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Phase II trial of dose-dense paclitaxel, cisplatin, 5-fluorouracil, and leucovorin with filgrastim support in patients with squamous cell carcinoma of the head and neck

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BACKGROUNDThe current study evaluated the feasibility and clinical activity of a combination of paclitaxel, cisplatin, 5-fluorouracil (5-FU), and leucovorin administered on a biweekly schedule to patients with recurrent or unresectable squamous cell
  Phase II Trial of Dose-Dense Paclitaxel, Cisplatin, 5-Fluorouracil, and Leucovorin with Filgrastim Supportin Patients with Squamous Cell Carcinoma of theHead and Neck  Ricardo Hitt,  M.D., Ph.D. 1 Antonio Jimeno,  M.D., Ph.D. 1 Jose Marı´a Milla´n,  M.D. 2 Daniel Castellano,  M.D. 1 Herna´n Corte´s-Funes,  M.D., Ph.D. 1 1 Department of Medical Oncology, University Hos-pital 12 de Octubre, Madrid, Spain. 2 Department of Radiology, University Hospital 12de Octubre, Madrid, Spain.Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, New Or-leans, Louisiana, May 20–23, 2000.The first two authors contributed equally to thiswork. Antonio Jimeno’s current address: Department ofOncology, The Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins, Baltimore, Mary-land. Address for reprints: Antonio Jimeno, M.D., Ph.D.,The Sidney Kimmel Comprehensive Cancer Centerat Johns Hopkins, 1650 Orleans Street, Room162A, Baltimore, MD 21231; Fax: (410) 614-9006;E-mail: ajimeno1@jhmi.eduReceived February 12, 2004; revision received April 23, 2004; accepted May 18, 2004. BACKGROUND.  The current study evaluated the feasibility and clinical activity of acombination of paclitaxel, cisplatin, 5-fluorouracil (5-FU), and leucovorin admin-istered on a biweekly schedule to patients with recurrent or unresectable squa-mous cell carcinoma of the head and neck (HNSCC). METHODS.  Patients with recurrent or unresectable HNSCC were eligible if they hadreceived a previous regimen of neoadjuvant chemotherapy, concurrent chemora-diotherapy, or no previous systemic therapy. Patients received paclitaxel (175mg/m 2 on Day 1), cisplatin (35 mg/m 2 on Days 1 and 2), leucovorin (200 mg/m 2 onDay 1), and 5-FU (1000 mg/m 2 per day as a 48-hour continuous intravenousinfusion on Days 1 and 2) every 2 weeks. Patients received subcutaneous filgrastim(300   g per day) on Days 3–9 of each cycle. Treatment was administered on anoutpatient basis for a maximum of six cycles. RESULTS.  Thirty-five patients received a combined total of 194 treatment cycles.Eighteen complete responses (51%) and 12 partial responses (34%) were docu-mented, for an overall response rate of 86% (30 of 35 patients). The medianprogression-free survival duration was 14 months, and the median overall survivalduration was 18 months. Two toxicity-related deaths were documented (one due toneutropenic sepsis and the other due to catheter-related pulmonary embolism).Grade 4 neutropenia was observed in one patient. Other severe (Grade 3 or 4) toxiceffects included mucositis (14%), anemia (6%), thrombosis (6%), thrombocytope-nia (3%), and neuropathy (3%). CONCLUSIONS.  The current dose-dense, four-agent, taxane-containing biweekly schedule was feasible and effective in patients with recurrent or unresectableHNSCC. However, given the single-center nature of the current study and thehighly selected study population, further validation of these findings is recom-mended.  Cancer   2004;101:768–75.  © 2004 American Cancer Society. KEYWORDS: head and neck, dose-dense, paclitaxel, filgrastim. S quamous cell carcinoma of the head and neck (HNSCC) accountsfor the majority of malignancies that arise in the head-and-neck region. 1 The prognosis for patients with early-stage HNSCC is favor-able, and treatment with surgery or radiotherapy yields 5-year overallsurvival (OS) rates of 70–90%. 