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© 2002 American Society for Clinical Oncology Organ Preservation Therapy Using Induction Plus Concurrent Chemoradiation for Advanced Resectable Oropharyngeal Carcinoma: A University of Pennsylvania Phase II TrialByFrom the Department of Radiation Oncology, Division of Medical Oncology, Department of Medicine, and Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Medical Center, Philadelphia, and Pocono Medical Center, East Stroudsburg, PA; and Department of Medical Oncology, Falmouth Hospital Oncology Center, Mashpee, MA. Address reprint requests to Mitchell Machtay, MD, Department of Radiation Oncology, 2 Donner Bldg, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104; email: machtay{at}xrt.upenn.edu
PURPOSE: To determine the efficacy, feasibility, and toxicity of a new regimen for locally advanced oropharyngeal carcinoma. PATIENTS AND METHODS: Patients had technically resectable stage III/IV squamous cell carcinoma of the oropharynx, exclusive of T1-2N1. Induction chemotherapy consisted of carboplatin (area under the curve formula equal to 6) and paclitaxel 200 mg/m2 for two cycles, followed by re-evaluation. Patients with major response continued to definitive radiotherapy (70 Gy over 7 weeks) plus concurrent once-weekly paclitaxel (30 mg/m2/wk). Patients with advanced neck disease also underwent post–radiation therapy neck dissection and two more chemotherapy cycles. RESULTS: Fifty-three patients were enrolled. Median follow-up was 31 months (minimum follow-up for survivors was 18 months). The major response rate to induction chemotherapy was 89%; 90% of patients had a complete response after concurrent chemoradiation. Actuarial survival at 3 years was 70%, and 3-year event-free survival was 59%. The 3-year actuarial locoregional control was 82% and the 3-year actuarial rate of distant metastases was 19%. Organ preservation was achieved in 77% of all patients. One patient (2%) died during therapy. Late grade 3 toxicity occurred in 24% of patients, consisting mainly of chronic dysphagia/aspiration and/or radiation soft tissue ulceration. The treatment-related mortality rate was 4% (two patients died from respiratory failure). CONCLUSION: Response to induction chemotherapy as studied in this trial was not useful as a predictive marker for ultimate outcome or organ conservation. Overall, however, this regimen offers good disease control and survival for patients with locally advanced oropharyngeal carcinoma, comparable with other concurrent chemoradiation programs. Further study of similar protocols is indicated.
SQUAMOUS CELL carcinoma of the head and neck (SCCHN), including oropharyngeal carcinoma, can be treated effectively with local therapy alone when it presents in an early stage.1,2 Unfortunately, advanced disease is a common presentation, and the prognosis is then poor.3-6 For advanced oropharyngeal carcinoma, surgery plus postoperative radiation therapy (XRT) is a commonly used strategy, in an effort to improve local control over XRT alone.4,7,8 However, this strategy may result in significant functional/cosmetic deficits (for T3-4 tumors) and does not address the potential for occult distant micrometastases (a common problem in N2-3 disease). Data from our institution show that patients with stage III/IV oropharyngeal carcinoma (exclusive of T1-2N1 disease) treated with surgery and postoperative XRT have approximately a 30% risk of locoregional relapse, a 30% risk of distant relapse, and a 60% risk of having a poor functional outcome.9 In this historical series of surgery and postoperative XRT, functional outcome was good for T2N1-2 lesions but suboptimal for T3-4 cancers. In light of these data, we designed a prospective phase II trial that attempted to address the challenges of locoregional control, distant control, and functional organ preservation/function. We decided to use induction chemotherapy (before concurrent chemoradiotherapy) so that nonresponders to induction chemotherapy could undergo early surgical therapy in a nonirradiated operative bed as performed in the Veterans Affairs (VA) larynx preservation trial.10 Induction chemotherapy was also used in an effort to maximize freedom from distant metastases.
