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© 1999 American Society for Clinical Oncology Phase II Trial of Docetaxel, Cisplatin, Fluorouracil, and Leucovorin as Induction for Squamous Cell Carcinoma of the Head and NeckFrom the Head and Neck Oncology Program and Department of Biostatistics, Dana-Farber Cancer Institute; Department of Internal Medicine, Brigham and Women's Hospital, Joint Center for Otolaryngology, Joint Center for Radiation Therapy, Harvard Medical School; Harvard Vanguard Medical Associates; and Massachusetts General Hospital, Boston, MA. Address reprint requests to A.D. Colevas, MD, Head and Neck Oncology Program, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email alexander_colevas{at}dfci.harvard.edu
PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.
SQUAMOUS CELL carcinoma of the head and neck (SCCHN) is potentially curable when treated with either radiotherapy or surgery. However, advanced, locoregional SCCHN (stages III to IV, M0) often recurs after local therapy, and 3- to 5-year survival rates remain below 30%.1-6 Surgical management is associated with significant morbidity in a large proportion of patients, and there has been no change in survival of surgically treated patients in the past two decades. Randomized trials have shown that induction chemotherapy is effective in preserving organ function in a subset of patients by reducing the need for surgery of the primary tumor site in patients with resectable disease without changing survival, and improving survival in patients with unresectable disease.2,4,6 The standard induction regimen consists of cisplatin and continuous-infusion fluorouracil (5-FU), and has been associated with a complete response rate of about 30% in randomized trials.2,6,7 Survival of patients with stage III and IV disease remains poor despite these improvements. Building upon the results of cisplatin/5-FU–based chemotherapy, the cisplatin, 5-FU, and leucovorin (PFL) combination was developed as an induction regimen for SCCHN.8-13 This regimen is based on improved pharmacokinetics of cisplatin when given by continuous infusion, in vitro data of an interaction between cisplatin and 5-FU that enhances 5-FU antitumor activity, as well as the synergistic inhibition of thymidylate synthase by 5-FU and leucovorin.13 Among patients with locally advanced disease, PFL can result in a 50% complete response (CR) rate, an 85% overall response (OR), a 67% primary tumor site CR rate, and long-term survival of approximately 50%.12 Following the observation that docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) possesses significant single-agent antitumor activity in SCCHN, a modification of PFL, ie, a 5-day regimen docetaxel, cisplatin, 5-FU, and leucovorin, with shorter chemotherapy infusion time and earlier intervention with growth factors and antibiotics (TPFL5), was studied in a phase I/II protocol.14-18 In this regimen, docetaxel is added to PFL and 1 day of 5-FU, and leucovorin is eliminated, yielding a 5-day overall infusion for TPFL5. Docetaxel acts by a different mechanism than the agents in PFL and has shown an additive effect with cisplatin and supra-additive antitumor activity with 5-FU in vitro and in murine models of xenografted human tumors.19-23 TPFL5 was associated with a CR rate of 61% and an OR rate of 100% in 23 patients treated in the phase I/II study. At the maximum-tolerated dose, febrile neutropenia (22%) and grade 3 or 4 mucositis (45%) resulted in hospitalization for toxicity in 35% of all cycles of TPFL5 delivered, despite the use of granulocyte colony-stimulating factor (G-CSF) and prophylactic antibiotics.18 Thus, despite the promising response data, the toxicity profile of TPFL5 was significant and necessitated revision of the regimen. This report describes an attempt to develop an induction regimen that preserves TPFL dose-intensity and simultaneously decreases toxicity. A 4-day regimen of TPFL (TPFL4) delivers the same total dose of docetaxel, cisplatin, and 5-FU as TPFL5 but permits earlier administration of G-CSF and other postchemotherapy prophylactic measures, in an attempt to diminish the incidence of severe toxicities of TPFL. The primary end points of this study were to evaluate the toxicity of TPFL4 with G-CSF and ciprofloxacin and to obtain preliminary assessment of the efficacy of this regimen in patients with advanced, previously untreated SCCHN.