2 Occurrence of a second primary tumoris one of the major concerns for patients with this stage of disease. 3 However, two-thirds of patients present with advanced locoregional(Stage III/IV) disease. Despite combined-modality approaches involv-ing chemotherapy and radiotherapy or surgery, locoregional and dis-tant recurrence, respectively, are noted in up to 60% and 25% of  768 © 2004 American Cancer SocietyDOI 10.1002/cncr.20439Published online 2 July 2004 in Wiley InterScience (  patients who receive this type of treatment, and the3-year survival rate associated with such treatment is   30%. 2,4  After disease recurrence, the median sur-vival period associated with standard treatment is 6months. 5–8 For patients with locally advanced or recurrentdisease, the combination of cisplatin and infusional5-fluorouracil (5FU) is accepted as standard chemo-therapy. The response rates range from 60% to 80% inthe neoadjuvant setting and from 30% to 40% forpatients with recurrent disease. 5–9 The taxanes, used as single agents or in combina-tion with other cytotoxic agents, have demonstratedactivity in patients with HNSCC. 10 Cisplatin    pacli-taxel, with or without 5-FU, yielded response rates of 21–38% in patients with recurrent disease 11–14 andresponse rates of 60–88% in patients with unresect-able disease. 15–17 The main side effect of paclitaxel incombination with cisplatin is peripheral neuropathy,and mucositis and diarrhea are observed when 5-FU isincluded in the regimen.The concept of dose density refers to the admin-istration of drugs with a shortened intertreatment in-terval. It is based on the observation in experimentalmodels that a given dose kills a certain fraction, ratherthan a certain number, of exponentially growing neo-plastic cells. 18 It has been hypothesized that morefrequent administration of cytotoxic therapy would bemore effective in minimizing residual tumor burdenthan would dose escalation. 19 On the basis of thisexperimental model, which has yielded a survival ben-efit for patients with breast carcinoma, 19,20  we hypoth-esized that a dose-dense schedule combining fouractive agents could be efficacious in terms of responserate in patients with unresectable HNSCC. We anticipated that a biweekly 120-hour infusionof 5-FU in combination with cisplatin and paclitaxel would induce severe mucositis. 15 Therefore, we in-stead opted for a 48-hour infusion of 5-FU with leu-covorin modulation, similar to the one used by DeGramont et al. to treat patients with colorectal carci-noma. 21 This combination of 5-FU and leucovorinallows the safe delivery of a high dose of modulated5-FU on a biweekly basis.The current study was designed to evaluate thefeasibility and clinical activity of a dose-dense, four-agent, paclitaxel-containing biweekly schedule in pa-tients with recurrent or unresectable HNSCC. MATERIALS AND METHODS Patient Eligibility For inclusion in the study, patients were required tobe older than 18 years and to have histologically doc-umented, bidimensionally measurable HNSCC that was recurrent or deemed unresectable. All patients were required to have an Eastern Cooperative Oncol-ogy Group performance status (PS) of 0–1, life expect-ancy   12 weeks, and adequate bone marrow, hepatic,and renal function (i.e., absolute neutrophil count[ANC]    2.0    10 9 /L, platelet count    100    10 9 /L,hemoglobin level    10.0 g/dL, aspartate aminotrans-ferase or alanine aminotransferase levels    1.5 timesthe upper limit of normal, alkaline phosphatase level  5 times the upper limit of normal, normal bilirubinlevel, creatinine clearance  50 mL/min, and a normalserum calcium level).Patients who had undergone previous chemother-apy for recurrent disease or received previous taxanetherapy, systemic anticancer treatment in the previ-ous 6 months, or irradiation to major bone marrow areas were excluded from the study. Patients withGrade    2 peripheral neuropathy or other seriousmedical or psychiatric conditions were