Supradose Intra-Arterial Cisplatin and Concurrent Radiation Therapy for the Treatment of Stage IV Head and Neck Squamous Cell Carcinoma Is F
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《临床肿瘤学》
the Southern Illinois University School of Medicine, Springfield, IL
University of Southern California, Keck School of Medicine, Los Angeles
University of California San Diego, San Diego
University of California San Francisco, San Francisco, CA
Radiation Therapy Oncology Group, Philadelphia, PA
University of Iowa, Iowa City, IA
Vanderbilt University Medical Center, Nashville, TN
University of Vermont, Burlington, VT
University of Virginia, Charlottesville, VA
The George Washington University, Washington, DC
University of Washington, Seattle, WA.
ABSTRACT
PATIENTS AND METHODS: Eligibility included T4 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received cisplatin (150 mg/m2 IA with sodium thiosulfate 9 g/m2 intravenous [IV], followed by 12 g/m2 IV over 6 hours, weekly for 4 weeks) and concurrent RT (70 Gy, 2.0 Gy/fraction, daily for 5 days over 7 weeks). Between May 1997 and December 1999, 67 patients from three experienced and eight inexperienced centers were enrolled, of whom 61 were eligible for analysis.
RESULTS: Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT) in 53 patients (87%). The complete response (CR) rate was 85% at the primary site and 88% at nodal regions, and the overall CR rate was 80%. At a median follow-up of 3.9 years for alive patients (range, 0.9 to 6.1 years), the estimated 1-year and 2-year locoregional tumor control rates are 66% and 57%, respectively. The estimated 1-year and 2-year survival rates are 72% and 63%, respectively. The estimated 1-year and 2-year disease-free survival rates are 62% and 46%, respectively. The rates of grade 4 and 5 toxicities at the experienced and the inexperienced institutions were 14% and 0% v 47% and 4%, respectively.
CONCLUSION: This intensive treatment regimen for head and neck cancer is feasible and effective in a multi-institutional setting.
INTRODUCTION
The high-dose IA cisplatin and concurrent radiation therapy (RADPLAT) program incorporates infusing cisplatin directly into the tumor bed IA while minimizing the effects of the drug systemically. This is achieved by using microcatheters placed angiographically to permit superselective rapid infusions while sodium thiosulfate, a neutralizing agent for cisplatin, is simultaneously infused systemically. The direct IA infusion allows the tumor bed to initially receive the full dose of cisplatin before the neutralizing agent and for the systemic organs to receive the neutralizing agent before the cisplatin. Because of this, it is feasible to increase the dose-intensity of cisplatin by a magnitude that is at least five times higher relative to standard chemotherapy protocols, thereby enabling the delivery of an enormous amount of drug over a relative short time interval.
Robbins et al3 previously conducted a phase I study designed to determine the maximum-tolerated dose of cisplatin that could be administered IA. The maximum-tolerated dose was 150 mg/m2/wk for 4 weeks. When radiotherapy was administered concomitantly with targeted cisplatin chemotherapy, preliminary observations indicated an extremely high complete pathologic response rate, sustained disease control above the clavicles, and a relatively low rate of toxicity.4,5 The single-institutional experience included 213 patients treated between 1993 and 1998 at the University of Tennessee (Memphis, TN).6 Of the 213 patients entered onto the treatment program, complete response (CR) in the primary site was obtained in 171 patients (80%). Of the 152 patients with clinically node-positive disease, a CR was obtained in 92 patients (61%). Ninety-five instances of grade 3 to 4 toxicity occurred among the 213 patients. These were related to the chemotherapy, radiation therapy (RT), and the infusion technique. With a median follow-up interval of 30 months (range, 16 to 69 months), the Kaplan-Meier plot-projected rate of disease control above the clavicle for all patients was 74.3% (standard deviation [SD], 3.6%) at 5 years, and the corresponding disease-specific and overall survival rates at 5 years were 53.6% (SD, 3.9%) and 38.8% (SD, 3.7%).
Importantly, the RADPLAT experience in Memphis showed that this highly technical sophisticated concept can result in high rates of locoregional tumor control, survival, and organ preservation with acceptable toxicity for locally advanced, functionally or anatomically unresectable, head and neck squamous cell carcinoma. The ability to export RADPLAT to the multi-institutional forum now became a critical question. In an attempt to answer this question, a phase II trial (Protocol 9615) funded by the National Cancer Institute (Bethesda, MD) was conducted under the auspices of the Radiation Therapy Oncology Group (RTOG) to determine the feasibility, tolerance, and efficacy of RADPLAT in the multi-institutional setting. The results of this trial are herein reported.
PATIENTS AND METHODS
Pretreatment Evaluation
All patients underwent a complete clinical evaluation by the head and neck surgeon, radiation oncologist, and medical oncologist. The extent of disease was defined by history and physical examination, endoscopic evaluation, and computed tomography and/or magnetic resonance imaging studies. Staging work-up also included chest x-ray or thoracic computed tomography scan.
Treatment Protocol
The drug infusion procedure was performed in the radiology suite by the interventional radiologist. All of the IA catheterizations were accomplished transcutaneously through the femoral artery. Transfemoral cervical carotid arteriography was first performed to assess vascular anatomy and any potential pathology. The appropriate vessels supplying the region of primary disease were then infused with cisplatin. This was usually achieved by placing a microcatheter (tracker 325 or Renegade HI-FLO; Boston Scientific Corporation, Netick, MA), introduced through an angiographic catheter (Vertebral, DAV and Simmons; Cook Inc, Bloomington, IN), into the external cervical carotid artery at the level of the orifice of the dominant branching artery supplying the tumor. Thus, cisplatin could be rapidly infused to selectively encompass on its initial exposure only the territory of the targeted tumor. Bilateral catheterizations and infusions were performed in patients who had disease extending across the midline and with fluoroscopic evidence of both external carotid artery systems supplying it. In each patient, the goal was to infuse the component of the disease considered to be bulky and/or infiltrative and likely to fail radiotherapy alone. No specific attempt was made to infuse the regional lymph nodes.
