1 Medical Oncology Division, 2 Otorhinolaryngology Service, 3 Radiation Oncology Division, 4 Radiology Department, Hospital Universitario 12 de Octubre, Madrid; 5 Radiotherapy Department, Hospital Gregorio Marañón, Madrid; 6 Bristol-Myers Squibb, Madrid, Spain
Received 17 October 2001; revised 21 February 2002; accepted 27 March 2002
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Abstract |
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The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Methods:
Seventy patients with previously untreated stage IIIIV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m2 as a 3-h infusion on day 1, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil (5-FU) 500750 mg/m2/day as a 24-h continuous infusion on days 26, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m2/day to 500 mg/m2/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery.
Results:
Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 23, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 4063 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively.
Conclusions:
The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.
Key words: chemotherapy, cisplatin, 5-fluorouracil, head and neck cancer, paclitaxel, phase II
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Introduction |
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The role of induction chemotherapy in the treatment of locally advanced SCCHN has evolved over the last 20 years [39]. It produces overall response rates of 80%, with complete response (CR) rates of
30%, and reduces the rate of development of distant metastases by half. Induction chemotherapy is effective in preserving organ function in certain subtypes of SCCHN, such as laryngeal and hypopharyngeal carcinomas [3, 6]. Induction chemotherapy has not consistently improved survival when compared with loco-regional treatment alone. New regimens continue to be evaluated in the induction setting, and it is in this clinical context that an optimal assessment of the true activity of drug combinations can be achieved.
New single agents clinically tested in SCCHN include the taxanes. Paclitaxel and docetaxel have shown significant activity in multiple phase II trials, with response rates of 2042% as single agents [1014]. Because of the novel mechanism of action and toxicity profile of paclitaxel, this agent has been incorporated into several combination regimes for advanced SCCHN. The combinations of paclitaxelcisplatin and paclitaxel5-fluorouracil (5-FU) showed remarkable response rates of 3377% and 49%, respectively, in patients with metastatic or recurrent disease [1518]. The main side effect of paclitaxel in combination with cisplatin was peripheral neuropathy [1517], while mucositis and diarrhea were the principal toxicities for the paclitaxel5-FU combination [18]. Recently, we have published the results of a study of escalating doses of paclitaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) support in patients with locally advanced SCCHN [19]. The overall response rate was 78%, including 48% complete remissions. The major toxicities were paresthesias and myalgias, and the survival rate at 3 years was 50%.
Based on the encouraging anti-neoplasic activity and the non-overlapping toxicity profiles of two-drug paclitaxel combinations, we hypothesized that adding paclitaxel to the standard combination of cisplatin and 5-FU [20] could improve its therapeutic index. In the present manuscript we report the long-term results of a phase II trial of paclitaxel, cisplatin and 5-FU (PPF) as induction treatment in patients with locally advanced SCCHN.
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Patients and methods |
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Baseline evaluation and induction chemotherapy
Patients were evaluated by a multidisciplinary team that included medical oncologists, head and neck surgeons and radiotherapists so as to confirm eligibility, staging and treatment planning. Within 1 week of study entry, all patients had a complete clinical history and physical examination, complete blood counts, serum chemistries (liver and renal function test and electrolytes), urinalysis and electrocardiogram (ECG). A chest radiograph and a computed tomography (CT) scan of the head and neck were performed within 4 weeks of enrollment. Patients were staged by phy sical examination and radiological evaluation according to the criteria established by the American Joint Committee on Cancer [21]. Tumor unresectability was assessed at this stage based on the following criteria: (i) hypopharyngeal tumors extending across the midline of the posterior pharyngeal wall or fixed to the cervical spine; (ii) laryngeal tumors extending directly into surrounding muscle or skin, or with >3 cm of subglottic extension; (iii) oral cavity tumors that are so extensive that resection would preclude functional reconstruction; (iv) base of tongue tumors that extend into the root of the tongue, or patients requiring a total glossectomy; (v) tonsil tumors that extend into the pterygoid region, or tumors that extend across the midline of the pharyngeal wall or directly into the soft tissues of the neck; (vi) neck nodes metastases fixed to the carotid artery, mastoid, base of skull, or cervical spine.