also excluded.Patients were required to have received no previoustherapy or only 1 previous regimen of neoadjuvant oradjuvant chemotherapy or chemotherapy adminis-tered concurrently with radiotherapy, provided thatthe regimen did not include taxanes and was termi-nated  6 months before disease recurrence. Patients with previous malignancies were eligible if they hadbeen treated curatively and had been free of diseasefor    5 years. The scientific review board and theethics committee of the University Hospital 12 deOctubre (Madrid, Spain) granted protocol approval.Patients were required to provide written informedconsent before study enrollment. Within 1 week of study entry, physical examina-tion and acquisition of a complete clinical history  were performed for all patients, as were completeblood counts, serum biochemistry tests (including liver and renal function tests and monitoring of elec-trolyte levels), urinalysis, and electrocardiography.Chest radiographs and computed tomography (CT)scans of the head and neck were obtained within 3 weeks before study entry. Treatment Plan The treatment regimen consisted of a 2-day course of paclitaxel (175 mg/m 2 as a 3-hour intravenous [i.v.]infusion on Day 1), followed by cisplatin (35 mg/m 2 asa 30-minute i.v. infusion on Days 1 and 2), leucovorin(200 mg/m 2 as a 1-hour i.v. infusion on Day 1), and,finally, 5-FU (1000 mg/m 2 per day as a 48-hour con-tinuous i.v. infusion on Days 1–2), administered every 14 days. Chemotherapeutic agents were infused via animplantable subcutaneous device (Port-a-Cath, SIMSDeltec, Inc., St. Paul, MN). All patients were premed-icated with i.v. dexamethasone (20 mg), diphenhydra- Dose-Dense, Taxane-Containing CT for HNSCC/Hitt et al. 769  mine (50 mg), and cimetidine (300 mg) 30 minutesbefore paclitaxel administration. Standard mannitoland i.v. hydration accompanied cisplatin administra-tion. Prophylactic antiemetics included i.v. ondanse-tron (8 mg) before chemotherapy and oral ondanse-tron (8 mg) 3 times daily for 2 days. Patients receivedsubcutaneous filgrastim (300   g per day) on Days 3–9of each cycle. No prophylactic antibiotics were admin-istered. Treatment was administered on an outpatientbasis for a maximum of six cycles.Retreatment on Day 15 required an ANC count   1.5    10 9 /L, a platelet count    100    10 9 /L, acreatinine clearance rate  50 mL/min, and resolutionof all nonhematologic toxicities (except alopecia andfatigue) to baseline or less than Grade 1. In case of adelay     14 days, the patient was removed from thestudy. Predetermined dose adjustments (dose reduc-tion or delay in administration) were permitted for alldrugs after the occurrence of specific toxic effects. Thedoses of all 4 agents were reduced by 25% after any episode of febrile neutropenia, Grade 4 neutropenialasting   5 days, or Grade 4 thrombocytopenia. Dosesof 5-FU and leucovorin were reduced by 25% afterepisodes of Grade 4 mucositis or diarrhea, Grade 3mucositis, or diarrhea lasting     5 days. Toxic events were recorded on a continuous basis and followeduntil they resolved to baseline or  Grade 1.Follow-up history and physical examination,complete blood cell counts, and serum biochemistry tests were performed at weekly intervals during treat-ment. Restaging CT scans, chest radiographs, and up-per respiratory tract examinations were performed ev-ery 3 cycles (6 weeks) or when disease progression wasclinically suspected. Follow-Up  After therapy, patients were followed every 3 monthsfor the first year, every 6 months from the second yearthrough the fifth year, and once yearly thereafter. Fol-low-up visits included physical examination, endo-scopic evaluation, blood tests, chest radiography, CTscanning of the head and neck, and other tests whenclinically indicated. Study Endpoints The primary endpoint of the current study was tumorresponse. The criteria used to define response (com-plete response [CR], partial response [PR], stable dis-ease [SD], and progressive disease [PD]) were basedon standard World Health Organization definitions.Patients were considered evaluable for response oncetherapy was initiated. Secondary efficacy parametersincluded progression-free survival (PFS) and overallsurvival (OS). PFS was defined as the time from diag-nosis of recurrent or advanced disease to last contactor disease progression (either clinical or radiologic).Patients who died of causes other that HNSCC werecensored in the analysis of PFS. OS was defined as thetime from diagnosis of recurrent or advanced diseaseto last contact or death. Adverse events were classifiedand graded according to the National Cancer InstituteCommon Toxicity Criteria. Patients were consideredevaluable for toxicity once therapy was initiated. Statistical Analysis The trial followed a two-stage Simon minimax de-sign, 22 allowing early closure in case of treatment fail-ure. The null hypothesis, which stated that the trueresponse rate was    60%, was evaluated against thealternative hypothesis, which stated that the true re-sponse rate was    80% (alpha error, 0.05; beta error,0.20). Nine responses were required from the first 13patients to continue accrual, and 26 responses wererequired from 35 patients for the regimen to be con-sidered promising enough to warrant a comparativetrial. Ninety-five percent confidence intervals (CIs) were calculated using the exact method. In addition,survival was estimated using the Kaplan–Meier prod-uct-limit method. 23  All tests were two sided at the 0.05level of significance. The SPSS statistical package (Ver-sion 10.0; SPSS Inc., Chicago, IL) was used for allstatistical analyses. RESULTS Patients Between March 1999 and November 2000, 35 patients with locally advanced HNSCC were enrolled in thestudy. All patients were assessable for toxicity andsurvival, and response could be evaluated in 34 pa-tients (1 patient died of neutropenic sepsis beforeresponse assessment). Demographic and clinical char-acteristics of the study cohort are summarized in Ta-ble 1. Twenty-four patients presented with recurrenceof a previously diagnosed and treated HNSCC, and theremaining 11 patients presented with unresectabledisease at diagnosis and received the study regimen asinduction therapy. Five patients had received previouschemotherapy. Of these 5 patients, 4 (80%) had beentreated with a combination of cisplatin and 5-FU asneoadjuvant chemotherapy (resulting in 1 CR and 3PRs), and 1 (20%) had received cisplatin alone as con-current chemotherapy. Fourteen patients had re-ceived radiotherapy. The median interval between ini-tial diagnosis and disease recurrence was 18 months(range, 6–97 months). 770 CANCER August 15, 2004 / Volume 101 / Number 4  Treatment Administered  A total of 194 cycles of the study regimen were deliv-ered (median, 6 cycles per patient; range, 2–6 cycles):28 patients (80%) received the 6 planned cycles, 2patients (6%) received 5 cycles, 2 patients (6%) re-ceived 4 cycles, 2 patients (6%) received 3 cycles, and1 patient (3%) received 2 cycles. Most chemotherapy cycles (92%) were delivered at the planned doses.Doses were reduced in four patients (after the firstcycle in three patients and after the second cycle inone) due to mucositis. Five treatment cycles weredelayed by 1 week (due to an episode of Grade 1neutropenia in 1 case, an episode of Grade 3 throm-bocytopenia in 1 case, and an episode of Grade 2mucositis in 3 cases). Seven patients did not completethe six planned cycles: two patients died of toxicity  while on study, three patients were removed from thestudy (after three, four, and five cycles, respectively)due to the absence of clinical benefit, one patientpresented with PD (after five cycles), and one patientdeveloped Grade 4 mucositis (during the third cycle)despite a previous dose reduction.The median duration of treatment was 12 weeks(range, 4–14 