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© 2003 American Society for Clinical Oncology Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer
From the Department of Medicine, Section of Hematology/Oncology, Department of Radiation and Cellular Oncology, Section of Otolaryngology/Head and Neck Surgery and the Cancer Research Center, University of Chicago; the Departments of Medicine, Radiation Oncology, and Otolaryngology/Head and Neck Surgery and the Cancer Research Center, Northwestern University; the Departments of Medicine, Radiation and Cellular Oncology, and Otolaryngology/Head and Neck Surgery, University of Illinois, Chicago, IL. Address reprint requests to: Everett E. Vokes, MD, University of Chicago, 5841 S. Maryland Ave, MC 2115, Chicago, IL 60637-1470; email: evokes{at}medicine.bsd.uchicago.edu.
Purpose: The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. Patients and Methods: Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. Results: Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. Conclusion: Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.
THE ROLE of chemotherapy for locoregionally advanced head and neck cancer continues to evolve.1,2 Recent randomized trials and meta-analyses have demonstrated improved disease-free and/or overall survival with concomitant chemoradiotherapy and confirmed its role as standard therapy for patients with locoregionally advanced unresectable disease.3–9 The positive effects on disease-free and overall survival seem to be predominantly mediated through improved locoregional control, thus affecting the traditionally predominant pattern of failure for this disease. Induction chemotherapy, in contrast, has been less conclusively demonstrated to result in improved survival.10–12 However, induction therapy has been shown to decrease the incidence of distant metastases, indicating activity against systemic micrometastatic disease. In addition, it allows for the omission of laryngectomy as a first-line procedure for patients with laryngeal or hypopharyngeal cancer,13,14 although a concomitant approach more frequently allows for larynx preservation.9
Recent studies at the University of Chicago, Northwestern University, and the University of Illinois have focused on intensive concomitant chemoradiotherapy regimens.15–19 We recently reported two studies investigating paclitaxel, fluorouracil, hydroxyurea, and twice-daily radiotherapy (TFHX) administered on 5 consecutive days of every other week (total radiotherapy dose 75 Gy).18,19 In patients with stage IV disease, this TFHX regimen resulted in a high locoregional control rate and encouraging 3-year progression-free and overall survival rates of approximately 60% (Table 1
We postulated that administration of induction chemotherapy before intensive concomitant chemoradiotherapy might be necessary for effective eradication of systemic micrometastases. The most successful induction chemotherapy regimen studied to date remains the combination of cisplatin and fluorouracil.10,22 This regimen requires the administration of infusional chemotherapy and is associated with cisplatin-related toxicities as well as fluorouracil-related mucositis. In recent years, the taxanes have emerged as similarly active agents in recurrent head and neck cancer and do not produce mucositis.22,23 In this study (University of Chicago protocol 9502), we investigated the feasibility of the weekly administration of carboplatin and paclitaxel for a brief, intensive, 6-week course of induction chemotherapy.24,25 This regimen had been shown to be active in advanced non–small-cell lung cancer and feasible as a brief dose-dense regimen, thus avoiding a long delay of curative intent concomitant chemoradiotherapy and possible selective repopulation of resistant tumor cells.26–28 The goals of protocol 9502 were to evaluate the response activity of carboplatin and paclitaxel and the feasibility of subsequent administration of the previously used TFHX combination and to assess the effect of the entire treatment sequence on survival and locoregional and systemic disease control rates.
This study opened in November 1998 and closed to accrual in January 2000. Patients were followed through January 2002. Eligible patients had squamous cell carcinoma, poorly differentiated carcinoma, or lymphoepithelioma of the head and neck. Patients had stage IV (M0) disease; those with stage III disease were eligible only if the primary site was located at the base of tongue or hypopharynx. Before study entry, each patient was reviewed at a joint conference with representatives from surgical, radiation, and medical oncology. Patients had a performance status of 0 to 2 and had received no prior chemotherapy or radiotherapy. Surgical therapy before induction chemotherapy was allowed only if it consisted of organ-sparing procedures such as simple excision of the primary, debulking of airway-compromising tumors, or a neck dissection. Initial staging procedures consisted of a history and physical, panendoscopy and biopsy with tumor measurements, dental evaluation, head and neck and chest computed tomography (CT) scan, bone scan, barium swallow, and quality of life and speech and swallowing assessment. Placement of a feeding device was recommended. All patients signed informed consent before beginning therapy.