Dexamethasone (4 mg IV or orally every 6 hours for four doses) was started the evening before treatment. Patients received pretreatment IV hydration over 2 hours, consisting of 2 L of normal saline containing 20 mEq potassium chloride and 2 g of magnesium sulfate. The cisplatin at 150 mg/m2 was dissolved in 400 mL of normal saline and administered IA by push over 3 to 5 minutes. Simultaneous with the IA infusion of cisplatin, sodium thiosulfate at 9 g/m2 dissolved in 300 mL of distilled water was administered IV over 3 to 5 minutes. This allowed the tumor bed to initially receive the full dose of cisplatin before the neutralizing agent and for the systemic organs to receive the neutralizing agent before exposure to the cisplatin. Sodium thiosulfate at 12 g/m2 in distilled water was continued IV post-IA infusion over 6 hours. Post-treatment hydration consisted of 1 L of 5% dextrose and two parts normal saline containing 20 mEq potassium chloride and 2 g of magnesium sulfate over 6 hours. Cisplatin and sodium thiosulfate infusions were administered on days 1, 8, 15, and 22 of the protocol.
RT, which was started on day 1 before the chemotherapy, was administered using megavoltage linear accelerators with photon beam energy of 1.25 to 6 MV and appropriate electron energies. Opposed lateral fields were used to encompass the primary and overt nodal disease at 2.0 Gy per fraction once daily 5 days a week, to a total planned dose of 70.0 Gy in 35 fractions using a shrinking field technique. The entire treatment volume received a dose of 50 Gy for microscopic subclinical disease with a margin of 3 cm. All areas of gross primary tumor or lymphadenopathy received a total dose of 70 Gy (60 Gy with a 2-cm margin and 70 Gy with a 1-cm margin). A boost of up to 6 Gy (total dose, 76 Gy) was allowed in cases of persistent clinical residual disease or to compensate for potential treatment interruptions during therapy. The uninvolved lower neck was treated with a single AP supraclavicular field at 50.0 Gy at 2.0 Gy per fraction (prescribed to a depth of 3 cm) once daily. The spinal cord was shielded at 40.0 Gy, and treatment to the posterior necks was continued with electrons. The overtly involved posterior neck was boosted with electrons to 70 Gy, whereas the clinically negative neck was treated to 50 Gy.
Dose modifications were made for an absolute neutrophil count of less than 1,800/μL (treatment held until absolute neutrophil count > 1,800/μL, then treatment administered at 100% dose), a platelet count of less than 75,000/μL (treatment held until platelets > 75,000/μL, then treatment administered at 100% dose), neurotoxicity (paralysis, moderate myopathy, moderate weakness, seizure, or peripheral neuropathy; treatment withheld), and creatinine more than 1.2 and/or creatinine clearance less than 50 mL/min (cisplatin withheld). All chemotherapy courses were held pending recovery of toxicity to less than grade 1. If the delay in treatment was greater than 14 days, the patient was taken off study.
Statistical Methods
The trial was designed to test whether the RADPLAT therapy was at least 80% feasible (ie, transportable) at the inexperienced institutions. The estimated required sample size was 60 patients, with 40 being entered from the inexperienced institutions. Feasibility was defined as the ability to give either three or four infusions of the IA cisplatin and the full dose of RT (≥ 95%) with ≤ 7 days of treatment interruptions. Previous multivariate analyses of the Memphis RADPLAT data had shown no difference in local control or survival between three versus four infusions.7,8 The primary efficacy end point was overall survival (ie, death as a result of any cause). Survival was measured from the date of registration to the protocol to the date the patient died or the date the patient was last known alive. Yearly estimates were calculated along with their associated 95% CIs using the Kaplan-Meier method. Overall survival in RTOG 9615 was also compared with the survival results from RTOG protocol 8117, which treated patients with conventional RT and IV cisplatin. A Cox proportional hazards model stratified by RTOG recursive partitioning analysis classification was used for this survival comparison to adjust for prognosis.9 For this comparison, patients were limited to T4 and stage IV disease, a Karnofsky performance score of 60+, and a primary site of oral cavity, oropharynx, hypopharynx, or larynx.
Secondary efficacy end points were CR rates, locoregional tumor control (ie, failure being defined as persistent or recurrent disease in the primary or regional nodes), and disease-free survival. CR at the primary site must have been achieved through protocol treatment, whereas CR in the regional nodes could also be achieved through salvage surgery. A patient was classified as a complete responder only if the disease cleared at both the primary and regional nodes before any progression or recurrence. Time to locoregional failure was measured from the date of registration to the date of disease relapse, the date of death, or the date the patient was last known to be alive and free of disease. If the patient never achieved a CR, the patient was considered as having treatment failure at the date of registration. Locoregional failure rates were calculated using the method of cumulative incidence because this accounts for the competing risk of death without locoregional failure. These failure rates were subtracted from 1 to obtain the locoregional control rates. Locoregional failure, distant metastases, second primary disease, or death were all considered failures for disease-free survival. Yearly disease-free survival rates were estimated with the Kaplan-Meier method.
RESULTS
IA Cisplatin Infusions
Overall, IA cisplatin infusions were delivered as follows: three or four infusions in 13 (21%) and 45 (74%) patients, respectively; two infusions in two patients (3%); and one infusion in one patient (2%; Table 2). At the experienced centers, all 14 patients underwent either three (n = 4) or four (n = 10) IA infusions. At the inexperienced institutions, either three (n = 9 patients) or four (n = 35) IA infusions were delivered in 94% of the patients; two patients underwent only two IA infusions, whereas one patient completed only one cycle of chemotherapy. Toxicity was the reason for the inability to deliver all four cycles of the IA cisplatin infusions in all patients.