The PPF treatment regimen consisted of a 6-day course of paclitaxel (175 mg/m2 as a 3-h infusion on day 1), cisplatin (100 mg/m2 as a 1-h infusion on day 2) and 5-FU (500750 mg/m2/day as a 120-h continuous i.v. infusion on days 26). Courses were repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m2/day to 500 mg/m2/day due to the excessive toxicity observed in the first 14 patients enrolled. The PPF treatment was administered on an outpatient basis for a maximum of three cycles. All patients were pre-medicated with intravenous dexamethasone (20 mg), diphenhydramine (50 mg) and cimetidine (300 mg) 30 min before paclitaxel administration. Standard mannitol (12.5 g) and intravenous hydration accompanied cisplatin administration. Prophylactic antiemetics included additional oral dexamethasone (8 mg) twice daily on days 2 and 3 of the cycle, and ondansetron (8 mg i.v. or p.o.) every 812 h on days 15. Prophylactic administration of hematopoietic growth factors was not permitted within the protocol.
Re-treatment on day 22 required an ANC 1.5 x 109/l, a platelet count
100 x 109/l, a creatinine clearance rate >50 ml/min, and resolution of all other non-hematological toxicities (except alopecia, musculoskeletal pain and fatigue) to baseline or less than grade 1. If there was a delay of subsequent cycles beyond day 35, the patient was removed from the study. The doses of all three drugs were reduced by 25% following any episode of febrile neutropenia, grade 4 neutropenia lasting >5 days, or grade 4 thrombocytopenia. The dose of 5-FU was reduced by 25% following episodes of grade 4 mucositis or diarrhea, or grade 3 mucositis or diarrhea lasting >5 days. Paclitaxel and cisplatin were reduced by 25% following persistent neurosensensorial toxicity of grade
2. Treatment was discontinued immediately upon evidence of tumor progression or following two cycles should no response be observed.
Patients were monitored for toxicity (medical interview, physical examination and complete blood cell counts) every week during treatment. Blood chemistries were performed before each cycle of therapy. Re-staging CT scans and upper respiratory/digestive tract examinations performed under anesthesia by a head and neck surgeon were scheduled to be performed during the 3rd or 4th week of the third cycle of induction chemotherapy. Clinical response was defined for each patient according to the combined findings of CT and physical exam according to World Health Organization (WHO) criteria. Clinical responses following chemotherapy treatment were confirmed by biopsy when feasible.
Loco-regional therapy
A consensus post-induction treatment for each patient was agreed upon by the evaluation of a multidisciplinary team based on the following protocol guidelines. Surgery of the primary site and neck was recommended for patients with resectable disease who failed to achieve at least a partial response (PR) after three PPF courses. Neck dissection, when feasible, was recommended before definitive radiotherapy for patients with bulky nodal disease at study entry and/or suboptimal response to induction chemotherapy. Primary tumor surgery and neck dissection were carried out 4 weeks after the 1st day of the last chemotherapy cycle. Patients with CR or PR of the primary site were treated with chemo-radiotherapy, or radiotherapy alone if concomitant treatment was not feasible.
Radiotherapy was initiated 46 weeks after the 1st day of the last induction chemotherapy cycle or as soon as the patient recovered from surgery, if performed. Wide treatment fields were planned so as to encompass the primary tumor site and the involved neck areas. Treatment consisted of a single, daily, isocentric external-beam megavoltage irradiation administered at 1.8 to 2.0 Gy per fraction. The primary tumor and disease-associated neck received 6570 Gy (non-resected tumors) or 60 Gy (post-operative radiation). A minimum of 45 Gy was delivered bilaterally to clinically uninvolved neck areas and supraclavicular regions.