Protocol Treatment
Concomitant chemoradiotherapy with TFHX has been previously described.18,19,29,30 Briefly, radiotherapy was administered bid during five cycles of chemotherapy and administered every other week. Chemotherapy consisted of hydroxyurea at 500 mg PO every 12 hours for 6 days (11 doses), with the first daily dose of hydroxyurea on days 1 to 5 given 2 hours before the first fraction of daily radiotherapy, a continuous infusion of 5-fluorouracil (FU) at 600 mg/m2/d x 5 days (120 hours), and 100 mg/m2 of paclitaxel as a 1-hour infusion on day 1 after the first dose of radiation. Radiation therapy was administered bid at 1.50 Gy per fraction with a minimum of 6 hours between fractions on days 1 to 5. Radiotherapy doses and fields were determined as previously described.18 No chemotherapy or radiotherapy was administered on days 6 to 14 of each cycle. Chemoradiotherapy cycles were repeated every 14 days until completion of radiotherapy. For grade 3 neutropenia on previous cycles or neutropenia  grade 2 on day 1 of the next cycle, granulocyte colony-stimulating factor (GCSF) support (5 µg/kg SQ) was given on days 6 through 12 of any remaining cycles, beginning 12 hours after completion of FU. Utilization of antifungal mouthwashes and the application of Natural Care Gel (CR Bard, Inc., Covington, GA) to the skin within the radiation field were often recommended.
Dose modifications during induction chemotherapy were based on blood counts obtained on the day of treatment. For a granulocyte or platelet count of 1,000 to 1,499/mL or 75,000 to 100,000/mL, respectively, 50% of paclitaxel and carboplatin were administered; for values less than 1,000/mL or less than 75,000/mL, respectively, chemotherapy was held. For neutropenic fever, chemotherapy was to be delayed until the patient was afebrile and off intravenous antibiotics and the absolute neutrophil count (ANC) was more than 1,500/mL. Subsequent doses of paclitaxel and carboplatin were reduced by 25%. The use of GCSF was not prohibited. For grade 2 to 4 nonhematologic toxicities (excluding alopecia, nausea, or vomiting) therapy was held for 1 week and resumed at 50% when toxicities had resolved to Dose adjustments during TFHX chemoradiotherapy have been described.18 The protocol plan was to continue treatment cycles despite mucositis or dermatitis. For grade 4 in-field toxicity lasting more than 7 days or on day 1, FU was decreased to 500 mg/m2/d and paclitaxel to 75 mg/m2. For myelosuppression, treatment cycles could be postponed for 1 week or interrupted if the patient experienced persistent fever or if a serious infection was detected. For a WBC cell count of 1,000 to 1,999/µL or a platelet count of 50,000 to 74,000/µL, the paclitaxel dose was decreased to 75 mg/m2, and the hydroxyurea dosage was reduced by 50%. If a WBC count less than 1,000/µL or a platelet count less than 50,000/µL occurred during a treatment cycle, paclitaxel and hydroxyurea were withheld, but FU and radiotherapy continued.
Surgery
Quality of Life/Performance Outcome
Treatment Evaluation and Statistical Considerations
Time to progression was measured as time from the first day of therapy until first disease progression; patients dying of toxicity and those with residual disease at the primary site 30 days after treatment were counted as treatment failures. Location of progressive disease within or outside the irradiated area was documented. Survival was measured from the date of study entry until date of last follow-up or death. The expected response rate to induction was 75% and to the entire regimen, 90%. A Simon two-stage phase II design was used.38,39 Time to progression and survival time were calculated using Kaplan-Meier curves. Quality-of-life data were analyzed using the
A total of 69 patients were registered. The median follow-up time was 28 months. The baseline patient characteristics are summarized in Table 2  . The median age was 58 years. The majority of tumors originated from the oropharynx, larynx, or hypopharynx. Sixty-six patients had stage IV and three patients had stage III disease (Table 3). A feeding support device was placed in 60% of patients before initiation of therapy; feeding tubes were placed in an additional 7% during treatment. Initial surgical procedures are listed in Table 4. They allowed for organ preservation in all cases.