RT
The median total dose to the primary site was 70 Gy (range, 30 to 74 Gy). Median elapsed time during RT treatments was 51 days (range, 30 to 65 days). Median total time of interruption was 0 days (range, 0 to 26 days). Total RT dose was per protocol (ie, ≥ 95% of required protocol dose) in 56 patients (92%) and less than protocol dose in five patients (8%). At the experienced centers, all 14 patients received the full RT dose as per protocol. At the inexperienced institutions, the RT dose to the primary site was per protocol in 42 patients (89%) and less than protocol dose in five patients (11%; death related to protocol therapy, n = 2; patient refusal, n = 1; long delay because of toxicity, n = 1; and unknown reason, n = 1).
IA Cisplatin and RT
Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT with ≤ 7 days of treatment interruptions) in 53 patients (87%). For the 14 patients enrolled from the experienced centers, the feasibility rate of the multi-RADPLAT protocol was 100%. At the inexperienced centers, the protocol therapy was feasible in 39 patients (83%); in five patients, either four (n = 3) or three (n = 2) IA infusions were delivered, but the RT was not per protocol. In the remaining three patients, the RT was per protocol, but patients underwent either two (n = 2) or one (n = 1) IA cisplatin infusion.
Response Rates
At the primary site, a CR was obtained in 52 patients (85%). The CR rates at the primary site at the experienced and inexperienced centers were 79% and 87%, respectively. Five of the 12 patients in whom a CR could not be achieved had salvage surgery. At the nodal regions, a CR was attained in 36 (88%) of 41 clinically node-positive patients, four of whom achieved a CR through salvage neck dissection. CR rates at the nodal regions were high for both experienced (seven of seven patients; 100%) and inexperienced centers (29 of 34 patients; 85%). Overall, a CR of all locoregional disease was achieved in 49 patients (80%).
Survival
At a median follow-up interval of 3.9 years (range, 0.9 to 6.1 years) for patients still alive, 32 (52%) of 61 patients have died. The estimated 1-year and 2-year survival rates are 72.1% (95% CI, 60.8% to 83.4%) and 63.4% (95% CI, 51.2% to 75.6%), respectively (Fig 1, Table 3). In the 32 patients who died, 20 deaths were related to their index cancer, two were caused by a second primary tumor, two were protocol treatment-related (grade 5 toxicity), one was related to other treatment, four were unrelated to treatment, and three were of unknown cause.
Pattern of Relapse
Twelve patients had persistent locoregional disease. In the 49 patients who achieved a locoregional CR, six patients relapsed in the primary site alone, three patients relapsed in the nodal regions only, and seven patients had both primary and nodal recurrence. The 1-year and 2-year locoregional control rates are 65.6% (95% CI, 53.5% to 77.6%) and 57.2% (95% CI, 44.6% to 69.8%), respectively (Fig 2, Table 4). Eleven patients have developed distant metastases, and five patients have developed second primaries.
The pattern of first failure was as follows: persistent locoregional disease, n = 12; primary recurrence, n = 6; nodal recurrence, n = 5; primary and nodal recurrence, n = 1; primary and nodal recurrence and distant metastases, n = 1; distant metastases, n = 7; and second primary tumor, n = 5. Four patients died without evidence of disease progression (two of whom were listed as having study cancer as cause of death), and 20 patients are alive with no evidence of disease. The 1-year and 2-year disease-free survival rates are 62.3% (95% CI, 50.1% to 74.5%) and 45.5% (95% CI, 33.0% to 58.1%), respectively (Fig 3, Table 5).
Toxicity
The overall rates of grade 3, 4, and 5 (fatal) toxicities were 44%, 39%, and 3%, respectively (Table 6). Of significance, the rates of grade 3 and 4 mucositis were 48% and 10%, respectively. Grade 3 and 4 neurologic toxicity was observed in four patients (7%) and one patient (2%), respectively. This included two patients with clinical evidence of a transient ischemic attack who experienced complete recovery, two patients who had a peripheral neuropathy, and one patient who had a cerebrovascular accident with permanent sequelae.
A striking difference was observed in the rates of overall grade 4 and 5 toxicities between the experienced versus the inexperienced institutions. At the experienced centers, the rates of grade 4 and 5 overall toxicities were 14% and 0% compared with 47% and 4%, respectively, at the inexperienced institutions. When grade 4 toxicities were analyzed by category, there were 10 (21%) of 47 patients with hematologic events among the inexperienced centers compared with one (7%) of 14 patients among the experienced centers. There were 12 (26%) of 47 patients with grade 4 nonhematologic toxicities among the inexperienced centers compared with two (14%) of 14 patients among the experienced centers. The two patients who experienced treatment-related fatal toxicity at the inexperienced institutions represented the first patient enrolled onto the multi-RADPLAT protocol at their respective institutions. One patient developed leukopenia and pneumonia, which eventually led to sepsis and death. The patient finished the fourth infusion of IA cisplatin but refused to have her blood drawn for CBC. Twelve days later, this patient was found to have a WBC of 500 K/mm3 along with pneumonia that led to death. The other patient died from septic emboli that complicated a femoral vein thrombosis superimposed on a grade 3 neutropenia, which occurred after the fourth infusion of the IA cisplatin had been delivered but during the course of the RT treatments.