Definitive irradiation was scheduled with concurrent administration of paclitaxel in all patients except for those whose PS or residual toxicities precluded the co-administration of chemotherapy. Paclitaxel was given once a week at a dose of 25 mg/m2 as a 1-h intravenous infusion, starting on day 1 of radiation treatment. Usual pre-medication was given before each paclitaxel infusion. A complete blood cell count was performed every week before paclitaxel administration, and clinical toxicity was also monitored weekly during the radio-chemotherapy period. Paclitaxel doses were delayed if there was evidence of dehydration, grade 34 mucositis or skin toxicity, or grade 3 neurotoxicity. Patients with severe mucositis were provided with intensive support, and parenteral nutrition was administered intravenously.
Follow-up
After treatment patients were followed every 3 months during the 1st year, every 6 months during the 2nd, 3rd, 4th and 5th years, and once a year thereafter. At each visit, a physical examination was performed, including an ear, nose and throat exam, blood tests, chest X-ray, head and neck CT scans and other clinically oriented explorations.
Study end points and statistical analysis
The primary end points of the study were tumor response and toxicity to induction chemotherapy. The criteria used to evaluate CR, PR, no change (NC) and progressive disease (PD) were based on the standard definitions established by the WHO [22]. Toxicity was graded according to the NCI-CTC. Descriptive statistics were used to characterize response and toxicity rates [23]. Two-stage conditional exact binomial 95% confidence intervals (CIs) were used to describe the distribution of the response rates [24]. Time-to-disease progression (TTP) and overall survival (OS) were estimated according to the KaplanMeier product limit method [22]. TTP was defined as the time elapsed from the date of registration to the date of the first documented evidence of progressive disease. Patients dying from causes unrelated to the SCCHN before disease progression were considered censored in the analysis of TTP. OS was calculated from the time of registration to the date of death from any cause. The Cox proportional hazards model was used for adjusted analysis of prognostic factors for TTP and OS [25].
The sample size for the trial was calculated according to the primary end point of the study (the complete response rate to the PPF induction regimen) on the basis of a null hypothesis, defined as the probability of response P0 0.3, and an alternative hypothesis where the probability of response was P1
0.5, assuming a significance level of
= 0.05 (one-tail) and a power of 1 ß = 0.8. The target number of patients was calculated as 70.
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Results |
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Toxicities were assessed in all 70 patients and the results are summarized in Table 3. Severe myelosupression was infrequent. The most common acute non-hematological toxicities were mucositis, diarrhea, alopecia, peripheral neuropathy and myalgias. Overall, three out of 70 patients (4%) had a treatment-related death.
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Response to chemotherapy
Sixty-nine of the 70 patients were evaluable for response; one patient died from complicated febrile neutropenia and mucositis following the first course of therapy and before tumor status could be assessed. Overall, 41 patients (58.5%) achieved CR, 20 (28.5%) achieved PR, which, together, constitutes an overall response rate to PPF induction therapy of 87% (95% CI 62% to 97%) (Table 4). No independent response review was undertaken. However, biopsies of the primary tumor site were performed in 23 of 41 patients with clinical CR. Of these, 21 (91%) showed pathological CR, and two (9%) had residual microscopic tumor. Negative biopsies were obtained also from three of seven patients in clinical PR. Failure to respond to the PPF treatment was observed in eight patients (12%; 95% CI 4% to 19%). Of these, six had stable disease (no change) and two with larynx primaries developed distant subcutaneous metastasis (one patient) and progressive neck disease (one patient). When evaluating response with respect to disease site, CR was documented at the primary tumor site in 49 of 66 patients (74%), and PR was documented in 10 (15%). These responses included the two patients who died following two courses of therapy (one from a pulmonary embolism and the other from complicated febrile neutropenia and mucositis). Their tumor sites were assessed as having achieved CR and PR, respectively. Response assessment of the neck lymph node disease showed that CR was achieved in 34 of 55 patients (62%), and PR was achieved in 12 (22%).
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Loco-regional therapy
Forty-eight patients with CR of the primary tumor and three patients with no primary tumor at presentation were treated with radiotherapy with (n = 39) or without (n = 12) concomitant paclitaxel. Eleven of these 51 patients had post-chemotherapy neck lymph node dissections performed before radiotherapy due to bulky nodal disease at presentation. The other patient achieving a CR died after the third PPF course before any consolidation treatment was instituted.