Induction Chemotherapy Following 6 weeks of induction chemotherapy, 61 patients were evaluated for response. Eight patients were not evaluated for response because of the absence of measurable disease following initial organ-preserving surgery (Table 5 ). Five patients were not assessable for response: one patient died of sepsis following a complication of a feeding tube device, two patients refused continuation of their chemotherapy before completion of 6 weeks of therapy, one patient had declining performance status, and one patient changed hospitals for insurance reasons. Overall, 21 of 61 patients with measurable disease (35%; 95% confidence interval [CI], 23% to 47%) had a clinical complete response, 31 patients (57%; 95% CI, 39% to 75%) had a partial response, two patients had stable disease, and two patients had progressive disease (one patient progressed locally and one developed bone metastases). The overall response rate in patients with measurable disease was 87% (95% CI, 78% to 96%).
Toxicities to induction chemotherapy are listed in Table 6a . Neutropenia was grade 3 or 4 in 18% of patients, respectively. One patient died of sepsis and pancytopenia following a G-tube complication within 1 day of initiation of chemotherapy. GCSF was administered to three patients. Grade 2 or 3 neuropathy was noted in 6% and 2% of patients, respectively. The feasibility of administering 6 weeks of this chemotherapy was further evaluated by calculating the dose intensity. As shown in Table 7a, approximately 80% of patients received more than 75% of the intended weekly paclitaxel dose, and 80% received more than 75% of the intended weekly carboplatin dose.
Concomitant Chemoradiotherapy Following completion of induction chemotherapy, patients received locoregional therapy with TFHX and were evaluated for final response to therapy. Again, eight patients without measurable disease are not evaluable. Six patients were not assessed, including the same five patients described above and one patient who refused chemotherapy and received radiotherapy alone. Eighty-two percent had a complete response as final response, 5% a partial response, and 3% progressed (Table 5b  ).
The toxicities of TFHX were as previously described (Table 6b
Survival and Pattern of Failure
Only 10 patients have had documented progression of their disease. The first site of progression was locoregional (within the irradiated volume) in five of these patients; two of these patients subsequently also progressed systemically. The 2-year local control was 94% (95% CI, 88% to 100%). The 2-year distant control was 93% (95% CI, 86% to 99%). Five patients failed distantly without documented locoregional failure. One patient developed a second primary in the esophagus.
Surgery
Quality of Life/Performance Status On-treatment versus 12-month follow-up analysis is limited to 34 patients with baseline and 12-month data. The majority of symptoms worsened significantly on treatment, with most returning to pretreatment levels or better by 12 months. Dry mouth continued to be significantly worse at 12 months compared with baseline (41% v 10%, P = .02), with little change over the next year. At 12 months, 82% were eating solid foods, with 25% of this group able to eat soft foods only compared with 88% and 13% pretreatment. Fourteen of 57 patients alive at 12 months had feeding tubes. Three of these patients were able to take food orally and had tubes removed over the next 6 months; six were able to eat soft or blended foods but continued to use tubes to supplement intake; five were unable to take anything by mouth. The latter group represented one patient who had a salvage glossectomy for residual disease (primary was oral tongue), two patients with cancer of the hypopharynx, one with tonsillar cancer, and one with cancer of the supraglottic larynx. All five had T4 disease at diagnosis.
Previous trials investigating intensified concomitant chemoradiotherapy at our institutions demonstrated high locoregional control, organ preservation, and overall survival rates. These trials also suggested distant failure as the predominant pattern of failure in patients receiving intensive chemoradiotherapy.17–19 One goal of this study was to identify a well-tolerated, intensive, and brief outpatient regimen that might have activity against micrometastatic disease while minimizing the delay of locoregional therapy. Our experience with the weekly administration of carboplatin and paclitaxel shows a major response rate of 86% following 6 weeks of therapy, with approximately 35% of patients having a complete response. These response data are similar to those reported for cisplatin and fluorouracil or more recent regimens but are achieved with good subjective tolerance and less mucositis.10,11,40 Significant neuropathy was seen in only one patient. The administration of subsequent TFHX locoregional therapy was not compromised. These data suggest that a brief course of carboplatin and paclitaxel on a weekly schedule is active and well tolerated without compromising the ability to administer subsequent intensive chemoradiotherapy. Progression-free and overall survival data in this trial are highly encouraging. In addition, only one patient had residual disease in the neck at lymph node dissection, a marked reduction from the 35% previously reported when using chemoradiotherapy alone.41 Because the timing of neck dissection was not standardized, it is possible that factors other than the use of induction chemotherapy contributed to this difference. The 3-year progression-free and overall