weeks). The median dose intensities werepaclitaxel 87.5 mg/m 2 per week (range, 64–87.5 mg/m 2 ), cisplatin 35 mg/m 2 per week (range, 25.5–35 mg/m 2 ), 5-FU 1000 mg/m 2 per week (range, 730–1000mg/m 2 ), and leucovorin 100 mg/m 2 per week (range,73–100 mg/m 2 ). The dose intensity achieved was 97%of the planned dose intensity for all 4 study agents. Response Eleven responses were documented in the first stageof the trial ( n   13), and thus accrual continued. Theoverall response rate was 86% (30 of 35 patients; 95%CI, 74–97%). With regard to best response to therapy,there were 18 CRs (51%), 12 PRs (34%), 3 cases of SD(9%), and 1 case of PD (3%). One patient (3%) died of toxicity after Cycle 1, before the evaluation of re-sponses, and was therefore deemed unassessable. Themedian time to response was 6 weeks (range, 5–9 weeks). The median duration of response was 12.8months (range, 2.2–39 months).No differences were observed when analyzing re-sponse according to previous irradiation of the targetlesion. Overall response rates were 90% and 79%, re-spectively, for patients with nonirradiated and radi-ated lesions ( P   0.32), with CR rates of 62% and 36%( P     0.13) and PR rates of 29% and 43% ( P     0.45),respectively.It is noteworthy that only 5 of the 18 CRs wereachieved after the third cycle. The other 13 patientshad achieved PR by Week 6. In contrast, most patients(11 of 12) who ultimately achieved a PR as their bestresponse to therapy did so after the third cycle, andthere was only 1 late response. Toxicity Hematologic and nonhematologic toxicities are sum-marized in Table 2. We recorded only one episode of Grade 1 neutropenia and only one other episode of Grade 4 neutropenia. The latter was accompanied by fever and sepsis and led to the death of the patient,despite aggressive intensive care management. Themedian nadir ANC count was 6.7    10 9 /L (range,0.34–24.4  10 9 /L). We observed thrombocytopenia in6 patients (17%), with 1 (3%) having Grade 3 throm-bocytopenia. Anemia (predominantly Grade 1) wasdocumented in 27 patients (77%). Grade 3 anemia wasnoted in 2 patients (6%).Overall, 23% (8 of 35) of patients experiencedGrade 3/4 nonhematologic adverse events. Of theseevents, the most common and severe were episodes of mucositis (three patients had Grade 3 episodes, andtwo had Grade 4 episodes), which was unrelated toprevious radiotherapy. Mucositis was the only toxicity that required dose adjustments. One patient was re-moved from the study due to recurrent severe mucosi- TABLE 1Patient Characteristics ( n   35) Characteristic No. of patients (%) GenderMale 34 (97)Female 1 (3)Median age in yrs (range) 58 (29–77)ECOG performance status0 22 (63)1 13 (27)Initial disease stage at diagnosisII 8 (23)III 6 (17)IV 21 (60)Primary tumor siteOral cavity 9 (26)Oropharynx 6 (17)Hypopharynx 5 (14)Larynx 13 (37)Unknown origin 2 (6)Extent of diseaseLocoregional, recurrent 24 (77)Locoregional, unresectable 11 (23)Previous therapy Surgery alone 9 (26)Surgery and radiotherapy 10 (29)Surgery and chemotherapy 1 (3)Chemotherapy and radiotherapy 1 (3)Surgery, chemotherapy, and radiotherapy 3 (9)None 11 (31) ECOG: Eastern Cooperative Oncology Group. Dose-Dense, Taxane-Containing CT for HNSCC/Hitt et al. 771  tis despite a previous dose reduction. Two episodes of catheter-related thrombosis were observed. One re-solved after removal of the catheter (Grade 3), but theother was associated with massive pulmonary embo-lism (Grade 4) and accounted for the second toxicdeath in the current study. Neuropathy and myalgia were observed in 91% and 80% of patients, respec-tively. Only one patient experienced Grade 3 neurop-athy.Table 3 summarizes toxicity data by treatmentcycle. Anemia, neuropathy, myalgia, hand–foot syn-drome, and alopecia were cumulative. After the thirdcycle, 20 of 34 (59%) patients presented with neurop-athy, whereas this condition was reported by 26 of 28(93%) patients after