The Oncologist, Vol. 8, No. 4, 350–360,
August 2003
© 2003 AlphaMed Press
ORIGINAL PAPER
Head and Neck Cancer |
Intensive Concurrent Chemoradiotherapy for Head and Neck Cancer with 5-Fluorouracil- and Hydroxyurea-Based Regimens: Reversing a Pattern of Failure
Athanassios Argirisa,
Daniel J. Harafb,
Merrill S. Kiesa,
Everett E. Vokesb
a Division of Hematology-Oncology, Northwestern University, The Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA;
b University of Chicago, Section of Hematology-Oncology, and University of Chicago Cancer Research Center, Chicago, Illinois, USA
Correspondence:
Athanassios Argiris, M.D., Northwestern University, The Feinberg School of Medicine, 676 North St. Clair Street, Suite 850, Chicago, Illinois 60611, USA. Telephone: 312-695-6180; Fax: 312-695-6189; e-mail: a-argiris{at}northwestern.edu
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Discuss the results of multicenter trials with chemoradiotherapy with 5-FU- and hydroxyurea-based regimens for the treatment of locoregionally advanced head and neck cancer.
- Explain the rationale for the combination treatment of radiation, 5-FU, and hydroxyurea.
- Recognize the toxicities and potential functional impairment for patients treated with aggressive concurrent chemoradiotherapy.
- Discuss the experimental role of induction chemotherapy in the management of locoregionally advanced head and neck cancer.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Combined modality programs that were developed over the past two decades demonstrated that the nonsurgical therapy of locoregionally advanced head and neck cancer is feasible and produces survival outcomes that are at least comparable with surgery. The systemic therapy of head and neck cancer has gained momentum in recent years. Several randomized studies have shown that the concurrent administration of chemotherapy and radiation therapy is superior to radiation therapy alone. In consecutive clinical studies since 1986, we have developed multiagent chemoradiotherapy regimens based on initial observations with the 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy combination. Three consecutive multicenter phase II trials reported that the combination of 5-FU and hydroxyurea with either cisplatin or paclitaxel along with twice daily radiation therapy administered every other week is a highly effective regimen with local control rates that approach 90% and 3-year survival rates of approximately 60% in patients with stage IV disease. The vast majority of patients in these studies achieved anatomical organ preservation. A reversal of the historical pattern of failure was evident, with distant sites becoming the predominant site of failure in each trial. The paclitaxel-containing regimen was better tolerated than the cisplatin-containing regimen and was advanced to further clinical testing. The incorporation of induction chemotherapy may improve the results of treatment by targeting systemic micrometastatic disease.
Key Words. Head and neck cancer • Chemotherapy • Radiotherapy • 5-FU • Hydroxyurea
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INTRODUCTION
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The treatment of locoregionally advanced head and neck cancer has undergone evolution in recent years. Chemotherapy is being increasingly utilized as part of combined modality programs in order to achieve organ preservation and to improve survival. As a result, the medical oncologist now plays a more central role in the multidisciplinary tumor board. Multiple randomized studies support the use of concurrent chemoradiotherapy over radiotherapy alone, especially in patients with unresectable head and neck cancer [1]. However, the most efficacious chemotherapy regimen and the optimal way to deliver radiation therapy remain to be established. Over the past decade, our group has conducted consecutive clinical trials using concurrent chemoradiotherapy for locoregionally advanced head and neck cancer. The basis of these regimens has been the combination of 5-fluorouracil (5-FU), hydroxyurea, and radiation (Table 1
). As these combined modality therapies evolved, it became evident that locoregional control, the Achilles heel of traditional therapies, was optimized and that distant metastasis emerged as the predominant site of failure. In the following, we review our experience with 5-FU- and hydroxyurea-based regimens and the rationale for protocol development with a focus on our recent chemoradiotherapy trials.
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5-FU AND HYDROXYUREA—AN ODD COUPLE?
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5-FU has long been known to have single-agent activity in head and neck cancer [2]. Although hydroxyurea, a ribonucleotide reductase inhibitor, has never undergone an adequate phase II evaluation as a single agent in head and neck cancer, single-agent activity has been reported [2]. The rationale for the combined use of 5-FU and hydroxyurea is based on their preclinical synergistic action against various tumors such as the L1210 leukemia model [3] and the Erlich ascites tumor [4]. It is postulated that hydroxyurea modulates the activity of 5-FU by depleting cellular pools of deoxyuridine monophosphate (dUMP) thus facilitating the binding of the 5-FU metabolite 5-FdUMP to its target enzyme thymidylate synthase [3, 5]. More importantly, the concurrent administration of antimetabolites, such as 5-FU and hydroxyurea, and radiation therapy is theoretically attractive. Antimetabolites are selectively cytotoxic to cells in the S phase, a relatively radioresistant phase of the cell cycle, and may contribute to the overcoming of radiation resistance. Indeed, both 5-FU and hydroxyurea have been shown individually to act as radiation enhancers in vitro and in vivo [6, 7]. Preclinical data from the study of two cell lines derived from patients with squamous cell cancer of the oral cavity demonstrated additive cytotoxicity with 5-FU, hydroxyurea, and radiation [8]. This effect was seen in a relatively radiation-resistant cell line, SQ-20B, with a higher percentage of cells in S phase, but not in SQ38, a more radiation responsive cell line. Thus, 5-FU and hydroxyurea may be most effective in rapidly proliferating tumor cells with a lower sensitivity to radiation [8].