Patient Characteristics Patients with locally advanced nonmetastatic SCCHN or its histologic variants (eg, lymphoepithelioma, undifferentiated epidermoid carcinoma) were enrolled onto an institutional-review-board–approved phase II study of TPFL4 followed by definitive twice-daily radiation therapy. All patients signed informed-consent statements approved by our institution's human protection committee before enrollment. Enrollment was limited to patients with assessable, previously untreated stage III or IV disease, excluding those with metastatic disease, T3N0 exophytic tumors, or T1N1 lesions. Patients with previous head and neck cancers or any non-SCCHN malignancy within 3 years of entering the study, except for those with curatively treated skin or cervical cancers, were excluded. All subjects were required to have an Eastern Cooperative Oncology Group performance status (PS) of  2, an estimated enteral intake of more than 1,800 kcal/d, stable weight, life expectancy of more than 3 months, WBC count of  4,000 cells/µL, platelet count of 100,000/µL, hemoglobin level of 10 g/dL, AST level below 1.5 times the upper limit of normal (ULN), alkaline phosphatase level of less than 2.5 times ULN, total bilirubin level ULN, creatinine level of 1.5 mg/dL, or 24-hour creatinine clearance rate of more than 50 mL/min, and peripheral neuropathy of less than grade 2 by National Cancer Institute common toxicity criteria. They also had to be able to tolerate 3 L of intravenous normal saline per day. Patients were evaluated in a multidisciplinary clinic for confirmation of eligibility, staging, and treatment planning. Patients were staged by physical examination according to the criteria established by the American Joint Committee on Cancer.24 Radiologic evaluation was used to document baseline disease and response to therapy in sites not fully assessable by clinical examination. A CR was defined as disappearance of all clinically evident tumor. A partial response (PR) was defined as a greater than 50% reduction in the product of the two greatest perpendicular diameters of each measurable disease site. No response was defined as any response less than a PR, stable disease, progression of disease, or death while receiving chemotherapy. Pre- and posttherapy clinical staging included an upper aerodigestive examination under anesthesia (EUA) by a head and neck surgeon. Responses following chemotherapy treatment were confirmed by biopsy whenever feasible.
Treatment and Evaluation
There were no dose reductions in docetaxel or leucovorin. Subsequent cycles were delayed up to 1 week if at day 28 there was evidence of ongoing dehydration, serum creatinine levels in excess of 25% above the pretreatment value, and a decrease in creatinine clearance measured by 24-hour urine collection to less than 40 mL/min or less than 70% of baseline. Delay of subsequent cycles beyond day 35 necessitated withdrawal from study treatment. 5-FU was reduced by 10% after episodes of grade 4 National Cancer Institute common toxicity criteria mucositis, diarrhea, or skin toxicity or grade 3 mucositis or diarrhea lasting longer than 7 days. Re-treatment could be delayed for up to 7 days beyond the 28-day cycle for unresolved dehydration or renal abnormalities. No dose re-escalations were permitted. Patients were evaluated for toxicity and tumor response once per cycle on days 14 and 28, respectively. Treatment was discontinued immediately upon evidence of tumor progression and after two cycles with no response. During the fourth week of the third cycle, patients underwent an EUA, a biopsy of the primary tumor site, removal of indwelling central intravenous catheter, and placement of a gastrostomy feeding tube. Radiation therapy was planned for all patients who achieved a PR or CR after three cycles of chemotherapy. Definitive radiation therapy administered 5 days per week in two fractions of 1.2 Gy separated by 6 hours was delivered to the primary tumor site and neck. Radiation was targeted to begin within 5 weeks after the first day of the final cycle of chemotherapy. The total dose to the primary tumor site was between 72 and 74 Gy. Neck lymph nodes that were less than 2 cm at enrollment received 66 Gy, and those more than 2 cm received 70 Gy. Every effort was made to continue radiation on schedule. Treatment breaks were only allowed for confluent mucositis posing a threat to patient health, and total break time could not exceed 2 weeks. Surgery of the primary tumor site was recommended for operable patients with resectable disease who failed to achieve at least a PR after two cycles of chemotherapy. Postradiation neck dissection was recommended to all patients who failed to achieve a clinical CR in the neck at the end of chemotherapy without regard to disease status of the neck at enrollment or postradiation therapy. Neck dissections were carried out routinely 6 to 8 weeks after the completion of radiation therapy.
Statistical Considerations Efficacy was evaluated as a secondary end point. We assumed that TPFL4 would be worthy of further study if 29 (97%) of 30 patients were to experience a PR or CR. If 29 patients were to achieve a CR or PR, the exact 90% confidence interval for a true response rate would be 85.1% to 99.8%.