Patient Selection This study was activated in August 1997 and closed to accrual in June 2000. Potentially eligible patients were evaluated in the multidisciplinary Head and Neck Cancer Center at the University of Pennsylvania Medical Center. Eligibility required squamous cell carcinoma of oropharyngeal origin, stage T3-4N0-3M0 or T2N2-3M0 (American Joint Committee on Cancer 1997 staging system). In addition, there had to be a consensus opinion that the tumor was potentially resectable, so that there would be the opportunity for salvage surgery if indicated. Patients were selected for this study for one or more of three reasons: (1) consensus opinion was that surgery plus postoperative XRT would result in a significant likelihood of permanent serious functional disability (such as anticipated need for total laryngectomy); (2) consensus opinion was that surgery plus postoperative XRT was likely to be followed by early recurrence (particularly the risk of distant metastases associated with advanced nodal disease); and (3) patient preference for nonsurgical therapy for advanced oropharyngeal carcinoma. Patients whose tumors grossly invaded the mandible were ineligible, because of the greater potential for osteoradionecrosis after high-dose chemoradiation.
There was no age restriction, but Karnofsky performance status was required to be 70% to 100%. Adequate hematologic reserve (WBC The study was reviewed before activation and on an annual basis by the University of Pennsylvania Institutional Review Board. All patients signed study-specific Institutional Review Board–approved informed consent forms. Patient characteristics (N = 53) are listed in Table 1.
Treatment The treatment schema is shown in Fig 1. All patients received two cycles of neoadjuvant (induction) chemotherapy with carboplatin and paclitaxel (Taxol; Bristol-Myers-Squibb, Princeton, NJ) on days 1 and 22. Paclitaxel was administered as a 3-hour infusion at a dose of 200 mg/m2, and the carboplatin dose was determined using the area under the curve formula to equal 6. In the original study design, colony-stimulating factors were not included; however, because of a higher than expected neutropenic fever rate and resultant unacceptable delays in starting definitive local therapy, the study was modified after the first 22 patients to incorporate the use of granulocyte colony-stimulating factor. This was described in our initial report of the interim analysis of this study.11
Approximately 2 weeks after the second dose of carboplatin/paclitaxel, patients were reassessed for evidence of an early major response, defined as  50% reduction in the size of the primary tumor on the basis of endoscopic evaluation. Patients who did not respond to induction chemotherapy underwent re-evaluation for consideration of definitive surgical resection (and postoperative radiotherapy). Those patients who had a response proceeded to radical chemoradiation. This consisted of standard-fractionation XRT (70 Gy over 7 weeks, in 2-Gy once-daily fractions) plus once-weekly paclitaxel. Originally, the weekly paclitaxel dose was 50 mg/m2/wk; however, after the first six patients this was lowered to 30 mg/m2/wk because of excessive mucositis. This was also described in our interim analysis.11 All patients underwent placement of a prophylactic percutaneous endoscopic gastrostomy (PEG) tube before starting chemoradiation. Patients with N2-3 disease whose primary tumors were controlled after concurrent chemoradiation underwent a modified neck dissection (with efforts to preserve cranial nerve XI, the jugular vein, and/or the sternocleidomastoid muscle if possible). These patients with advanced neck disease also received two cycles of adjuvant carboplatin/paclitaxel at a dose/schedule identical to that used for induction therapy. Patients were seen at least once per month for the first year after treatment, at which time complete physical examination (including endoscopic examination) was performed. After the first year, patients were seen at least once every 2 to 3 months. Chest radiography and cross-sectional imaging (computed tomography or magnetic resonance imaging) of the neck were performed at least once per year. Further details regarding chemotherapy, radiotherapy, and surgical techniques for this study have been previously reported.11
Statistical Design Other planned end points of the study were overall survival (OS), locoregional control (LRC), distant metastases (DM) rate, response rates, acute and late toxicity, functional EFS (FEFS), organ preservation, functional organ preservation, and quality of life. Toxicity analysis used the Radiation Therapy Oncology Group (RTOG) acute morbidity scale for the first 6 months after therapy; subsequently, late complications were graded using the RTOG/European Organization for Research and Treatment of Cancer late morbidity scale.13 FEFS was defined as freedom from an event (as defined above) and freedom from requiring radical surgery, permanent PEG, or permanent tracheostomy. The organ preservation rate was calculated as the crude probability of avoiding local recurrence and/or need for radical surgery. The modified organ preservation rate was calculated as the crude probability of avoiding local recurrence, the need for radical surgery, the need for a permanent tracheostomy tube, and/or the need for a permanent PEG tube. Quality of life was measured by the List performance status scale for head and neck cancer,14 listed in Table 2.