DISCUSSION
Two different and unique factors may explain our success in the delivery of IA cisplatin on our protocol. First, the interventional radiology techniques have vastly improved during the last several decades. An interventional radiology procedure that may have seemed dauntingly sophisticated not too long ago is now much more widely known and practiced by the radiology community. Second, a training workshop was held for the key investigators, including interventional radiologists from the inexperienced centers, before the initiation of the multi-RADPLAT protocol. During this 2-day workshop, we presented formal didactic lectures and showed live demonstrations of the delivery of IA cisplatin. Among other things, we discussed some of the subtle nuances involved in the delivery of the IA chemotherapy, such as the importance of subselective external carotid artery catheterizations (whenever possible) and the timing of the IV delivery of sodium thiosulfate during and after the cisplatin. This workshop was undoubtedly a key factor in our success of the delivery of IA cisplatin on this protocol.
Although there was no major difference in the ability to administer the RADPLAT therapy between the inexperienced versus the experienced centers, the overall rate of grade 3 to 5 toxicities was much higher at the inexperienced institutions. Although it is unclear why this occurred, one may speculate that impending bone marrow failure may have been better predicted by the experienced team. The protocol allowed for withholding cisplatin for up to 2 weeks if the counts were decreasing, and it is possible that the experienced investigators more often recognized a plunging count in time to withhold therapy. The two protocol treatment-related deaths on the multi-RADPLAT protocol occurred at the inexperienced centers. In fact, both patients who experienced a treatment-related death represented the first patient enrolled onto the multi-RADPLAT protocol at each of their respective centers. Additionally, both patients died well after receiving the fourth infusion of the IA cisplatin but during the RT treatments. These two protocol treatment-related deaths led to a temporary hold on the enrollment of patients to the multi-RADPLAT protocol for approximately 3 months until a comprehensive reassessment of the toxicities could be conducted. This included a careful review of the two patients who suffered transient ischemic attacks. However, there were no obvious deviations from the protocol, and in each instance in which there was an adverse event, it was not related to any specific technical error. The protocol was reactivated after discussion with many of the coinvestigators, and no further grade 5 events were observed for the duration of the protocol. Hence, the marked difference in the toxicity rates between the experienced versus the inexperienced institutions definitely reveals a learning curve associated with the RADPLAT protocol therapy. Interestingly, we did not observe a learning curve in the technical delivery of the IA cisplatin.
Comparison of multi-RADPLAT therapy with other studies is hampered by the inclusion of patients with less advanced disease (ie, stage III disease or less),10-20 different timing of the chemotherapy with the RT (ie, sequential or alternating v concurrent),11-13 nonstandard fractionated RT,14-16 or noncisplatin-carboplatin-containing regimens17,18 in the trials. Because these obstacles eliminate many of the trials, there are only three important trials left for comparison based on a similar treatment regimen; these trials are the RTOG protocol 8117,10 the Head and Neck Intergroup Study (RTOG/Southwest Oncology Group),19 and the Groupe Oncologie Radiotherapie Teteaet Cou (GORTEC) trial.20 Common to all of these trials was the use of concurrent cisplatin- or carboplatin-based chemotherapy and conventionally fractionated RT. However, these studies also included patients who had less than T4 disease, and with the exception of the Head and Neck Intergroup Trial, all had a substantial proportion of stage III disease patients. The Head and Neck Intergroup study was a phase III randomized trial of stage IV (96%) head and neck cancer patients, comparing RT alone (70 Gy in 35 daily fractions) with the identical RT plus concurrent bolus cisplatin (100 mg/m2 on days 1, 22, and 43) or split-course RT plus infusional fluorouracil and bolus cisplatin. The GORTEC trial was a phase III randomized trial of stage III to IV oropharyngeal cancer patients, comparing conventional RT alone (70 Gy in 35 fractions) with the same RT plus concurrent carboplatin (70 mg/m2/d) and fluorouracil (600 mg/m2/d) on days 1 to 4, 22 to 25, and 43 to 46. The Head and Neck Intergroup, GORTEC, and RTOG 8117 trials reported 2-year survival outcomes of 41%, 49%, and 39.5%, respectively, for the concurrent chemoradiotherapy therapy arms, which used cisplatin- or carboplatin-containing regimens and standard RT. However, it should be emphasized that the Head and Neck Intergroup Trial and the GORTEC trial were phase III studies and RTOG 8117 was a phase II trial conducted 20 years previously. Thus, fair comparisons with our current phase II trial are problematic based on differences in patient selection, time frame, and study design.
We conclude that the RADPLAT therapy is feasible and transportable to the multi-institutional setting. There does not seem to be a learning curve associated with the technical delivery of the IA cisplatin with RT, although there is definitely a learning curve associated with the management of side effects and toxicities during the RADPLAT therapy. Given our favorable efficacy results, a phase III randomized trial comparing IA to IV cisplatin with concurrent RT for patients with stage IV unresectable head and neck squamous cell carcinoma should be conducted.
Authors’ Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank all the clinical investigators for enrolling patients onto this trial. In addition, we acknowledge the dedication and hard work of the statisticians, clinical research associates, dosimetrists, and administrative staff who have contributed to the success of this trial. In particular, we thank Thomas F. Pajak, PhD, for his valuable contributions in statistics, Linda Messett for data management, and Bernadine Dunning for radiation quality assurance.