Five of the 10 patients achieving PR at the primary tumor site were treated with surgery followed by consolidation radiotherapy, four received concomitant chemo-radiation as the sole treatment, and one patient died during the induction treatment. All five surgically treated patients underwent neck lymphadenectomies, with three of them also undergoing primary tumor site resections (radical laryngectomy in two patients, and partial laryngectomy and pharyngectomy in one patient).
Of the five patients with NC following induction chemotherapy, three underwent surgery (one radical laryngectomy, one total glossectomy, one radical pharyngectomy) and radiotherapy, and two with non-resectable disease were treated with radiotherapy alone. Of the two patients with progressive disease, one developed distant metastases and was treated with further chemotherapy, and the other had local progression and received palliative radiation therapy. Finally, one patient died after the first course of therapy before tumor response had been assessed.
Overall, 65 patients received radiotherapy treatment, either following combined surgery of the tumor plus neck dissection (six patients) or neck dissection alone (13 patients), or as the only consolidation treatment (46 patients). Forty-three of these patients received concomitant weekly paclitaxel during the irradiation period. The median duration of chemo-radiation therapy was 8 weeks (range 513 weeks) and the median number of concomitant paclitaxel administrations were 5 (range 18). Acute toxicities due to chemo-radiation treatment are presented in Table 5. The most common causes for interruption of paclitaxel administration were severe mucositis and skin toxicity in the head and neck. Nineteen patients (43%) required parenteral nutrition due to severe mucositis, and two patients needed red blood cell transfusions. Twenty-two patients had radiation therapy without concomitant paclitaxel due to grade 2 residual neuropathy (six patients), inadequate PS or comorbidity (six patients), patient refusal (five patients) or no response to PPF (five patients). The median duration of radiotherapy treatment was 7 weeks (range 510 weeks). In general, these patients developed less severe mucosa and skin toxicities than patients receiving concomitant chemotherapy, and only four patients (18%) required nutritional support.
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Outcome
In December 2001, with a median follow-up time of 51 months (range 4063 months), 41 of 70 patients (59%) had not progressed, and 29 patients (41%) had shown disease progression. These included 20 patients with recurrent disease after having been rendered disease-free. The estimated 5-year TTP was 56% (Figure 1). The sites of disease progression were the primary tumor sites in 11 cases, neck lymph nodes in four cases, loco-regional disease in seven cases, distant metastases in three cases, and neck lymph nodes and distant metastases in 4 cases. Twenty-eight of the 29 relapsing patients died.
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At the most recent follow-up, 30 patients were alive and tumor-free, and one was alive with disease. Thirty patients had died with SCCHN (28 with progressive disease, two from sepsis during induction PPF), and nine had died tumor-free (five from secondary tumors, two from pneumonia, one from a heart attack, and one from a pulmonary embolism during chemotherapy treatment). The disease-specific and overall survival rates at 5 years were 58% and 44%, respectively (Figure 2). Quality of life among the 31 surviving patients was good. All had a PS of 01, and none was dependent on a feeding tube. On the other hand, five and 21 patients complained of severe or mildmoderate xerostomy, and 11 and three patients had residual grade 1 or 2 peripheral neuropathy, respectively.
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Discussion |
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The combination of induction chemotherapy followed by radiotherapy given concurrently with non-intense radiation-sensitizing chemotherapy may offer a good therapeutic index with optimal loco-regional and systemic control, without the debilitating acute and late side effects of full chemo-radiation treatment [26, 27]. Vokes et al. have demonstrated the feasibility of administering induction chemotherapy followed by chemo-radiotherapy [28, 29]. The results of their series of 71 patients with stage III or IV SCCHN treated with three cycles of induction chemotherapy [cisplatin, fluorouracil, leucovorin and interferon -2b (PLF-IFN)] followed by optional surgery and radiotherapy with concurrent fluorouracil and hydroxyurea are particularly promising [29]. They have reported a CR rate to induction chemotherapy of 51%, and the progression-free and overall survival rates at 3 years were 69% and 60%, respectively. Toxicity was notable during the induction phase and included severe or life threatening mucositis (54% of the patients), myelosupression (60%) and five toxic deaths (7%).