At the clinical level, several randomized studies have investigated the role of the addition of single-agent 5-FU and hydroxyurea to radiation therapy in head and neck cancer. Three randomized trials compared radiation therapy and 5-FU with radiation therapy alone [9–11], two of which showed a survival benefit [9, 11]; one in subset analysis [9]. Three randomized trials with radiotherapy and hydroxyurea versus radiation alone were conducted in the late 1960s and early 1970s, all of which had flaws in methodology compared with current standards [12–14]. A study by Richards and Chambers showed improved local control with greater pathologic response rates in the hydroxyurea arm [13]. However, a study of 150 patients by Stefani et al. showed an inferior outcome in terms of the rate of distant metastasis and median survival in the hydroxyurea-treated patients [12, 15]. Finally, Hussey and Abrams reported results on 40 patients, 10 of whom had recurrent disease, randomized to either radiation therapy plus hydroxyurea or radiation therapy alone [14]. There were no statistically significant differences between the two treatment arms in survival outcomes. Overall, the role of single-agent hydroxyurea either alone, for the treatment of recurrent/metastatic disease, or with radiation, for locoregionally advanced head and neck cancer, has not been conclusively established, although the agent is approved by the U.S. Food and Drug Administration for use as a radiation sensitizer in head and neck cancer. Hydroxyurea has been studied as a radiosensitizer in other malignancies and has produced positive results for squamous cell carcinoma of the cervix [16]. Until recent data showed the superiority of cisplatin-based concomitant chemoradiotherapy, radiation plus hydroxyurea was considered the standard therapy for unresectable cervical cancer [17].
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5-FU, HYDROXYUREA, AND RADIOTHERAPY
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A phase I study was designed to identify the maximum tolerated dose (MTD) of 5-FU and hydroxyurea when administered with concomitant radiotherapy on a protracted schedule [18]. Radiotherapy was delivered once daily at 180–200 cGy, and 5-FU was administered as a 5-day continuous infusion at a dose of 800 mg/m2/day. Five days of treatment were followed by a 9-day rest period to allow for recovery from toxicities (1 week on, 1 week off). This alternate-week schedule of chemoradiotherapy was based on the previous experience of Byfield et al. with single-agent 5-FU [19] and Taylor et al. with cisplatin and 5-FU [20]. Therefore, the total duration of treatment was rather long: 70 Gy could be delivered in seven cycles or 13 weeks. The MTD of hydroxyurea was determined to be 1,000 mg administered orally every 12 hours for a total of 11 doses beginning 6–12 hours prior to the 5-FU infusion with one daily dose preceding radiotherapy by 2 hours [18]. These doses resulted in moderate-to-severe mucositis and mild-to-moderate myelosuppression. The regimen showed substantial locoregional activity, with objective response rates of more than 90% in both previously untreated and previously treated patients. This work led to additional phase I studies that suggested a role for chemoradiotherapy in locally recurrent disease [21–24].
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INTERMITTENT SCHEDULE OF CHEMORADIOTHERAPY
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When using multiagent chemotherapy in combination with concomitant radiotherapy, acute toxicities are frequently severe. As a result, chemotherapy and radiotherapy often have been integrated employing split-course radiotherapy, where interruptions of all therapy, similar to the administration of chemotherapy in cycles, are introduced to allow for normal tissue recovery. This approach is controversial, since protraction of radiotherapy as a single-treatment modality has been shown to be detrimental [25–28]. However, the addition of chemotherapy to a split course of radiotherapy may at least compensate for the planned interruption of radiotherapy [29]. Planned delays in chemoradiotherapy have been incorporated in efficacious aggressive chemoradiotherapy regimens [30]. Moreover, interruptions of therapy may be practically required even when continuous treatment is planned in order to ameliorate toxicities [31]. Following initial observations by Byfield et al. [19], Taylor et al. reported promising results with an alternate-week schedule (1 week on, 1 week off) of chemoradiotherapy with cisplatin and 5-FU [20]. A subsequent randomized trial showed improved locoregional control, albeit without improvement in survival, with cisplatin, 5-FU, and radiotherapy administered on an intermittent schedule compared with induction cisplatin and 5-FU followed by conventional radiotherapy [32]. Another split-course multiagent chemotherapy regimen with 5-FU and cisplatin, which incorporated optional surgery during the treatment break, was tested in a three-arm randomized comparison in patients with locally advanced unresectable head and neck cancer and showed no superiority over radiotherapy alone, whereas treatment with concurrent single-agent cisplatin and standard radiotherapy was optimal [33]. The interruption of the course of radiotherapy in this randomized trial was felt to be the reason for the suboptimal performance of the 5-FU, cisplatin, and radiation arm.