Between January 1997 and February 1998, 30 patients with locally advanced SCCHN were accrued to the study. The median age of patients at enrollment was 50 years, with a range of 18 to 68 years. At enrollment, we assessed 14 patients to be of Eastern Cooperative Oncology Group PS 0, 15 to be of PS 1, and one to be of PS 2. The distribution of patients' primary tumor sites were as follows: oropharynx, nine; larynx, seven; nasopharynx, seven; maxillary sinus, two; oral cavity, two; hypopharynx, one; unknown primary tumor site, two. All patients had stage III or IV disease, and 83% had stage IV disease (Table 1).
Eighty-five cycles of TPFL4 were administered. Twenty-six patients received three cycles of TPFL4, one patient received one cycle, and three patients received two cycles. One patient with a maxillary sinus tumor with positive surgical margins and rapidly regrowing tumor received only one cycle of chemotherapy because of tumor progression after that cycle. One patient died during the second cycle. One patient did not keep his follow-up appointment after his second cycle and was therefore removed from the protocol and treated with an additional cycle of cisplatin and 5-FU approximately 40 days after day 1 of the second cycle of TPFL4. One patient developed osteomyelitis, complicating an implanted central line infection, and sepsis and began radiation 56 days after day 1 of the second cycle of TPFL4. Radiation therapy was administered to 29 patients beginning a median of 39 days (range, 18 to 63 days) after day 1 of the last cycle of TPFL4 administered. The median duration of radiation was 42 days, and the median dose was 72 Gy in 1.2-Gy bid fractionation. Three patients did not receive radiation therapy according to the prospective plan. One patient (T3N0 hypopharynx) could not arrange for transportation for twice-daily treatments, so she received 72 Gy total in once-daily fractions of 1.8 Gy. One patient, because of noncompliance, received 50 Gy over a 58-day period. One patient with a progressive maxillary sinus tumor was treated with 67.8 Gy predominantly in 2-Gy bid fractions after one cycle of TPFL4.
Toxicity Hospitalization for toxicity management complicated 12 (14%) of 85 cycles. Primary reasons for hospitalization included infection (five cycles), venous thrombosis (one cycle), fluid and electrolyte disorders (five cycles), and gastrointestinal toxicity (four cycles—three cycles associated with more than one major reason for hospitalization). Febrile neutropenia (temperature above 38.0°C and absolute neutrophil count less than 500 cells/µL) requiring hospitalization and administration of intravenous antibiotics was seen in two of 85 cycles. One episode of febrile neutropenia was associated with severe mucositis and diarrhea, resulting in the death of the patient. Postchemotherapy median nadirs of absolute neutrophil counts for each cycle of TPFL4 were as follows: cycle 1, 3,150 cells/mm2; cycle 2, 2,030 cells/mm2; and cycle 3, 2,085 cells/mm2. Three (4%) of 85 and four (5%) of 85 cycles were associated with grades 4 and 3 neutropenia, respectively. Thrombocytopenia was mild, with five episodes (6%) of grade 3 or 4 thrombocytopenia and no clinically significant bleeding. There were two episodes of grade 3 or 4 anemia, and 10 cycles were associated with RBC transfusions. The most common acute nonhematologic toxicities included mucositis, nausea, vomiting, and diarrhea. Toxicities are listed in Table 2.
Response to TPFL4
Two patients with squamous cell carcinoma of the maxillary sinus failed to respond to TPFL4. One of these patients was treated with TPFL4 postoperatively when at the time of the operation it was apparent that potentially curative surgery could not be performed. This patient's tumor was noted to be more than 25% larger than it was at baseline during the second week of the first cycle, and the decision to proceed directly to radiation therapy was made. The second patient had a diagnostic maxillectomy to investigate what appeared by computed tomography to be either scar tissue or residual disease after three cycles of chemotherapy. The surgeon's assessment at the time of this procedure was that the patient's tumor response did not fulfill the criteria of a PR, so the assessment of stable disease was made. This patient proceeded to radiation therapy. All the remaining patients' tumors responded to TPFL4. Of the 28 patients with assessable primary tumor sites, 22 underwent EUAs and biopsy of the primary tumor site after the completion of induction chemotherapy. The remaining six patients did not have biopsies for the following reasons: One patient died, one patient proceeded immediately to radiation after one cycle of chemotherapy, one patient refused (this patient had been removed from protocol treatment because of noncompliance after the second TPFL4 cycle), one patient had an active infection and EUA was believed to pose unnecessary risk, and two patients' surgeons failed to perform biopsies of primary tumor sites that had achieved a clinical CR. Fifteen of 22 postchemotherapy biopsy specimens of the primary tumor site were pathologically negative. Of these 15, 12 had achieved clinical CR and three had achieved PR. Of these patients who had a pathologic CR at the primary tumor site, five subsequently relapsed (three with metastatic disease, one at the primary site [a clinical CR to chemotherapy], and one in the neck). The remaining seven patients with pathologically positive biopsy specimens after chemotherapy of the primary tumor site had achieved a clinical CR in four cases, a PR in two cases, and stable disease in one case. Three have relapsed: one in the neck, one with metastatic disease, and one (a clinical PR to chemotherapy) at the primary tumor site. Upon the completion of radiation, 28 of the original 30 patients were believed to have achieved an overall complete response, the two exceptions being the patient who died after the second cycle of TPFL4 and a patient with N3b neck disease at enrollment. The latter patient developed pulmonary metastases before a planned postradiation neck dissection. Three patients (two initially N3, one initially N2) underwent planned postradiation neck lymph node dissections. In all three patients, there was no pathologic evidence of residual disease. The two remaining patients did not have neck dissections because of death during chemotherapy (N2b) and diffuse lung metastases (N3b) documented after radiation before neck dissection.