PPF induced an impressive response rate of 88%, including CR in 59% of patients, despite 58% of the patients having T4 lesions and a similar percentage having N2N3 disease. Responses were also evaluated separately in the primary tumor site and neck lymph node disease. At the end of the induction phase, the primary site CR rate was 74%, and the nodal site CR rate was 62%. All the patients in our study were assessed before and after treatment by a multidisciplinary team. Response to induction chemotherapy was rigorously evaluated with CT scans and upper respiratorydigestive tract examination under anesthesia by a head and neck surgeon. Furthermore, in our study we were able to confirm pathologically CR in 91% of the 23 patients in clinical CR, in whom a repeat biopsy was performed. Less rigorous response evaluation in other studies may explain, in part, why the high response rates reported did not translate into clear benefits with respect to survival rates [79].
Toxicity analysis in our trial showed that paclitaxel may be added to the PF regimen. Ninety percent of patients received all three planned cycles of therapy and the median overall relative dose-intensity administered was 95%. Hematological toxicity was not severe. Grade 4 neutropenia was documented in only 14% of patients and 9% of the cycles, and was usually of short duration. Only three patients (4%) developed febrile neutropenia, even though the use of prophylactic CSFs or antibiotics was not permitted under the present protocol. Grade 34 anemia and thrombocytopenia were uncommon. Non-hematological toxicity consisted of universal alopecia, mild to moderate asthenia, mucositis, emesis, myalgias and peripheral neuropathy. The dose of 5-FU was reduced from 750 mg/m2/day to 500 mg/m2/day during the trial following the occurrence of two toxic deaths (complicated febrile neutropenia and mucositis) among the 14 initial patients. Thereafter, no further toxic deaths were observed and the incidence of grade 34 neutropenia and febrile neutropenia were significantly decreased from 50% and 14% to 29% and 2%, respectively. No significant changes in the incidence of other side effects, including mucositis and diarrhea, were observed with the reduced 5-FU dose. Of note was that five patients (7%) developed catheter-associated venous thrombosis, and that one patient died of a secondary pulmonary embolism. This may indicate, as has been suggested by others, a need for some form of anti-coagulation therapy when 5-FU is administered as a continuous infusion through an indwelling catheter [30].
Other groups have developed therapeutic triplets of paclitaxel, cisplatin and 5-FU [3134] using a similar sequence of drug administration and infusion time for paclitaxel (3 h), although some schedules fractionate cisplatin over 5 days [3133]. Recommended doses without G-CSF support were paclitaxel 135175 mg/m2, cisplatin 75100 mg/m2 and 5-FU 37504000 mg/m2. The observed toxicities in these reports have been consistent with the findings in our trial, although their incidence of severe mucositis and peripheral neuropathy was higher and was related, probably, to the larger amounts of 5-FU in each cycle and the higher number of cycles administered in those trials. In these schedules, the courses were repeated every 4 weeks. Therefore, the paclitaxel and cisplatin dose intensity achieved was lower than with our schedule, while that of 5-FU was comparable.