Despite employing an alternate-week schedule of chemoradiotherapy in the FHX regimen, efficacy results have been very encouraging. Due to the intensity of the FHX regimen, uninterrupted administration would not have been feasible.
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INDUCTION CHEMOTHERAPY FOLLOWED BY FHX
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Two sequential phase II trials were conducted using FHX after induction chemotherapy in patients with previously untreated locoregionally advanced disease [34, 35]. Patients received three cycles of induction chemotherapy with the cisplatin, 5-FU, leucovorin, and interferon combination (PFL-interferon) followed by optional organ-preserving surgery and the FHX regimen. The two trials differed only in the choice of leucovorin [34, 35]. Both studies showed high initial response rates to induction chemotherapy and high survival rates.
The first study enrolled 71 patients with locally advanced head and neck cancer [34]. Ninety-one percent of the patients had stage IV disease. Induction chemotherapy consisted of oral leucovorin along with 5-FU, interferon, and cisplatin for a total of three cycles. Fourteen patients were treated on a lower dose of interferon. All patients received the same FHX chemoradiotherapy regimen with total radiation doses of 65–75 Gy (Fig. 1). All 56 evaluable patients had at least a partial response to induction chemotherapy, and 59% achieved complete responses. The rate of grade III or IV mucositis during FHX therapy was 69%. Five toxic deaths occurred during induction chemotherapy. With a median follow-up of 37 months, the 3-year progression-free survival was 69% and the 3-year overall survival was 60% [34]. Twenty patients progressed with a predominant local pattern of failure: 15 patients progressed locally (approximately 25% at 3 years), four progressed distantly, and one progressed in both local and distant sites.
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Figure 1. Chemoradiotherapy regimens. Day 0 is Sunday. G-CSF is administered if the patient becomes neutropenic on previous cycles. Abbreviations: XRT = radiotherapy; HU = hydroxyurea; bid = twice daily; qd = once daily; po = orally.
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In the second trial, 93 patients were treated with PFL-interferon, but with the l- leucovorin stereoisomer administered as a continuous infusion, followed by FHX to 65–75 Gy (Fig. 1
) [35]. As in the previous study, organ-sparing surgery or neck dissection was performed after induction chemotherapy. Ninety-seven percent of patients had stage IV disease, including 66 patients who had stage N2 or N3. The complete response rate to induction chemotherapy was 66%. The toxicity of induction chemotherapy with PFL-interferon was considerable. Severe mucositis was frequent, and three deaths occurred due to neutropenic sepsis. The rate of grade III or IV mucositis observed during concurrent chemoradiotherapy with FHX was 81%. With a median follow up of 43 months, the 5-year progression-free survival was 68% and the 5-year overall survival was 62%. Similar to the previous phase II trial, patients failed predominantly in locoregional sites: 13 patients progressed locally (25% at 5 years), two progressed distantly, and five progressed in both local and distant sites. Thirty-five deaths occurred, 18 of which were from disease progression, six were treatment-related, two were from a second primary, and nine were from other medical causes, including toxicity. Although the induction chemotherapy with PFL-interferon was associated with considerable toxicity, its activity was comparable with newer taxane-based combination regimens, such as carboplatin, ifosfamide, and paclitaxel (TIC), cisplatin, 5-FU, leucovorin, and docetaxel (TPFL), and cisplatin, 5-FU, and docetaxel (TPF), that are currently under evaluation [36–38]. The reported survival rates with FHX were very promising, but locoregional control remained a major challenge.
The high efficacy of the FHX combination has been confirmed by other investigators [39–42]. The FHX regimen was one of the arms of a three-arm phase II randomized trial (R-9703) conducted by the Radiation Therapy Oncology Group (RTOG) in patients with stage III and IV head and neck cancer [39]. Regimens compared included: A) cisplatin (10 mg/m2) and 5-FU (400 mg/m2) during the last 10 days of radiation with 70 Gy over 7 weeks of consecutive daily radiation (XCF); B) weekly cisplatin (20 mg/m2) and paclitaxel (30 mg/m2) with 70 Gy of radiation over 7 weeks of consecutive daily therapy (XCT); and C) 5-FU (800 mg/m2) and hydroxyurea (1 g orally twice daily) with 70 Gy of radiation over 13 weeks, using an alternate-week schedule (FHX). Toxicities and survival rates were not statistically different among the three arms. Estimated 1- and 2-year survival rates were, respectively, 72% and 60% for XCF, 87% and 65% for FHX, and 80% and 67% for XCT. An analysis of patterns of failure showed a predominant locoregional failure pattern for all three arms. The survival rates on all three arms were superior to an historic control of radiotherapy and cisplatin that resulted in a 2-year survival rate of 46%. Therefore, conventional radiotherapy with concomitant chemotherapy given in consecutive weeks or on a protracted course yielded acceptable toxicities and response and survival rates. Thus, FHX is a feasible regimen in a national cooperative group setting with encouraging tumor-control results. In the past decade, the FHX regimen has been the platform for the development of combined modality strategies by our group in an attempt to improve locoregional control and survival of previously untreated patients with locoregionally advanced head and neck cancer. Moreover, promising results have been produced with FHX in stage II and III disease [43].