NOTES
Supported by grant No. ROI-CA-95-012 from the National Cancer Institute, Bethesda, MD (K.T.R.).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
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2. Robbins KT, Storniolo AM, Kerber C, et al: Rapid superselective high dose cisplatin infusion for advanced head and neck malignancies. Head Neck 14:364-371, 1992
3. Robbins KT, Storniolo AMS, 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
4. Robbins KT, Vicario D, Seagren S, et al: A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer. Am J Surg 168:419-421, 1994
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7. Kumar P, Wan J, Vieira F, et al: Five year outcome analyses following treatment of stage III/IV head and neck (H/N) squamous cell carcinoma (SCCa) using supradose intra-arterial targeted cisplatin (SIT-P) and concurrent radiation therapy (RT). Proc Am Soc Clin Oncol 18:396a, 1999 (abstr 1530)
8. Kumar P, Wan J, Proctor E, et al: The impact of radiation related factors upon long term outcome in the management of advanced head and neck (H/N) squamous cell carcinoma (SCCa) treated with supradose intra-arterial targeted (SIT) cisplatin (P) and radiation therapy (RT). Int J Radiat Oncol Biol Phys 42:321, 1998 (suppl 1, abstr 2188)
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13. Merlano M, Vitale V, Rosso R, et al: Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 327:1115-1121, 1992
14. Jeremic B, Shibamoto Y, Stanisavljevic B, et al: Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: A prospective randomized trial. Radiother Oncol 43:29-37, 1997
15. Wendt TG, Grabenbauer GG, Rdel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318-1324, 1998
16. 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
17. Browman GP, Cripps C, Hodson DI, et al: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12:2648-2653, 1994
18. Haffty BG, Son YH, Papac R: Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: Results of the Yale randomized trials. J Clin Oncol 15:268-276, 1997
19. Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-98, 2003
20. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081-2086, 1999(K. Thomas Robbins, Parves)
University of Southern California, Keck School of Medicine, Los Angeles
University of California San Diego, San Diego
University of California San Francisco, San Francisco, CA
Radiation Therapy Oncology Group, Philadelphia, PA
University of Iowa, Iowa City, IA
Vanderbilt University Medical Center, Nashville, TN
University of Vermont, Burlington, VT
University of Virginia, Charlottesville, VA
The George Washington University, Washington, DC
University of Washington, Seattle, WA.
ABSTRACT
PATIENTS AND METHODS: Eligibility included T4 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received cisplatin (150 mg/m2 IA with sodium thiosulfate 9 g/m2 intravenous [IV], followed by 12 g/m2 IV over 6 hours, weekly for 4 weeks) and concurrent RT (70 Gy, 2.0 Gy/fraction, daily for 5 days over 7 weeks). Between May 1997 and December 1999, 67 patients from three experienced and eight inexperienced centers were enrolled, of whom 61 were eligible for analysis.
RESULTS: Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT) in 53 patients (87%). The complete response (CR) rate was 85% at the primary site and 88% at nodal regions, and the overall CR rate was 80%. At a median follow-up of 3.9 years for alive patients (range, 0.9 to 6.1 years), the estimated 1-year and 2-year locoregional tumor control rates are 66% and 57%, respectively. The estimated 1-year and 2-year survival rates are 72% and 63%, respectively. The estimated 1-year and 2-year disease-free survival rates are 62% and 46%, respectively. The rates of grade 4 and 5 toxicities at the experienced and the inexperienced institutions were 14% and 0% v 47% and 4%, respectively.
CONCLUSION: This intensive treatment regimen for head and neck cancer is feasible and effective in a multi-institutional setting.
INTRODUCTION
The high-dose IA cisplatin and concurrent radiation therapy (RADPLAT) program incorporates infusing cisplatin directly into the tumor bed IA while minimizing the effects of the drug systemically. This is achieved by using microcatheters placed angiographically to permit superselective rapid infusions while sodium thiosulfate, a neutralizing agent for cisplatin, is simultaneously infused systemically. The direct IA infusion allows the tumor bed to initially receive the full dose of cisplatin before the neutralizing agent and for the systemic organs to receive the neutralizing agent before the cisplatin. Because of this, it is feasible to increase the dose-intensity of cisplatin by a magnitude that is at least five times higher relative to standard chemotherapy protocols, thereby enabling the delivery of an enormous amount of drug over a relative short time interval.
Robbins et al3 previously conducted a phase I study designed to determine the maximum-tolerated dose of cisplatin that could be administered IA. The maximum-tolerated dose was 150 mg/m2/wk for 4 weeks. When radiotherapy was administered concomitantly with targeted cisplatin chemotherapy, preliminary observations indicated an extremely high complete pathologic response rate, sustained disease control above the clavicles, and a relatively low rate of toxicity.4,5 The single-institutional experience included 213 patients treated between 1993 and 1998 at the University of Tennessee (Memphis, TN).6 Of the 213 patients entered onto the treatment program, complete response (CR) in the primary site was obtained in 171 patients (80%). Of the 152 patients with clinically node-positive disease, a CR was obtained in 92 patients (61%). Ninety-five instances of grade 3 to 4 toxicity occurred among the 213 patients. These were related to the chemotherapy, radiation therapy (RT), and the infusion technique. With a median follow-up interval of 30 months (range, 16 to 69 months), the Kaplan-Meier plot-projected rate of disease control above the clavicle for all patients was 74.3% (standard deviation [SD], 3.6%) at 5 years, and the corresponding disease-specific and overall survival rates at 5 years were 53.6% (SD, 3.9%) and 38.8% (SD, 3.7%).
Importantly, the RADPLAT experience in Memphis showed that this highly technical sophisticated concept can result in high rates of locoregional tumor control, survival, and organ preservation with acceptable toxicity for locally advanced, functionally or anatomically unresectable, head and neck squamous cell carcinoma. The ability to export RADPLAT to the multi-institutional forum now became a critical question. In an attempt to answer this question, a phase II trial (Protocol 9615) funded by the National Cancer Institute (Bethesda, MD) was conducted under the auspices of the Radiation Therapy Oncology Group (RTOG) to determine the feasibility, tolerance, and efficacy of RADPLAT in the multi-institutional setting. The results of this trial are herein reported.
PATIENTS AND METHODS
Pretreatment Evaluation
All patients underwent a complete clinical evaluation by the head and neck surgeon, radiation oncologist, and medical oncologist. The extent of disease was defined by history and physical examination, endoscopic evaluation, and computed tomography and/or magnetic resonance imaging studies. Staging work-up also included chest x-ray or thoracic computed tomography scan.