the sixth cycle. Subsequent Therapy  Among patients who completed the 6 planned cycles,12 were treated with radiotherapy, 5 were treated withsurgery, and 6 were treated with surgery plus radio-therapy. No patient underwent reirradiation. Five pa-tients did not receive any further therapy; all hadrecurrent disease following previous radiotherapy andsubsequently achieved CR in the current study. Thepatient who was withdrawn from the study due tomucositis continued therapy with cisplatin and under- went surgery. Two patients who were withdrawn fromthe study before completion and the patient who pre-sented with disease progression during therapy re-ceived methotrexate with palliative intent. The otherpatient who was removed from the study due to a lack of clinical benefit chose not to receive further therapy and was treated with supportive care alone. Outcome: Recurrence and Survival Twenty-one patients presented with disease progres-sion after therapy. Of these 21 patients, 17 patientshad locoregional disease recurrences, 2 had distantmetastases, and 2 presented with both locoregionaland distant disease. The median PFS was 14 months(95% CI, 11.8–19.3 months), and the median survivalafter disease progression was 3 months (95% CI, 0.7–5.3 months).Twenty-six deaths occurred—2 patients died of toxicity during treatment, 21 died of tumor progres-sion, and 3 died of causes unrelated to therapy orHNSCC (1 due to an acute myocardial infarction and 2due to second tumors [esophageal and small cell lung carcinoma]). The median OS was 18 months (95% CI,14.3–21.7 months). Characteristics of Long-Term Survivors  After a median follow-up of 34 months (range, 10–41months), 9 patients were alive and free of disease. Onepatient had previously received concurrent chemora-diotherapy, six had received surgical management,and two had received no previous therapy; seven of these patients entered the study with recurrent dis-ease, and two entered with primary malignancies. Twopatients had disease that partially responded to thedose-dense regimen and underwent surgery plus ra-diotherapy. The other 7 patients had complete re-sponses (after 3 cycles in 3 cases and after 6 cycles in4 cases) and received surgery ( n   1) or radiotherapy ( n   6). Comparison of Patients with Recurrent Disease andPatients with Unresectable Primary Disease Response rates were similar for patients with recur-rent disease and those with unresectable primary dis-ease (83% vs. 91%, respectively;  P     0.73). The lattergroup had a nonsignificantly higher CR rate (46% vs.64%;  P     0.33). Toxicity was equivalent in these twogroups. After the completion of treatment, all surviv-ing patients with unresectable disease at diagnosisreceived further therapy (radiotherapy [ n   5], surgery [ n   1], or surgery plus radiotherapy [ n   4]), whereas5 patients in the recurrent disease group did not re-ceive any complementary treatment. PFS (13.0 vs. 16.0months;  P     0.47) and OS (17.0 vs. 19.6 months;  P    0.74) also did not differ between patients with re-current disease and patients with unresectable pri-mary disease (Fig. 1). Nine patients are alive and freeof disease, including seven patients with recurrentdisease and two patients with unresectable primary disease. One death due to toxicity and 16 deaths dueto disease progression were observed among patients TABLE 2Summary of Hematologic and Nonhematologic Toxicities ( n   35) Toxicity  All grades Grade 3–4No. of patients (%) No. of patients (%) Hematologic Anemia 27 (77) 2 (6)Thrombocytopenia 6 (17) 1 (3)Neutropenia 2 (6) 1 (3)Nonhematologic Alopecia 33 (94) — (—)Neuropathy 32 (91) 1 (3)Myalgia 28 (80) 0 (0)Mucositis 12 (34) 5 (15)Nausea 12 (34) 0 (0)Emesis 10 (29) 0 (0)Diarrhea 8 (23) 0 (0)Hand–foot syndrome 6 (17) 0 (0) Asthenia 5 (14) 0 (0)Thrombosis 2 (6) 2 (6) 772 CANCER August 15, 2004 / Volume 101 / Number 4
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