Some investigators have chosen to add docetaxel, another taxane active in SCCHN, to the PF induction schedules [1314, 3539]. The best chemotherapeutic combinations evaluated in this setting are the TPFL (docetoxel, cisplatin, 5-FU, leucovorin) regimens from the Dana Farber Cancer Institute [36, 37]. These regimens consisted of docetaxel (60 mg/m2) on day 1, followed by cisplatin infusion (125 mg/m2) and 5-FU (2800 mg/m2) with leucovorin support (500 mg/m2/day). The TPFL5 regimen delivers the chemotherapy over 5 days, while the later TPFL4 regimen delivers it over 4 days. Patients were admitted to hospital during the administration of chemotherapy. Early administration of prophylactic growth factors and antibiotics were included in an attempt to decrease toxicity. Both regimens yielded excellent response rates of 93100% (including 6163% overall CR and 7286% CR at the primary site) in a patient population similar that in the present study. Responders to the TPFL regimens received definitive subsequent radiotherapy twice daily. With short follow-up, the progression-free and overall survival rates at 2 years were 78% and 78%, and 53% and 83% for the TPFL5 and the TPFL4 series of patients, respectively. The higher toxicity observed with the initial TPFL5 regimen was somewhat reduced with the TPFL4 version (febrile neutropenia in 17% compared with 40% of patients, hospitalization in 14% of cycles compared with 35%, and renal damage and diarrhea in 5% of cycles compared with 10%, respectively). Grade 34 mucositis was observed, however, in 48% of the cycles with both regimens. Compared with the TPFL schedules, the addition of docetaxel to a PF regimen (TPF; docetaxel 75 mg/m2 on day 1, cisplatin 75100 mg/m2 on day 1 and 5-FU 1000 mg/m2/day on days 14, given with antibiotics) seems to reduce substantially the number of adverse events [38, 39]. No toxic deaths were observed with TPF; however, 30% and 19% of patients develop grade IIIIV mucositis and febrile neutropenia, respectively. Responses of 8093%, half being CR, were observed with this regimen. All these data suggest that the incorporation of paclitaxel or docetaxel into the PF regimen results in improved anti-tumor activity and a manageable toxicity profile. Nevertheless, the real impact of these novel chemotherapy programs will be addressed in randomized phase III trials, which are currently underway in the USA and Europe [35, 38].
In summary, the combination of paclitaxel, cisplatin and 5-FU is one of the most active regimens for SCCHN. The toxicity profile is pronounced but compares favourably with standard therapies as well as other novel regimens currently available. The medium- to long-term data presented here on survival rates justify further evaluation of the PPF regimen in randomized trials. Indeed, based on these results, a phase III study is currently being completed in Spain. The study seeks to compare PPF with PF as induction treatment in resectable and non-resectable locally advanced SCCHN.
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Acknowledgements |
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Footnotes |
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This manuscript was presented in part at the 34th Annual Meeting of the American Society of Clinical Oncology, May 1998, Los Angeles, CA, USA.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Clayman GL, Lipman SM, Laramore GE, Ki Hong W. Head and neck neoplasms. In Holland JF, Kufe DW, Pollock RE et al. (eds): HollandFrei Cancer Medicine, 5th edition. Philadelphia, PA: BC Decker 2000; 11731220.
3. The Department of Veterans Affairs Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991; 324: 16851690.[Abstract]
4. Pacagnella A, Orlando A, Marchiori et al. A phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study of the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994; 86: 265272.[Abstract]
5. Merlano M, Benasso M, Corvo R et al. Five year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in the treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996; 88: 583589.
6. Lefebre JL, Chevalier D, Luboinski B et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer Phase III trial. J Natl Cancer Inst 1996; 88: 890898.
7. Munro A. An overview of randomized trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995; 71: 8391.[ISI][Medline]
8. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: a meta-analysis of prospective randomized trials. J Clin Oncol 1996; 14: 838847.[Abstract]
9. Pignon JP, Bourhis J, Domenge C et al. on behalf of the MACH-NC Collaborative Group. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 2000; 355: 949955.[ISI][Medline]
10. Forastiere AA, Shank D, Neuberg D et al. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (PA390). Cancer 1998; 82: 22702274.[ISI][Medline]
11. Smith R, Thorton D, Allen J. A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative studies. Semin Oncol 1995; 22: 4146.[ISI][Medline]
12. Gebbia V, Testa A, Cannata G et al. Single agent paclitaxel in advanced squamous cell head and neck carcinoma. Eur J Cancer 1996; 32: 901902.
13. Catimel G, Verweij J, Mattijissen V et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. Ann Oncol 1994; 5: 533537.[Abstract]
14. Dreyfuss A, Clark JR, Norris CM et al. Docetaxel: an active drug against squamous cell carcinoma of the head and neck. J Clin Oncol 1996; 14: 16721678[Abstract]
15. Frasci G, Comella P, Parziale A et al. Cisplatinpaclitaxel weekly schedule in advanced solid tumors: a phase I study. Ann Oncol 1997; 8: 291293.[Abstract]
16. Schilling T, Heinrich B, Kau R et al. Paclitaxel administered over 3h followed by cisplatin in patients with advanced head and neck squamous cell carcinoma: a clinical phase I study. Oncology 1997; 54: 8995.[ISI][Medline]
17. Adamo V, Maisano R, Laudani A et al. Phase II study of placitaxel and cisplatin in advanced and recurrent head and neck cancer. Eur J Cancer 1999; 35 (Suppl 4): 178.