Treatment Protocol
The drug infusion procedure was performed in the radiology suite by the interventional radiologist. All of the IA catheterizations were accomplished transcutaneously through the femoral artery. Transfemoral cervical carotid arteriography was first performed to assess vascular anatomy and any potential pathology. The appropriate vessels supplying the region of primary disease were then infused with cisplatin. This was usually achieved by placing a microcatheter (tracker 325 or Renegade HI-FLO; Boston Scientific Corporation, Netick, MA), introduced through an angiographic catheter (Vertebral, DAV and Simmons; Cook Inc, Bloomington, IN), into the external cervical carotid artery at the level of the orifice of the dominant branching artery supplying the tumor. Thus, cisplatin could be rapidly infused to selectively encompass on its initial exposure only the territory of the targeted tumor. Bilateral catheterizations and infusions were performed in patients who had disease extending across the midline and with fluoroscopic evidence of both external carotid artery systems supplying it. In each patient, the goal was to infuse the component of the disease considered to be bulky and/or infiltrative and likely to fail radiotherapy alone. No specific attempt was made to infuse the regional lymph nodes.
Dexamethasone (4 mg IV or orally every 6 hours for four doses) was started the evening before treatment. Patients received pretreatment IV hydration over 2 hours, consisting of 2 L of normal saline containing 20 mEq potassium chloride and 2 g of magnesium sulfate. The cisplatin at 150 mg/m2 was dissolved in 400 mL of normal saline and administered IA by push over 3 to 5 minutes. Simultaneous with the IA infusion of cisplatin, sodium thiosulfate at 9 g/m2 dissolved in 300 mL of distilled water was administered IV over 3 to 5 minutes. This allowed the tumor bed to initially receive the full dose of cisplatin before the neutralizing agent and for the systemic organs to receive the neutralizing agent before exposure to the cisplatin. Sodium thiosulfate at 12 g/m2 in distilled water was continued IV post-IA infusion over 6 hours. Post-treatment hydration consisted of 1 L of 5% dextrose and two parts normal saline containing 20 mEq potassium chloride and 2 g of magnesium sulfate over 6 hours. Cisplatin and sodium thiosulfate infusions were administered on days 1, 8, 15, and 22 of the protocol.
RT, which was started on day 1 before the chemotherapy, was administered using megavoltage linear accelerators with photon beam energy of 1.25 to 6 MV and appropriate electron energies. Opposed lateral fields were used to encompass the primary and overt nodal disease at 2.0 Gy per fraction once daily 5 days a week, to a total planned dose of 70.0 Gy in 35 fractions using a shrinking field technique. The entire treatment volume received a dose of 50 Gy for microscopic subclinical disease with a margin of 3 cm. All areas of gross primary tumor or lymphadenopathy received a total dose of 70 Gy (60 Gy with a 2-cm margin and 70 Gy with a 1-cm margin). A boost of up to 6 Gy (total dose, 76 Gy) was allowed in cases of persistent clinical residual disease or to compensate for potential treatment interruptions during therapy. The uninvolved lower neck was treated with a single AP supraclavicular field at 50.0 Gy at 2.0 Gy per fraction (prescribed to a depth of 3 cm) once daily. The spinal cord was shielded at 40.0 Gy, and treatment to the posterior necks was continued with electrons. The overtly involved posterior neck was boosted with electrons to 70 Gy, whereas the clinically negative neck was treated to 50 Gy.
Dose modifications were made for an absolute neutrophil count of less than 1,800/μL (treatment held until absolute neutrophil count > 1,800/μL, then treatment administered at 100% dose), a platelet count of less than 75,000/μL (treatment held until platelets > 75,000/μL, then treatment administered at 100% dose), neurotoxicity (paralysis, moderate myopathy, moderate weakness, seizure, or peripheral neuropathy; treatment withheld), and creatinine more than 1.2 and/or creatinine clearance less than 50 mL/min (cisplatin withheld). All chemotherapy courses were held pending recovery of toxicity to less than grade 1. If the delay in treatment was greater than 14 days, the patient was taken off study.
Statistical Methods
The trial was designed to test whether the RADPLAT therapy was at least 80% feasible (ie, transportable) at the inexperienced institutions. The estimated required sample size was 60 patients, with 40 being entered from the inexperienced institutions. Feasibility was defined as the ability to give either three or four infusions of the IA cisplatin and the full dose of RT (≥ 95%) with ≤ 7 days of treatment interruptions. Previous multivariate analyses of the Memphis RADPLAT data had shown no difference in local control or survival between three versus four infusions.7,8 The primary efficacy end point was overall survival (ie, death as a result of any cause). Survival was measured from the date of registration to the protocol to the date the patient died or the date the patient was last known alive. Yearly estimates were calculated along with their associated 95% CIs using the Kaplan-Meier method. Overall survival in RTOG 9615 was also compared with the survival results from RTOG protocol 8117, which treated patients with conventional RT and IV cisplatin. A Cox proportional hazards model stratified by RTOG recursive partitioning analysis classification was used for this survival comparison to adjust for prognosis.9 For this comparison, patients were limited to T4 and stage IV disease, a Karnofsky performance score of 60+, and a primary site of oral cavity, oropharynx, hypopharynx, or larynx.
Secondary efficacy end points were CR rates, locoregional tumor control (ie, failure being defined as persistent or recurrent disease in the primary or regional nodes), and disease-free survival. CR at the primary site must have been achieved through protocol treatment, whereas CR in the regional nodes could also be achieved through salvage surgery. A patient was classified as a complete responder only if the disease cleared at both the primary and regional nodes before any progression or recurrence. Time to locoregional failure was measured from the date of registration to the date of disease relapse, the date of death, or the date the patient was last known to be alive and free of disease. If the patient never achieved a CR, the patient was considered as having treatment failure at the date of registration. Locoregional failure rates were calculated using the method of cumulative incidence because this accounts for the competing risk of death without locoregional failure. These failure rates were subtracted from 1 to obtain the locoregional control rates. Locoregional failure, distant metastases, second primary disease, or death were all considered failures for disease-free survival. Yearly disease-free survival rates were estimated with the Kaplan-Meier method.