survival rates of 80% and 70%, respectively, nominally exceed those of our previous trials and are among the highest published in the literature. They support a randomized comparison and definitive evaluation of this approach. Only five patients each have progressed locally or systemically. These findings are consistent with our hypothesis that induction chemotherapy as given here can result in reduced distant disease failure rates in the context of intensive concomitant chemoradiotherapy. However, definitive proof of this will require a randomized trial. As in our other recent trials, the great majority of patients were treated without disabling surgery. Only two patients had a major resection of the primary tumor site (larynx and tongue, respectively). Functionally, we describe a number of patients with swallowing dysfunction, particularly those patients with primary oropharyngeal disease. Data from other published trials of concomitant chemoradiotherapy are not available for comparison. Organ function has become the focus of ongoing trials in our network, aiming at reducing radiation doses and long-term treatment sequelae. Clearly, long-term organ function in the context of anatomic organ preservation is emerging as a treatment goal of current investigations. Altered methods of radiation delivery (eg, intensity-modulated radiotherapy) and/or the use of mucosal protectant agents are strategies of interest in that setting.42 Although concomitant chemoradiotherapy represents current standard therapy, there is large diversity in the specific concomitant regimens. There is evidence to suggest that treatment intensity may matter. For example, single-agent cisplatin has been advocated by the US Intergroup; however, in this population of "unresectable" patients, 3-year survival data were only 37% (and 20% for radiotherapy alone).43 Recent regimens using combination chemotherapy have shown higher survival rates of approximately 50%.5,6,40 Finally, the intensive regimens studied in our Chicago network or similar regimens studied at the Cleveland Clinic seem to yield even higher local control and survival rates.17–20 Collectively, these findings support a hypothesis that the treatment intensity of concomitant chemoradiotherapy is important. In our opinion, it would be appropriate to directly compare the regimens described by Brizel et al6 or Calais et al8 to the approach described here in a randomized trial design. Such a trial would define an optimal regimen and clarify the role of treatment intensity in the concomitant therapy setting. This would require a national Cooperative Group to adopt these regimens because only the Calais regimen was developed in a Cooperative Group. In summary, we have identified a treatment approach that results in high disease-control, organ-preservation, and survival rates in a population of stage IV patients. Although toxicities are significant, this regimen has been shown to be feasible at multiple institutions representing a variety of practice settings. Furthermore, the TFHX regimen has now been studied in three consecutive trials that have remarkable consistency in their findings. Although each single trial was designed as a phase II study, the collective experience now includes over 200 patients treated in a multi-institutional setting with consistent results. Given the strong survival and organ-preservation rates reported here, a comparison of this regimen with less-intensive current chemoradiotherapy regimens seems indicated. Similarly, the addition of one of the recently identified targeted agents with activity in head and neck cancer should be pursued44–46 because their inclusion in a successful chemoradiotherapy strategy might allow for a further increase in disease control and/or the definition of a less toxic approach.
We thank Michelle Scheuer for assistance with the preparation of the manuscript and Jan-Marie McEvilly, Mary Jesse, Rosalyn Williams, Gary Gordon, MD, Athanassios Argiris, MD, and Rod Humerickhouse, MD, for assistance with data management and patient care.
Supported in part by the University of Chicago/Northwestern University Oral Cancer Center (P50 DE11921-04), University of Chicago Cancer Research Center (P30 CA14599), The Francis Lederer Foundation, The Geraldi Norton Memorial Corporation, The Robert and Valda Svendsen Memorial, and Bristol-Myers Squibb, Princeton, New York. Presented at the Annual Meetings of the American Society of Clinical Oncology in May 2000 in New Orleans, LA, and in May 2002 in Orlando, FL.
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42. Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339–3345, 2000 43. Adelstein DJ, Adams GL, Ki Y, et al: A phase III comparison of starndard radiation therapy (RT) versus RT plus concurrent cisplatin (DDP) versus split-course RT plus concurrent DDP and 5-fluorouracil (5FU) in patients with unresectable squamous cell head and neck cancer (SCHNC): An Intergroup study. Proc Am Soc Clin Oncol 19:411a, 2000 (abstr 1624) 44. Senzer N, Soulieres D, Siu L, et al: Phase II evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 20:2a, 2001 (abstr 6) 45. Cohen E, Rosen F, Dekker A, et al: Phase II study of ZD1839 (Iressa) in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 21:225a, 2002 46. Hong W, Arquette M, Nabell L, et al: Efficacy and safety of the anti-epidermal growth factor antibody (EGFR) IMC-C225, in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 20:224a, 2001 (abstr 895) Submitted June 4, 2002; accepted September 26, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. 
