-2521, 1998[Abstract] 16. Kies MS, Haraf DJ, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16: 2715-2721, 1998[Abstract]
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Robbins KT, Storniolo AM, Kerber C, et al: Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer. J Clin Oncol 12: 2113-2120, 1994 18. Robbins KT, Vicario D, Seagren S, et al: A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer. Am J Surg 168: 419-422, 1994[Medline] 19. Robbins KT, Kumar P, Regine WF, et al: Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: The Memphis experience. Int J Radiat Oncol Biol Phys 38: 263-271, 1997[Medline] 20. Regine WF, Valentino J, John W, et al: High-dose intra-arterial cisplatin and concurrent hyperfractionated radiation therapy in patients with locally advanced primary squamous cell carcinoma of the head and neck: Report of a phase II study. Head Neck 22: 543-549, 2000[Medline] 21. Beahrs O, Henson DE, Hutter RVP, et al: Manual For Staging of Cancer ( ed 4 ). Philadelphia, PA, J.B. Lippincott Co, 1993 22. Fleming ID, Cooper JS, Henson DE, et al: AJCC Cancer Staging Manual ( ed 5 ). Philadelphia, PA, Lippincott-Raven, 1998 23. Kaplan E: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 475-481, 1953 24. Horiot JC, Le Fur R, N’Guyen T, et al: Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 25: 231-241, 1992[Medline] 25. Parsons JT, Mendenhall WM, Stringer SP, et al: Twice-a-day radiotherapy for squamous cell carcinoma of the head and neck: The University of Florida experience. Head Neck 15: 87-96, 1993[Medline] 26. Thames HD Jr, Peters LJ, Withers HR, et al: Accelerated fractionation vs hyperfractionation: Rationales for several treatments per day. Int J Radiat Oncol Biol Phys 9: 127-138, 1983[Medline] 27. Peters LJ, Ang KK, Thames HD Jr: Accelerated fractionation in the radiation treatment of head and neck cancer: A critical comparison of different strategies. Acta Oncol 27: 185-194, 1988[Medline] 28. Withers HR, Taylor JM, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27: 131-146, 1988[Medline] 29. Cox JD, Pajak TF, Marcial VA, et al: Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: Preliminary report of radiation therapy oncology group protocol 83-13. Int J Radiat Oncol Biol Phys 18: 515-521, 1990[Medline] 30. Fu KK, Pajak TF, Marcial VA, et al: Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: Long-term follow-up results of RTOG 83-13. Int J Radiat Oncol Biol Phys 32: 577-588, 1995[Medline] 31. Howell SB, Tastle R: Effect of sodium thiosulfate on cis-dichlorodiammineplatinum (II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat Rep 64: 611-616, 1980[Medline] 32. Howell SB: Pharmacokinetic principles of regional chemotherapy. Contr Oncol 29: 1-8, 1988
33.
Garden AA, Glisson BS, Ang KK, et al: Phase I/II trial of radiation with chemotherapy boost for advanced squamous cell carcinomas of the head and neck: Toxicities and responses. J Clin Oncol 17: 2390-2395, 1999 34. Suntharalingam M, Haas ML, Conley BA, et al: The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 47: 49-56, 2000[Medline] Submitted August 29, 2000; accepted April 18, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