RESULTS
IA Cisplatin Infusions
Overall, IA cisplatin infusions were delivered as follows: three or four infusions in 13 (21%) and 45 (74%) patients, respectively; two infusions in two patients (3%); and one infusion in one patient (2%; Table 2). At the experienced centers, all 14 patients underwent either three (n = 4) or four (n = 10) IA infusions. At the inexperienced institutions, either three (n = 9 patients) or four (n = 35) IA infusions were delivered in 94% of the patients; two patients underwent only two IA infusions, whereas one patient completed only one cycle of chemotherapy. Toxicity was the reason for the inability to deliver all four cycles of the IA cisplatin infusions in all patients.
RT
The median total dose to the primary site was 70 Gy (range, 30 to 74 Gy). Median elapsed time during RT treatments was 51 days (range, 30 to 65 days). Median total time of interruption was 0 days (range, 0 to 26 days). Total RT dose was per protocol (ie, ≥ 95% of required protocol dose) in 56 patients (92%) and less than protocol dose in five patients (8%). At the experienced centers, all 14 patients received the full RT dose as per protocol. At the inexperienced institutions, the RT dose to the primary site was per protocol in 42 patients (89%) and less than protocol dose in five patients (11%; death related to protocol therapy, n = 2; patient refusal, n = 1; long delay because of toxicity, n = 1; and unknown reason, n = 1).
IA Cisplatin and RT
Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT with ≤ 7 days of treatment interruptions) in 53 patients (87%). For the 14 patients enrolled from the experienced centers, the feasibility rate of the multi-RADPLAT protocol was 100%. At the inexperienced centers, the protocol therapy was feasible in 39 patients (83%); in five patients, either four (n = 3) or three (n = 2) IA infusions were delivered, but the RT was not per protocol. In the remaining three patients, the RT was per protocol, but patients underwent either two (n = 2) or one (n = 1) IA cisplatin infusion.
Response Rates
At the primary site, a CR was obtained in 52 patients (85%). The CR rates at the primary site at the experienced and inexperienced centers were 79% and 87%, respectively. Five of the 12 patients in whom a CR could not be achieved had salvage surgery. At the nodal regions, a CR was attained in 36 (88%) of 41 clinically node-positive patients, four of whom achieved a CR through salvage neck dissection. CR rates at the nodal regions were high for both experienced (seven of seven patients; 100%) and inexperienced centers (29 of 34 patients; 85%). Overall, a CR of all locoregional disease was achieved in 49 patients (80%).
Survival
At a median follow-up interval of 3.9 years (range, 0.9 to 6.1 years) for patients still alive, 32 (52%) of 61 patients have died. The estimated 1-year and 2-year survival rates are 72.1% (95% CI, 60.8% to 83.4%) and 63.4% (95% CI, 51.2% to 75.6%), respectively (Fig 1, Table 3). In the 32 patients who died, 20 deaths were related to their index cancer, two were caused by a second primary tumor, two were protocol treatment-related (grade 5 toxicity), one was related to other treatment, four were unrelated to treatment, and three were of unknown cause.
Pattern of Relapse
Twelve patients had persistent locoregional disease. In the 49 patients who achieved a locoregional CR, six patients relapsed in the primary site alone, three patients relapsed in the nodal regions only, and seven patients had both primary and nodal recurrence. The 1-year and 2-year locoregional control rates are 65.6% (95% CI, 53.5% to 77.6%) and 57.2% (95% CI, 44.6% to 69.8%), respectively (Fig 2, Table 4). Eleven patients have developed distant metastases, and five patients have developed second primaries.
The pattern of first failure was as follows: persistent locoregional disease, n = 12; primary recurrence, n = 6; nodal recurrence, n = 5; primary and nodal recurrence, n = 1; primary and nodal recurrence and distant metastases, n = 1; distant metastases, n = 7; and second primary tumor, n = 5. Four patients died without evidence of disease progression (two of whom were listed as having study cancer as cause of death), and 20 patients are alive with no evidence of disease. The 1-year and 2-year disease-free survival rates are 62.3% (95% CI, 50.1% to 74.5%) and 45.5% (95% CI, 33.0% to 58.1%), respectively (Fig 3, Table 5).
Toxicity
The overall rates of grade 3, 4, and 5 (fatal) toxicities were 44%, 39%, and 3%, respectively (Table 6). Of significance, the rates of grade 3 and 4 mucositis were 48% and 10%, respectively. Grade 3 and 4 neurologic toxicity was observed in four patients (7%) and one patient (2%), respectively. This included two patients with clinical evidence of a transient ischemic attack who experienced complete recovery, two patients who had a peripheral neuropathy, and one patient who had a cerebrovascular accident with permanent sequelae.
A striking difference was observed in the rates of overall grade 4 and 5 toxicities between the experienced versus the inexperienced institutions. At the experienced centers, the rates of grade 4 and 5 overall toxicities were 14% and 0% compared with 47% and 4%, respectively, at the inexperienced institutions. When grade 4 toxicities were analyzed by category, there were 10 (21%) of 47 patients with hematologic events among the inexperienced centers compared with one (7%) of 14 patients among the experienced centers. There were 12 (26%) of 47 patients with grade 4 nonhematologic toxicities among the inexperienced centers compared with two (14%) of 14 patients among the experienced centers. The two patients who experienced treatment-related fatal toxicity at the inexperienced institutions represented the first patient enrolled onto the multi-RADPLAT protocol at their respective institutions. One patient developed leukopenia and pneumonia, which eventually led to sepsis and death. The patient finished the fourth infusion of IA cisplatin but refused to have her blood drawn for CBC. Twelve days later, this patient was found to have a WBC of 500 K/mm3 along with pneumonia that led to death. The other patient died from septic emboli that complicated a femoral vein thrombosis superimposed on a grade 3 neutropenia, which occurred after the fourth infusion of the IA cisplatin had been delivered but during the course of the RT treatments.