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C-FHX AND T-FHX REGIMENS
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As negative data on induction chemotherapy emerged from randomized trials in locoregionally advanced head and neck cancer, it was felt that FHX was likely to be the major active component of the overall treatment sequence. However, locoregional failure remained the predominant site of failure. In order to enhance the potential activity of the FHX regimen, a third drug was added, initially cisplatin (C-FHX) and then paclitaxel (T-FHX). Both cisplatin and paclitaxel have been used as radiation enhancers in preclinical models and in the clinical setting against a variety of malignant tumors. The C-FHX and T-FHX regimens were evaluated in poor-prognosis patients in phase I trials that included pharmacological and clinical parameter evaluation [22–24]. In a phase I trial, cisplatin (100 mg/m2) was added on every other cycle of FHX, that is, every 28 days, and hydroxyurea was escalated [22]. With G-CSF support, a hydroxyurea dose of 1 g every 12 hours was tolerated. A phase II study with the C-FHX regimen was subsequently conducted and is discussed below [44]. Another phase I study was designed to identify the MTD of 120-hour infusional paclitaxel when added to fluorouracil, hydroxyurea, and twice-daily radiation therapy with G-CSF between treatment cycles [23, 45]. With 5-FU administered at 600 mg/m2/day and hydroxyurea at 500 mg given orally every 12 hours, the recommended phase II dose of paclitaxel was 100 mg/m2 per cycle (20 mg/m2/day for 5 days) [23]. This combination was also tested in the phase II setting [46]. A subsequent phase I study used paclitaxel, on day 1, only administered over 1 hour. This was shown to be feasible with a recommended phase II dose of paclitaxel of 100 mg/m2 [24]. Tolerability was better than with the cisplatin-containing regimen, and hematologic toxicity was markedly lower than with the 120-hour infusion schedule. The resulting T(1-h)-FHX regimen became the platform regimen for future phase II studies from our group [47, 48]. Typically, patients are treated as inpatients and are admitted on a Sunday for a 6-day hospital stay. Careful clinical monitoring in both the inpatient and outpatient settings and aggressive supportive care are critical. Intensive chemoradiotherapy is demanding for both the patient and the oncologist. We have found that the use of an inpatient regimen optimizes patient management in many aspects, including monitoring of toxicities and improving compliance and supportive care.
In the above studies, radiation therapy was intensified by using twice-daily radiation therapy in order to increase locoregional control (hyperfractionation at 150 cGy twice daily, or 1,500 cGy/week). This approach shortened the overall treatment duration and allowed for delivery of 75 Gy of radiation over five cycles, or 9 weeks of therapy, while also allowing for administration of intensive concomitant chemotherapy using three drugs [49]. Hyperfractionated radiation therapy has already been shown to result in improved disease-free survival when used as a single-treatment modality and may be an important feature of curative-intent therapy [11, 26, 50]. Phase III randomized trials have shown that locoregional control may be optimal with altered fractionation [51]. A recent large randomized phase III study by the RTOG (R-9003) compared standard fractionation with hyperfractionation, accelerated fractionation with split, and accelerated fractionation with concomitant boost [26]. A total of 1,073 patients was available for analysis. Although patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly higher rates of locoregional control and a trend toward improved disease-free survival compared with those treated with conventional fractionation, overall survival was not different. The acute, but not the late, toxicity was greater in all three altered fractionation arms. The use of hyperfractionation in combined-modality therapy is currently the subject of many investigations in phase II trials. In the most recent phase II trials reviewed here, it is very likely that the ability to improve local control stems from the use of hyperfractionated radiotherapy as well as from the use of multiagent concomitant chemotherapy.
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PHASE II TRIALS WITH C-FHX AND T-FHX
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From 1993 to 1998, our group conducted three consecutive phase II trials in patients with previously untreated locoregionally advanced head and neck cancer that evaluated the use of triple multiagent combination chemotherapy that included 5-FU and hydroxyurea and concomitant hyperfractionated radiotherapy. Similarly to previous phase II studies from our group, these trials enrolled patients with locoregionally advanced stage IV head and neck cancer and patients with stage III base of tongue or hypopharynx cancer, two sites that are associated with poor prognoses. The first study evaluated the C-FHX regimen and the next two trials investigated the T-FHX regimen, one using a 120-hour infusion of paclitaxel (T(120-h)-FHX) and the other using the T(1-h)-FHX regimen (Fig. 1). The latter study also investigated the potential benefit of adding erythropoietin to prevent treatment-induced anemia.