Feasibility A total of 53 patients were enrolled. Patient characteristics are listed in Table 1. This study was feasible; all but one patient received both doses of induction chemotherapy (IC) and only one patient failed to receive the full dose of XRT. Of 50 patients slated for concurrent chemotherapy, a full course of seven doses was given to 33 (66%). An additional eight patients received six of seven doses successfully. A minimum of five doses of concurrent paclitaxel (of seven possible) was given to all but two patients (96%). There was less compliance with post-XRT treatment: only 78% of N2-3 patients underwent posttreatment neck dissection and only 53% of N2-3 patients received adjuvant chemotherapy. There was also poor compliance among IC nonresponders to proceed to radical surgery: there were six nonresponders to IC, only three of whom underwent radical surgery.
Response
EFS and Survival
An exploratory analysis of possible factors predicting for survival was performed. The most significant factor was T stage (T2-3 v T4). For patients with T2-3 tumors (n = 32), OS was 83%. In contrast, patients with T4 tumors (n = 21) had an OS rate of 46%. This was highly statistically significant (P = .002). Age (< v the median age) was a borderline significant predictor of survival (P = .07). Other factors, including sex, N stage, or subsite within the oropharynx, were not predictive of survival.
Patterns of Failure
Among the nine patients who experienced locoregional failure, the median time to locoregional failure was 9 months. One of these nine patients has no evidence of disease 18 months after salvage subtotal glossectomy and laryngectomy; the remaining eight patients have died of subsequent recurrences. For patients who had DM, the median time to DM was 15 months. An exploratory analysis of possible factors influencing the risk of locoregional failure and/or DM was performed. T stage was highly predictive of LRC. T stage was not a statistically significant predictor of DM (crude rate, 24% for T4, 9% for T2-3; P = .15). All patients who developed DM had clinically node-positive disease. However, reliable statistical comparisons could not be made among N stages and risk of DM, because 41 of 53 patients in the entire study had N2 disease and only four patients had N0 disease. The only significant risk factor predictive for DM was pathologic response in the neck dissection specimen (P = .02). Of the eight patients suffering distant metastases, only two had a pathologic CR in the neck, whereas four had multiple residual lymph nodes and two patients did not undergo post-XRT ND despite having clinical N2 disease. Of the 24 patients with sterile ND specimens after XRT, only two developed DM.
Toxicity Induction chemotherapy was extremely well tolerated. In the first 22 patients (who did not receive granulocyte colony-stimulating factor), the neutropenic fever rate was 27% (all were uncomplicated). In the subsequent 31 patients, none developed neutropenic fever or other complications. Of the patients who received concurrent XRT/paclitaxel, 98% developed grade 3 mucositis. There were six patients (12%) who developed nonhealing soft tissue and/or mucosal radiation ulcers, two of whom had evidence also of osteoradionecrosis. All of these areas of necrosis healed with conservative management and/or hyperbaric oxygen, without the need for radical surgery. However, there were also six patients (12%) who experienced severe (grade 3), prolonged chronic dysphagia more than 9 months after chemoradiation despite objectively healed mucositis; these patients have had varying outcomes with treatments including hyperbaric oxygen, dilatation procedures, corticosteroids, and physical therapy. Thus, the overall rate of late grade 3 toxicity was 24%. There was no statistical association between grade 3 toxicity and potential prognostic factors including age and T stage.