DISCUSSION
Two different and unique factors may explain our success in the delivery of IA cisplatin on our protocol. First, the interventional radiology techniques have vastly improved during the last several decades. An interventional radiology procedure that may have seemed dauntingly sophisticated not too long ago is now much more widely known and practiced by the radiology community. Second, a training workshop was held for the key investigators, including interventional radiologists from the inexperienced centers, before the initiation of the multi-RADPLAT protocol. During this 2-day workshop, we presented formal didactic lectures and showed live demonstrations of the delivery of IA cisplatin. Among other things, we discussed some of the subtle nuances involved in the delivery of the IA chemotherapy, such as the importance of subselective external carotid artery catheterizations (whenever possible) and the timing of the IV delivery of sodium thiosulfate during and after the cisplatin. This workshop was undoubtedly a key factor in our success of the delivery of IA cisplatin on this protocol.
Although there was no major difference in the ability to administer the RADPLAT therapy between the inexperienced versus the experienced centers, the overall rate of grade 3 to 5 toxicities was much higher at the inexperienced institutions. Although it is unclear why this occurred, one may speculate that impending bone marrow failure may have been better predicted by the experienced team. The protocol allowed for withholding cisplatin for up to 2 weeks if the counts were decreasing, and it is possible that the experienced investigators more often recognized a plunging count in time to withhold therapy. The two protocol treatment-related deaths on the multi-RADPLAT protocol occurred at the inexperienced centers. In fact, both patients who experienced a treatment-related death represented the first patient enrolled onto the multi-RADPLAT protocol at each of their respective centers. Additionally, both patients died well after receiving the fourth infusion of the IA cisplatin but during the RT treatments. These two protocol treatment-related deaths led to a temporary hold on the enrollment of patients to the multi-RADPLAT protocol for approximately 3 months until a comprehensive reassessment of the toxicities could be conducted. This included a careful review of the two patients who suffered transient ischemic attacks. However, there were no obvious deviations from the protocol, and in each instance in which there was an adverse event, it was not related to any specific technical error. The protocol was reactivated after discussion with many of the coinvestigators, and no further grade 5 events were observed for the duration of the protocol. Hence, the marked difference in the toxicity rates between the experienced versus the inexperienced institutions definitely reveals a learning curve associated with the RADPLAT protocol therapy. Interestingly, we did not observe a learning curve in the technical delivery of the IA cisplatin.
Comparison of multi-RADPLAT therapy with other studies is hampered by the inclusion of patients with less advanced disease (ie, stage III disease or less),10-20 different timing of the chemotherapy with the RT (ie, sequential or alternating v concurrent),11-13 nonstandard fractionated RT,14-16 or noncisplatin-carboplatin-containing regimens17,18 in the trials. Because these obstacles eliminate many of the trials, there are only three important trials left for comparison based on a similar treatment regimen; these trials are the RTOG protocol 8117,10 the Head and Neck Intergroup Study (RTOG/Southwest Oncology Group),19 and the Groupe Oncologie Radiotherapie Teteaet Cou (GORTEC) trial.20 Common to all of these trials was the use of concurrent cisplatin- or carboplatin-based chemotherapy and conventionally fractionated RT. However, these studies also included patients who had less than T4 disease, and with the exception of the Head and Neck Intergroup Trial, all had a substantial proportion of stage III disease patients. The Head and Neck Intergroup study was a phase III randomized trial of stage IV (96%) head and neck cancer patients, comparing RT alone (70 Gy in 35 daily fractions) with the identical RT plus concurrent bolus cisplatin (100 mg/m2 on days 1, 22, and 43) or split-course RT plus infusional fluorouracil and bolus cisplatin. The GORTEC trial was a phase III randomized trial of stage III to IV oropharyngeal cancer patients, comparing conventional RT alone (70 Gy in 35 fractions) with the same RT plus concurrent carboplatin (70 mg/m2/d) and fluorouracil (600 mg/m2/d) on days 1 to 4, 22 to 25, and 43 to 46. The Head and Neck Intergroup, GORTEC, and RTOG 8117 trials reported 2-year survival outcomes of 41%, 49%, and 39.5%, respectively, for the concurrent chemoradiotherapy therapy arms, which used cisplatin- or carboplatin-containing regimens and standard RT. However, it should be emphasized that the Head and Neck Intergroup Trial and the GORTEC trial were phase III studies and RTOG 8117 was a phase II trial conducted 20 years previously. Thus, fair comparisons with our current phase II trial are problematic based on differences in patient selection, time frame, and study design.
We conclude that the RADPLAT therapy is feasible and transportable to the multi-institutional setting. There does not seem to be a learning curve associated with the technical delivery of the IA cisplatin with RT, although there is definitely a learning curve associated with the management of side effects and toxicities during the RADPLAT therapy. Given our favorable efficacy results, a phase III randomized trial comparing IA to IV cisplatin with concurrent RT for patients with stage IV unresectable head and neck squamous cell carcinoma should be conducted.
Authors’ Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank all the clinical investigators for enrolling patients onto this trial. In addition, we acknowledge the dedication and hard work of the statisticians, clinical research associates, dosimetrists, and administrative staff who have contributed to the success of this trial. In particular, we thank Thomas F. Pajak, PhD, for his valuable contributions in statistics, Linda Messett for data management, and Bernadine Dunning for radiation quality assurance.
NOTES
Supported by grant No. ROI-CA-95-012 from the National Cancer Institute, Bethesda, MD (K.T.R.).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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