In the first phase II study, 76 previously untreated patients received cisplatin, 5-FU, hydroxyurea, and twice-daily radiotherapy (C-FHX regimen): 93% had stage IV disease, with 54% of patients having N2 disease and 21% having N3 disease [44]. Nine patients underwent initial surgery at the primary site along with node dissection; six patients underwent diagnostic or debulking procedures, and three had partial glossectomies. After chemoradiotherapy, four additional patients had surgery at the primary site; only one had residual microscopic disease. Overall, surgery at the primary site was performed in only 13 patients, while 39 patients underwent neck dissection. With a median follow-up of 38 months, the progression-free survival rate was 72% at 3 years and the overall survival rates were 55% at 3 years and 48% at 4 years. Six patients progressed locally, and 11 progressed in distant sites. The 3-year locoregional progression-free survival was 92% and the 3-year distant progression-free survival rate was 83% (Table 2). This was the first trial suggesting that intensive concomitant chemoradiotherapy could lead to high locoregional control and survival rates and also allow for organ preservation. Its use in both unresectable and resectable locoregionally advanced disease in an attempt at organ preservation could, therefore, be justified. More importantly, a reversal of the historical pattern of failure of head and neck cancer (local more often than distant) [52] was observed; a higher percentage of patients were found to fail distantly, usually in the lungs, than locally or regionally. An important study component was the prospective evaluation of quality of life (QOL) and functional outcomes [53]. Acute treatment toxicities were severe, with declines in all QOL and functional domains during treatment. Although QOL decreased during therapy, it returned to baseline or improved by 12 months following completion of therapy. Up to one-third of patients had chronic problems with swallowing, hoarseness, and mouth pain; however, these problems were equally frequent at baseline. Xerostomia, difficulties in taste, and the need for a soft food diet were seen more frequently at 12 months than at baseline. The evaluation of QOL and functional outcomes has been an integral part of all subsequent trials by our group. In the C-FHX study, patients were also offered the option to receive adjuvant chemoprevention for up to 1 year, consisting of interferon-
and cis-retinoic acid. Compliance with this chemoprevention regimen was found to be extremely poor, and this approach was abandoned in subsequent protocols. Pharmacological evaluation showed that steady-state 5-FU plasma concentrations were not significantly different between patients who developed disease recurrence and those with continued control. Similarly, there was no difference in plasma 5-FU concentration or dihydropyrimidine dehydrogenase activity in patients with distant failure compared with those developing locoregional failure. The survival results with concomitant chemoradiotherapy with C-FHX suggest that this was an extremely powerful approach, allowing for curative-intent therapy for the majority of patients with advanced head and neck cancer. Furthermore, organ preservation could be achieved in the overwhelming majority of patients. However, the toxicity of this regimen was high. Eighty-one percent of patients developed grade 3 or 4 leukopenia, 78% had grade 3 or 4 thrombocytopenia, and 57% experienced grade 3 or 4 mucositis; three patients died of treatment-related sepsis.
In the second phase II study, paclitaxel (100 mg/m2) was given as a 120-hour infusion during the 5 days of radiation—the T(120h)-FHX regimen [46]. In addition, the doses of 5-FU and hydroxyurea were lower than with the C-FHX regimen, based on our phase I experience [23]. A total of 64 patients with stage IV head and neck cancer or stage III cancer of the hypopharynx or base of tongue were treated with this regimen. Fifty-eight percent of patients had T4 disease, 67% were stage N2, and 14% were stage N3. With a median follow-up of 34 months, the progression-free survival rate was found to be 63% at 3 years, and the overall survival rate was 60% at 3 years (Table 2). Seventeen patients died of recurrent head and neck cancer, two due to the development of second malignancies, four as a result of treatment-related toxicities, and four of intercurrent illnesses. The pattern of failure was reminiscent of what was previously observed with C-FHX: five patients relapsed in locoregional sites, nine relapsed in distant sites, and three relapsed in both locoregional and distant sites. The locoregional control rate was 86%, and the systemic disease control rate was 79% (Fig. 2). Only four patients required conventional, surgical resection as a component of primary treatment management, so that organ preservation was again achieved in the overwhelming majority of patients. Toxicities were more manageable than with the C-FHX regimen. This may have been due to the substitution of paclitaxel for cisplatin but also to the use of lower doses of 5-FU and hydroxyurea in the T(120-h)-FHX regimen. Thirty-four percent of patients developed grade 3 or 4 leukopenia, and severe thrombocytopenia was seen in only 2% of patients. Nausea and vomiting were infrequent. However, mucositis and dermatitis were observed in the majority of patients. Four treatment-related deaths occurred (6%), two were due to postoperative events and two were due to chronic laryngeal effects. QOL analyses showed that, at 12 months, the T(120-h)-FHX regimen was better tolerated than the C-FHX regimen [54]. There was a favorable difference in the percentage of patients who were unable to eat a normal diet (47% versus 82%) as well as a lower percentage of patients being uncomfortable eating with others (27% versus 64%). Overall, T(120-h)-FHX was considered to be better tolerated and as active as C-FHX.
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Figure 2. The use of intensive chemoradiotherapy regimens resulted in a reversal of the historical pattern of failure: distant failure became predominant. Results with T(120-h)-FHX (protocol 7929) are displayed. Similar patterns of failure were seen with C-FHX and T(1-h)-FHX. Reprinted with permission from Lippincott Williams and Wilkins [46].