Additional complications that may or may not be treatment-related include five patients hospitalized for nonneutropenic infection and four patients with vascular thromboses (one fatal myocardial infarction, one popliteal thrombosis, one superior mesenteric vein thrombosis, and one stroke). Overall, excluding neutropenic fever and mucositis, 22 of 53 patients (42%) had one or more grade
Functional Outcome There were 38 patients who had no evidence of disease after chemoradiation and were assessable for follow-up functional assessment on the basis of the List performance status scale scales. The median and mean follow-up diet normalcy scores were 70% and 65%, respectively. The median and mean follow-up eating-in-public scores were 75% and 67%, respectively. The median and mean speech understandability scores were 100% and 97%, respectively. The eating-in-public and speech understandability scores did not differ greatly from patients’ pretreatment scores. However, the average decline in diet normalcy score from pretreatment to follow-up levels was 18% (from 83% to 64%).
Our study is one of few prospective trials to combine both induction and concurrent chemoradiation for advanced oropharyngeal carcinoma or other SCCHN. The results are similar to those reported by several other investigators who performed this hybrid approach.15-19 Taken together, these data strongly suggest that the efficacy of this combination is at least as good if not better than surgery plus postoperative XRT. For example, this study had a 3-year survival rate of 70%, compared with our historical controls treated with surgery/XRT, who had a 51% 3-year survival rate.9 Both our current study and our historical control series consisted of stage III/IV oropharyngeal cancer (exclusive of T1-2N1 disease) with similar patient age and performance status levels. Of course, equivalence cannot be proven without a large randomized trial (as was done for laryngeal cancer a decade ago by the VA group10), but it is unlikely that a phase III trial of surgical versus nonsurgical management of locally advanced oropharyngeal cancer would now be feasible. The Eastern Cooperative Oncology Group is currently performing a multicenter phase II study (Eastern Cooperative Oncology Group 2399) with a design almost identical to our study (patients with nonoropharyngeal SCCHN are eligible). Possibly an even more provocative question is the role of induction and/or adjuvant chemotherapy, particularly in the setting of definitive concurrent chemoradiation. The rationale for systemic-dose chemotherapy is two-fold: first, to eradicate micrometastatic disease; and second, to serve as an in vivo predictor of subsequent outcome. Our observed rate of DM was lower than we observed in our previous study of local therapy alone.9 There have been some trials that only used concurrent chemotherapy (usually at doses below systemic induction chemotherapy doses) that also showed good distant control.20,21 Other studies of concurrent chemoradiotherapy, however, found that concurrent chemoradiotherapy does not seem to reduce the risk of DM compared with XRT alone.22-24 The high risk of DM in some concurrent chemoradiation studies may reflect their exceptionally high local control rates, leading to increased risk for surviving patients to develop DM.25 In our series, the crude rate of DM was 15%, which we believe to be lower than expected for this patient population (most of the patients had N2-3 neck disease). This study did consist entirely of patients with potentially resectable disease, and patients with gross mandible invasion were ineligible. This could bias the results favorably in comparison with studies that included a mixture of patients with advanced resectable and grossly unresectable disease. Follow-up remains relatively short, so it is unclear whether the aggressive chemotherapy used in this program actually prevents—or merely delays—the onset of DM. The possible contribution of induction chemotherapy to the excellent outcome in this series remains unclear. The second rationale for induction chemotherapy was championed by the VA larynx preservation trials and several other studies.10,26-28 In theory, patients who do not respond to induction chemotherapy might undergo early salvage with radical surgery and/or other aggressive locoregional therapies. Our study does not support this concept for two reasons: first, the response rate to induction chemotherapy with our regimen was extremely high (89%); and second, among nonresponders, compliance with the recommendation for radical surgery was low. In an era in which molecular prognostic markers are quickly becoming available, it is increasingly difficult to defend the use of induction chemotherapy solely as a predictive assay. There have