Events Ten (37%) of the remaining 27 patients have relapsed after completion of TPFL4 therapy. One patient with a T1N3b larynx tumor achieved a PR in the neck to TPFL4 and was thus scheduled to undergo neck dissection after radiation therapy. A preoperative chest radiograph documented multiple pulmonary metastases. This patient died of tumor progression at 10 months. A patient with a T4N2c larynx tumor relapsed simultaneously at the primary tumor site and with multiple regional cutaneous metastases at 9 months and died of disease at 12 months. Two patients with nasopharynx tumors have relapsed with distant metastases at 13 and 14 months. One of them died from widespread disease at 16 months; the other is alive at 17 months. One patient with a T3N2b nasopharynx primary tumor relapsed in a regional neck lymph node site at 12 months. He received salvage surgery chemotherapy and was alive at 19 months without evidence of metastatic disease or another locoregional recurrence. A patient with a T4N0 larynx tumor relapsed regionally in the oropharynx at 9 months, underwent salvage surgery (organ sparing, no laryngectomy), and had no evidence of disease at 17 months. A patient with a T3N0 oropharynx tumor relapsed in the neck at 13 months, underwent surgical salvage therapy, and was alive with recurrent disease at 18 months. A patient with a T4N1 tongue tumor relapsed in the mandible at 9 months, underwent salvage surgery, and was alive without apparent tumor at 16 months. A patient with a T4N3 tongue lesion relapsed in the hypopharynx at 8 months and was alive with disease at 9 months. A patient with a T4N2c nasopharynx cancer relapsed at 11 months at the primary tumor site and lung and is receiving palliative therapy (Figs 2 and 3).
We developed TPFL4 with the hope that this compressed (relative to TPFL518) TPFL regimen would yield similar response rates and an improved side-effect profile. Results presented in this article show that, within the limits inherent to comparison of two sequential single-institution studies, we were able to preserve the activity of TPFL with a substantial reduction in toxicity. As we predicted, there were major reductions in hematologic and infectious toxicities for patients treated with TPFL4 when compared with those treated with TPFL5. The incidence of grade 3 or greater neutrophil toxicity fell from 22% to 8%, and febrile neutropenia declined from 22% to 2%. The 95% confidence intervals for febrile neutropenia do not overlap, suggesting that if the patients in these two sequential studies are similar, a significant reduction in febrile neutropenia in the compressed TPFL4 was achieved. No reduction was seen in gastrointestinal toxicity. The rates of grade 3 toxicity for nausea, mucositis, and diarrhea were 11%, 47%, and 11%, respectively, for TPFL5 and 15%, 48%, and 5%, respectively, for TPFL4 (Table 4). The reductions in toxicity were clinically relevant: 35% of all cycles of TPFL5 were associated with hospitalization to manage toxicity, whereas only 14% of all TPFL4 cycles necessitated hospitalization for toxicity.