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Finally, the third study used the same dose of paclitaxel but delivered the drug over 1 hour during the first day of radiation—the T(1-h)-FHX regimen. In addition, the role of erythropoietin was evaluated in a randomized fashion. Preliminary data were recently presented [48]. The progression-free survival rate was 62% at 3 years, and a higher locoregional than systemic control was again observed (Table 2). The toxicities of this regimen were similar to those previously observed with infusional paclitaxel.
A long-term analysis of combined data from the three phase II studies (C-FHX, T(120-h)-FHX, and T(1-h)-FHX), as well as the previous two studies with induction PFL-interferon followed by FHX that were discussed above, has been conducted [55]. The overall survival rates were not different among the PFL-interferon/FHX, the C-FHX, and the T-FHX trials and have been approximately 60% at 3 years across all studies. However, the patterns of failure were significantly different. The combined 5-year locoregional failure rates were 31% in the PFL-interferon/FHX regimens and 17% with the C-FHX and T-FHX regimens, and the 5-year distant failure rates were 13% in the PFL-interferon/FHX studies and 22% in the C-FHX and T-FHX studies [55].This analysis emphasizes the important role of intensive concurrent chemoradiotherapy for improving locoregional control. On the other hand, induction chemotherapy may impact on distant disease control.
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IMPLICATIONS FOR FUTURE STUDIES
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With the use of intensive chemoradiotherapy regimens, such as C-FHX and T-FHX, high survival rates are achieved in patients with stage IV head and neck cancer. The historical pattern of relapse is reversed, and the distant failure rate is higher than the locoregional failure rate: approximately 22% of patients will ultimately develop distant metastases, whereas 17% of patients will fail locoregionally. Similar observations were reported recently by other investigators who used aggressive locoregional therapies [56]. Adelstein et al. used hyperfractionated radiation therapy (72 Gy at 1.2 Gy twice per day) with two courses of concurrent chemotherapy with 5-FU (1,000 mg/m2/day) and cisplatin (20 mg/m2/day), both given as 96-hour continuous i.v. infusions during weeks 1 and 4 of radiation therapy. They reported their results from 41 patients with stage IV head and neck cancer. The 3-year overall survival rate was 59%, the local control rate without surgical resection was 91%, and the distant disease control rate was 74% [56]. Therefore, as seen in our phase II trials with the C-FHX and T-FHX regimens, high rates of locoregional control are achieved and distant sites of failure are predominant.
Based on data from previous randomized trials [57], it is likely that the rate of distant metastasis will be reduced with effective induction chemotherapy. Although this reduction in distant metastases has generally failed to translate into a survival difference in randomized studies, the more effective locoregional control realized with concomitant multiagent chemotherapy and concomitant hyperfractionated radiation could allow this improvement in systemic control to lead to a survival benefit. Therefore, a subsequent trial from our group investigated the addition of induction chemotherapy to T-FHX therapy. In our older studies, PFL-interferon was shown to be an active but poorly tolerated combination. Therefore, in subsequent studies (protocol 9520), the combination of carboplatin and paclitaxel was selected as the induction regimen based on its documented activity in advanced head and neck cancer and its good tolerability. Myelosuppression is less common with carboplatin and paclitaxel, and unlike 5-FU-based regimens, the regimen does not result in mucositis, which is an overlapping toxicity with subsequent chemoradiotherapy. Moreover, cisplatin-associated toxicities, such as emesis and nephrotoxicity, are avoided with the use of carboplatin. We used a weekly regimen of carboplatin (at an area under the concentration time curve of 2) and paclitaxel (135 mg/m2) that was administered weekly for 6 weeks followed 2 weeks later by the T-FHX regimen (protocol 9502). Induction chemotherapy with carboplatin and paclitaxel was well tolerated and resulted in an objective response rate of approximately 85% [47]. We also observed a promising 3-year progression-free survival rate of 80% and a distant failure rate that was no longer predominant (Figs. 2 and 3). Longer follow-up is needed to establish the merits of this strategy. Other investigators have also reported promising results with induction chemotherapy [58]. Posner and colleagues have developed an induction regimen consisting of 5-FU, cisplatin, and docetaxel that has substantial activity in locoregionally advanced head and neck cancer with reported response rates of 90% or more and promising short-term survival [38]. Of interest is that locoregional failure was predominant with that approach [59], which is reminiscent of our PFL-interferon/FHX data [34, 35]. A randomized trial that is investigating the addition of a third drug, docetaxel, to an induction regimen of cisplatin and 5-FU is ongoing. Both arms receive a chemoradiotherapy regimen with concurrent weekly carboplatin. Further investigations of novel induction regimens as well as more active and potentially more tolerable concomitant chemoradiotherapy regimens are warranted. Successful strategies in both directions will need to converge to develop the optimal therapy for locoregionally advanced head and neck cancer.
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Figure 3. With the addition of induction chemotherapy with carboplatin and paclitaxel (protocol 9520), we observed that recurrences were equally divided between local and distant sites. Reprinted with kind permission from Lippincott Williams and Wilkins [47].