been two recently reported randomized studies of oropharyngeal cancer that showed improved survival by adding chemotherapy to XRT: one used concurrent chemoradiation29 and the other used induction chemotherapy.30 The recent meta-analysis of randomized trials of chemotherapy added to local therapy showed that the survival benefit is almost entirely attributable to concurrent, rather than induction, chemotherapy trials.31 There are only a few trials directly randomizing patients to concurrent versus induction chemoradiation.21,32,33 These studies, although suggesting that concurrent therapy gave better LRC, do not show conclusive evidence of improved survival with concurrent combined therapy (compared with sequential). There has not been a randomized study comparing induction plus concurrent chemoradiation to concurrent chemoradiation alone. As local therapy improves by fine-tuning conventional therapy, distant failure seems to be an increasing problem, particularly in node-positive patients.34-40 Because adjuvant chemotherapy has not been well tolerated in SCCHN studies,41-43 induction chemotherapy deserves continued attention in clinical trials to address systemic micrometastases. Our study provides additional data regarding the feasibility of adjuvant chemotherapy, as only 53% of our N2-3 patients actually received it as planned according to the study design. The head/neck contracts randomized study suggested a possible advantage to maintenance chemotherapy for patients with N2 disease; thus, we will continue to use adjuvant chemotherapy in our next phase II chemoradiation trial. However, current data do not support the use of induction and/or adjuvant chemotherapy outside of the prospective research setting.31,44 One of the notable aspects of our trial is the disappointing results for patients with T4 tumors. Although the EFS and OS of the T4 subgroup seem to be similar to that obtained with surgical therapy, the results are grossly suboptimal. In our next trial for oropharyngeal carcinoma, we will explore the feasibility and efficacy of intensifying treatment for T4 tumors by using accelerated concomitant boost XRT in addition to chemotherapy. Accelerated XRT was shown in two large randomized trials to improve LRC and disease-free survival compared with standard XRT.45,46 We previously demonstrated the feasibility of combining continuous-course accelerated XRT with paclitaxel in a phase I study.47 Other groups have tested accelerated XRT plus nontaxane chemotherapy,48 including a recently completed though as yet unpublished phase II RTOG study (RTOG 99-14). Several European randomized studies of accelerated XRT plus chemotherapy have been reported in abstract form.49,50 As with other studies of chemoradiation, toxicity in our trial was formidable. The vast majority of serious complications were related to mucositis and dysphagia and its sequelae, including chronic mucosal ulceration, prolonged PEG dependence, and/or aspiration pneumonia. Many of these problems are similar to those seen with radical surgical approaches, raising the question of whether there is truly a quality-of-life advantage to concurrent chemoradiation.51 Clearly, there is a need to reduce the toxicity of combined-modality therapy, and there are three possible avenues to explore: (1) altering radiation delivery, such as using intensity-modulated XRT to reduce XRT doses to critical structures while maintaining (or even increasing) dose-intensity to gross tumor52; (2) addition of radioprotectors53; and/or (3) replacing some of the concurrent chemoradiotherapy dose-intensity with effective biologic agents that do not share overlapping toxicities.54 For our follow-up study, we have opted to add the radioprotector amifostine to the treatment regimen. Although one major study did not show a decrease in mucositis from amifostine,53 there are other data supporting its role in diminishing the epithelial/mucosal toxicities of chemoradiation.55,56 In summary, this phase II trial of induction plus concurrent (with or without adjuvant) paclitaxel-based chemotherapy for locally advanced oropharyngeal carcinoma was feasible and efficacious. This should be considered as an acceptable chemoradiation regimen for appropriately selected patients. The results warrant further investigations of regimens such as this in future phase II and/or phase III studies in comparison to immediate concurrent chemoradiation.
Supported in part by a grant from Bristol-Myers-Squibb, Princeton, NJ.
The partial funder of this study, Bristol-Myers-Squibb (the manufacturer of Taxol and carboplatin), did not have any role in the collection or analysis of the data in this trial or the writing of this article.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
1.5 g/dL) were also required. 