18. Constela-Figueiras M, Mel-Lorenzo JR, García-Arroyo FR et al. A phase II study of weekly 1-hour paclitaxel (T) and 24-hour infusion with high-dose fluorouracil (5-FU) with leucovorin (LV) for advanced carcinoma of the head and neck. Ann Oncol 1996; 7 (Suppl 5): 80.
19. Hitt R, Paz-Ares L, Hidalgo M et al. Phase I/II of paclitaxel/cisplatin as first line therapy for locally advanced head and neck cancer. Semin Oncol 1997; 24 (Suppl 19): 2024.
20. Harari PM. Why has induction chemotherapy for advanced head and neck cancer become a United States Community standard of practice? J Clin Oncol 1997; 15: 20502055.[Abstract]
21. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 5th edition. Philadelphia, PA: Lippincott-Raven; 1997.
22. World Health Organization. WHO Handbook for reporting results of cancer treatment. WHO offset publication No. 48. Geneva, Switzerland: World Health Organization; 1979.
23. Armitage P, Berry G. Statistical Methods in Medical Research. Oxford: Blackwell Scientific Publications; 1994.
24. Atkinson EN, Brown BW. Confidence limits for probability of response in multistage phase II clinical trials. Biometrics 1985; 41: 741744.[ISI][Medline]
25. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187220.[ISI]
26. Wendt TG, Grabenbauer GG, Rodel CM et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998; 16: 13181324.[Abstract]
27. 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: 638644.
28. Vokes EE, Weichselbaum RR, Mick R et al. Favorable long-term survival following induction chemotherapy with PFL and concomitant chemoradiotherapy for locally advanced head and neck cancer. J Natl Cancer Inst 1992; 84: 877882.[Abstract]
29. 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: 876883.[Abstract]
30. Carr KM, Rabinowitz I. Physician compliance with warfarin prophylaxis for central venous catheters in patients with solid tumors. J Clin Oncol 2000; 18: 36653667.
31. Ilson DH, Ajani J, Bhaja K et al. Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 1998; 16: 18261834.[Abstract]
32. Bhalla KN, Kumar GN, Walle UK et al. Phase I and pharmacological study of a 3-hour infusion of paclitaxel followed by cisplatinum and 5-fluorouracil in patients with advanced solid tumors. Clin Cancer Res 1999; 5: 17231730.
33. Kim YH, Shin SW, Kim BS et al. Paclitaxel, cisplatin and 5-fluorouracil combination chemotherapy for the treatment of advanced gastric carcinoma. Cancer 1999; 85: 295301.[ISI][Medline]
34. Hussain M, Gadgeel S, Kucuk O et al. Paclitaxel, cisplatin and 5-fluorouracil for patients with advanced or recurrent squamous cell carcinoma of the head and neck. Cancer 1999; 86: 23642369.[ISI][Medline]
35. Brockstein B. Integration of taxanes into primary chemotherapy for squamous cell carcinoma of the head and neck: promise fulfilled? Curr Opin Oncol 2000; 12: 221228.[ISI][Medline]
36. Colevas AD, Busse PM, Norris CM et al. Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase II trial. J Clin Oncol 1998; 16: 13311339.[Abstract]
37. Colevas AD, Norris CM, Tishler RB et al. A 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: 35033511.
38. Posner MR, Glisson B, Frenette G et al. Multicenter phase III trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2000; 19: 10961104.
39. Schrijvers D, Van Herpen C, Kerger J et al. Phase III study with docetaxel (D), cisplatin (C), and 5-fluorouracil (5-FU) in patients (PTS) with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 1999; 18: 394a (Abstr 1534).