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ACKNOWLEDGMENT
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Supported in part by the University of Chicago/Northwestern University Oral Cancer Research 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, NJ. The authors wish to thank Kerstin Stenson, Fred R. Rosen, Alfred W. Rademaker, Bruce E. Brockstein, Louis Portugal, Bharat B. Mittal, Harold Pelzer, Barry Wenig, and Ralph R. Weichselbaum for serving as investigators in the study protocols.
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REFERENCES
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- Argiris A. Update on chemoradiotherapy for head and neck cancer. Curr Opin Oncol 2002;14:323–329.[CrossRef][Medline]
- Hong WK, Bromer R. Chemotherapy in head and neck cancer. N Engl J Med 1983;308:75–79.[Medline]
- Moran RG, Danenberg PV, Heidelberger C. Therapeutic response of leukemic mice treated with fluorinated pyrimidines and inhibitors of deoxyuridylate synthesis. Biochem Pharmacol 1982;31:2929–2935.[CrossRef][Medline]
- Frankfurt OS. Enhancement of the antitumor activity of 5-fluorouracil by drug combinations. Cancer Res 1973;33:1043–1047.[Abstract/Free Full Text]
- Vokes EE, Haraf DJ, Panje WR et al. Hydroxyurea with concomitant radiotherapy for locally advanced head and neck cancer. Semin Oncol 1992;19:53–58.
- Vokes EE. Interactions of chemotherapy and radiation. Semin Oncol 1993;20:70–79.[Medline]
- Vokes EE, Weichselbaum RR. Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990;8:911–934.[Abstract]
- Vokes EE, Beckett M, Karrison T et al. The interaction of 5-fluorouracil, hydroxyurea, and radiation in two human head and neck cancer cell lines. Oncology 1992;49:454–460.[Medline]
- Lo TC, Wiley AL Jr, Ansfield FJ et al. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. Am J Roentgenol 1976;126:229–235.[Abstract]
- 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 1994;12:2648–2653.[Abstract/Free Full Text]
- Sanchiz F, Milla A, Torner J et al. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 1990;19:1347–1350.[Medline]
- Stefani S, Eells RW, Abbate J. Hydroxyurea and radiotherapy in head and neck cancer. Results of a prospective controlled study in 126 patients. Radiology 1971;101:391–396.[Medline]
- Richards GJ Jr, Chambers RG. Hydroxyurea: a radiosensitizer in the treatment of neoplasms of the head and neck. Am J Roentgenol Radium Ther Nucl Med 1969;105:555–565.[Medline]
- Hussey DH, Abrams JP. Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy. Prog Clin Cancer 1975;6:79–86.[Medline]
- Stefani S, Chung TS. Hydroxyurea and radiotherapy in head and neck cancer—long term results of a double blind randomized prospective study. Radiat Oncol Biol Phys 1980;6:1398a.
- Piver MS, Barlow JJ, Vongtama V et al. Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study. Am J Obstet Gynecol 1983;147:803–808.[Medline]
- Rose PG. Chemoradiotherapy for cervical cancer. Eur J Cancer 2002;38:270–278.
- Vokes EE, Panje WR, Schilsky RL et al. Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study. J Clin Oncol 1989;7:761–768.[Abstract]
- Byfield JE, Sharp TR, Frankel SS et al. Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck. J Clin Oncol 1984;2:406–413.[Abstract]
- Taylor SG 4th, Murthy AK, Showel JL et al. Improved control in advanced head and neck cancer with simultaneous radiation and cisplatin/5-FU chemotherapy. Cancer Treat Rep 1985;69:933–939.[Medline]
- Haraf DJ, Vokes EE, Weichselbaum RR et al. Concomitant chemoradiotherapy with cisplatin, 5-fluorouracil and hydroxyurea in poor-prognosis head and neck cancer. Laryngoscope 1992;102:630–636.[CrossRef][Medline]
- Vokes EE, Haraf DJ, Mick R et al. Intensified concomitant chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer. J Clin Oncol 1994;12:2351–2359.[Abstract/Free Full Text]
- Brockstein B, Haraf DJ, Stenson K et al. Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J Clin Oncol 1998;16:735–744.[Abstract]
- Brockstein B, Haraf DJ, Stenson K et al. A phase I-II study of concomitant chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer. Ann Oncol 2000;11:721–728.[Abstract/Free Full Text]
- Parsons JT, Mendenhall WM, Cassisi NJ et al. Hyperfractionation for head and neck cancer. Int J Radiat Oncol Biol Phys 1988;14:649–658.[Medline]
- Fu KK, Pajak TF, Trotti A et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7–16.[CrossRef][Medline]
- Peters LJ, Withers HR. Applying radiobiological principles to combined modality treatment of head and neck cancer—the time factor. Int J Radiat Oncol Biol Phys 1997;39:831–836.[CrossRef][Medline]
- Amdur RJ, Parsons JT, Mendenhall WM et al. Split-course versus continuous-course irradiation in the postoperative setting for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1989;17:279–285.[Medline]
- Keane TJ, Cummings BJ, O’Sullivan B et al. A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 1993;25:613–618.[Medline]
- 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 1998;338:1798–1804.[Abstract/Free Full Text]
- 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 1999;91:2081–2086.[Abstract/Free Full Text]
- Taylor SG 4th, Murthy AK, Vannetzel JM et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 1994;12:385–395.[Abstract]
- 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 2003;21:92–98.[Abstract/Free Full Text]
- Vokes EE, Kies M, Haraf DJ et al. Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease. J Clin Oncol 1995;13:876–883.[Abstract]
- Kies MS, Haraf DJ, Athanasiadis I et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998;16:2715–2721.[Abstract]
- Shin DM, Glisson BS, Khuri FR et al. Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck. Cancer 2002;95:322–330.[CrossRef][Medline]
- Colevas AD, Norris CM, Tishler RB et al. Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck. J Clin Oncol 1999;17:3503–3511.[Abstract/Free Full Text]
- Posner MR, Glisson B, Frenette G et al. Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2001;19:1096–1104.[Abstract/Free Full Text]
- Garden AS, Pajak TF, Vokes E et al. Preliminary data of RTOG 9703—a phase II randomized trial of concurrent radiation and chemotherapy for advanced squamous cell of the head and neck. Proc Am Soc Clin Oncol 2001;20:A891.