TPFL4 yielded response rates similar to those for TPFL5, with CR rates of 68% and 61%, respectively, and overall response rates of 93% and 100%, respectively. The inclusion of patients with nasopharyngeal carcinoma in the two trials did not seem to alter the comparative response rates in the TPFL5 and TPFL4 patients. Analysis of non–nasopharyngeal carcinoma patients demonstrated a CR rate of 66% (eight of 12 patients) and an OR rate of 100% (12 of 12) in the TPFL5 patients and a CR rate of 61% (14 of 23 patients) and an OR rate of 91% (21 of 23) in the TPFL4 patients There was a suggestion that the primary tumor site CR rate, both clinically and pathologically, was lower in the TPFL4 cohort. Unfortunately, these data are confounded by a postchemotherapy biopsy selection bias in the TPFL4 group. Although 21 of 22 patients with primary tumor sites in the TPFL5 trial underwent postchemotherapy biopsy, six of the 28 patients on the TPFL4 trial with assessable primary tumor sites were not biopsied after chemotherapy. Additional data collected in a randomized fashion would be necessary to validate these differences definitively in pathologic response rates and relapse rates. Preliminary follow-up data suggest that the early relapse rate after TPFL4 is greater than that seen in patients treated with TPFL5 (Fig 2). Given the sequential, nonrandomized nature of these two cohorts of patients, it is impossible to know whether this difference is significant and, if so, whether it is a result of the difference in therapy or patient populations. The TPFL4 experience confirms our finding with TPFL5 that addition of docetaxel to a modified PFL regimen adds considerably to the response rate in SCCHN, diminishing the nonresponse rate from at least 20% to 40%2,4,6,7,12,25 to less than 10%.18 The questions of whether the addition of docetaxel to cisplatin and 5-FU will reduce the need for surgery on the primary tumor site and neck or ultimately cure more patients remain unanswered. A multi-institutional, randomized phase III study that will address these issues isunder development (Posner et al, manuscript submitted for publication). The optimal sequence and combination of chemotherapy and radiation for curative treatment of locally advanced SCCHN remain controversial. Advocates of concomitant chemoradiotherapy argue that radiation sensitizers and early treatment with aggressive radiation protocols are most likely to circumvent inherent tumor radioresistance and accelerated tumor repopulation. Although the results of randomized trials are mixed, meta-analysis data confirm an advantage of chemoradiation over radiation alone, and two compelling recent trials suggest an advantage to chemoradiation over radiation alone.26-29 Unfortunately, in these two recently published randomized trials, concomitant and adjuvant chemotherapies were both part of the experimental arm, confounding interpretation of the results. The data supporting induction chemotherapy followed by radiation versus radiation alone are less impressive. Meta-analyses fail to show a significant improvement in overall survival for the sequential combined approach, despite a reproducible decrease in the incidence of distant metastasis in the combined therapy arms. However, many of these trials are flawed because many of the chemotherapy and radiation therapy regimens used would be regarded as suboptimal by today's standards. Organ preservation and function were not addressed in these randomized trials. Chronic gastrostomy tube dependence rates as high as 18% have been reported after aggressive concomitant chemoradiotherapy regimens.30 Phase III trials that have compared induction chemotherapy followed by radiation to combined chemoradiation have been inconclusive. Most studies failed to demonstrate an overall survival improvement, despite an improvement in disease-free survival.31-33 TPFL4 is less toxic than TPFL5. Although preliminary data concerning response rates, survival, and organ preservation are promising, longer follow-up and greater experience are necessary before any conclusions concerning these end points can be drawn. A larger database will be necessary before the significance of the difference in pathologic response rates between various TPFL regimens can be assessed. Although TPFL4 is better tolerated than TPFL5, the regimen is arduous and still requires inpatient hospitalization for administration of chemotherapy. It is likely that with further modifications, docetaxel-containing induction regimens will be given routinely on an outpatient basis with less acute toxicity. We are currently accruing subjects to a phase I/II study in which TPFL is given on an outpatient basis with intensive home nursing support (Norris et al, manuscript submitted for publication). Preliminary data from this study show that hospitalization is not necessary for most patients, the regimen can be delivered every 21 days, and the dose of docetaxel can be significantly intensified without an increase in clinically relevant toxicity. Development of a phase III trial that will directly compare induction docetaxel/cisplatin/5-FU with cisplatin/5-FU, with response rate, organ preservation, quality of life, and survival as end points, is under way. Additional trials will be necessary to determine the optimal chemotherapy administration schedule of docetaxel-, cisplatin-, and 5-FU-containing regimens and to determine the relative benefits and toxicities of sequential chemotherapy and radiation therapy versus concomitant chemoradiotherapy. Ultimately, a hybrid strategy may prove to be most useful. Although we believe that the promising results obtained with TPFL regimens justify additional trials with similar regimens, until definitive phase III data are available, such regimens should be restricted to the clinical trial setting. It is likely that such regimens will ultimately play an important role in the treatment of selected patients with locoregionally advanced SCCHN.
Grant-in-Aid funding was provided by Rhône-Poulenc Rorer, Collegeville, PA, for data management support.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