- De Crevoisier R, Domenge C, Wibault P et al. Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer 2001;91:2071–2076.[CrossRef][Medline]
- Wheeler RH, Harris J, Spencer S et al. RTOG 9610: Phase II study of reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck: survival results. Proc Am Soc Clin Oncol 2001;20:A887.
- Gandia D, Wibault P, Guillot T et al. Simultaneous chemoradiotherapy as salvage treatment in locoregional recurrences of squamous head and neck cancer. Head Neck 1993;15:8–15.[Medline]
- Haraf DJ, Kies M, Rademaker AW et al. Radiation therapy with concomitant hydroxyurea and fluorouracil in stage II and III head and neck cancer. J Clin Oncol 1999;17:638–644.[Abstract/Free Full Text]
- Vokes EE, Kies MS, Haraf DJ et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000;18:1652–1661.[Abstract/Free Full Text]
- Vokes EE, Haraf DJ, Brockstein BE et al. Paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant radiation therapy for poor-prognosis head and neck cancer. Semin Radiat Oncol 1999;9(suppl 1):70–76.[Medline]
- Kies MS, Haraf DJ, Rosen F et al. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 2001;19:1961–1969.[Abstract/Free Full Text]
- Vokes EE, Stenson K, Rosen FR et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 2003;21:320–326.[Abstract/Free Full Text]
- Rosen FR, Haraf D, Brockstein B et al. Multicenter randomized phase II study of 1 hour infusion paclitaxel, fluorouracil and hydroxyurea with concomitant hyperfractionated radiotherapy with or without erythropoietin for advanced head and neck cancer. Proc Am Soc Clin Oncol 2001;20:A902.
- Vokes EE, Moormeier JA, Ratain MJ et al. 5-Fluorouracil, leucovorin, hydroxyurea, and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study. Cancer Chemother Pharmacol 1992;29:178–184.[CrossRef][Medline]
- Dische S, Saunders M. The rationale for continuous, hyperfractionated, accelerated radiotherapy (CHART). Int J Radiat Oncol Biol Phys 1990;19:1317–1320.[Medline]
- Horiot JC, Bontemps P, van den Bogaert W et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111–121.[CrossRef][Medline]
- Hong WK, Bromer RH, Amato DA et al. Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy. Cancer 1985;56:1242–1245.[CrossRef][Medline]
- List MA, Siston A, Haraf D et al. Quality of life and performance in advanced head and neck cancer patients on concomitant chemoradiotherapy: a prospective examination. J Clin Oncol 1999;17:1020–1028.[Abstract/Free Full Text]
- List MA, Haraf D, Stracks J et al. Quality of life/performance in head & neck cancer: comparison between paclitaxel-based and cisplatin-based concomitant chemoradiotherapy regimens. Proc Am Soc Clin Oncol 2000;19:A1625.
- Brockstein BE, Haraf DJ, Kies MS et al. Survival, patterns of failure, and risk factors for recurrence after intensive concomitant chemoradiation (CRT) for squamous cell head and neck cancer (SCHNC). Proc Am Soc Clin Oncol 2002;21:A918.
- Adelstein DJ, Saxton JP, Lavertu P et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 2002;20:1405–1410.[Abstract/Free Full Text]
- Paccagnella A, Orlando A, Marchiori C et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265–272.[Abstract/Free Full Text]
- Posner MR, Colevas AD, Tishler RB. The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck. Semin Oncol 2000;27:13–24.
- Haddad R, Colevas AD, Tishler R et al. Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck: the Dana Farber Cancer Institute experience. Cancer 2003;97:412–418.[CrossRef][Medline]
Received December 10, 2002;
accepted for publication April 21, 2003.
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