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Clinical Trials |
Department of Medicine, Section of Hematology/Oncology [F.R.R.], Department of Radiation Oncology, and Department of Otolaryngology/Head and Neck Surgery [L.P.], University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine [M.S.K.], Radiation Oncology [B.B.M.], and Otolaryngology/Head and Neck Surgery [H.P.] and the Cancer Research Center [A.W.R.], Northwestern University, Chicago, Illinois; Department of Medicine, Section of Hematology/Oncology [B.E.B., E.E.V.], Department of Radiation and Cellular Oncology [D.J.H., M.E.W., R.R.W., E.E.V.], Section of Otolaryngology/Head and Neck Surgery [K.S.], Center [M.A.L.], University of Chicago, Chicago, Illinois
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients and Methods: A total of 90 patients with locally advanced head and neck cancers (stage IV, 96%; N2/N3, 66%) were treated on a regimen of 1-h infusion of paclitaxel (100 mg/m2/day, day 1), 120-h infusion of 5-fluorouracil (600 mg/m2/day, days 0–5); hydroxyurea 500 mg p.o. every 12 h for 11 doses; and radiation 150cGy bid, days 1–5 of each 14-day cycle repeated for five cycles over 10 weeks (7200–7500 cGy). Before initiating therapy, patients were randomized to receive r-HuEpo 40,000 IU s.c. once weekly.
Results: At median follow-up of 40 months, 3-year progression-free survival is 62%, locoregional control is 84%, and systemic control is 79%. Overall survival is 59%. Anemia, leucopenia, dermatitis, and mucositis were the most frequent grade 3 or 4 toxicities. Patients randomized to erythropoietin experienced less grade 2/3 anemia (52 versus 77%; P = 0.02), but transfusion requirements were not significantly different.
Conclusions: T-FHX is an active and tolerable regimen inducing local tumor control and promising survival with organ preservation in high-risk patients. One h infusion of paclitaxel simplified the regimen without compromising efficacy. Addition of erythropoietin does not reduce the need for transfusion with this nonplatinum-containing regimen. T-FHX should be advanced to a randomized trial and compared with a cisplatin-based concomitant regimen.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There is evidence suggesting that cytotoxicity of radiation is dependent on good oxygenation of the target tumor tissue and that anemia before or during chemoradiotherapy could have a negative impact on response and survival (10) . Treatment options for chemotherapy-related anemia are red cell transfusions and/or the administration of r-HuEpo (11) . The current study builds on a previous Phase I trial (12) and replaces the 120-h continuous infusion paclitaxel in T-FHX with a 1-h infusion of the same total dose on day 1 of each cycle in an attempt to ease its administration. The complete response rate, toxicity, and disease-free and overall survival were the primary objectives of this Phase II trial. Patients were also randomized to receive r-HuEpo with the objective of maintaining baseline hemoglobin levels or increase hemoglobin during chemoradiation and prevent or reduce transfusion requirements. To achieve this objective the number of transfusions required to maintain a hemoglobin of at least 10 throughout all treatment cycles, and mean hematocrit values were compared in each group.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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60%. Baseline laboratory requirements included an absolute neutrophil count 1500 cells/µl; platelet count 100,000/µl, and hemoglobin 
16 g/dl. Initial staging procedures consisted of a history and physical, panendoscopy and biopsy with tumor measurements, dental evaluation, head and neck and chest CT scans, bone scan, barium swallow; quality of life; and speech and swallowing assessment. Placement of a feeding device was recommended. Patients with sensitivity to cremaphor EL, human albumin or mammalian, or Escherichia coli-derived proteins were excluded. All patients signed institutional review board-approved informed consent forms.
Surgery.
Decisions as to the timing and advisability of surgery were made on an individual basis. A general goal of the protocol was to obtain organ preservation. Most often, patients underwent chemotherapy and radiation as planned primary therapy. Simple excision of the primary lesion was allowed as the initial treatment. The extent of surgery varied, and it ranged from laser resection or wide excisional biopsy to resection of an oral cavity or tonsillar primary. Modified neck dissection could also be performed. Salvage surgery was recommended for residual disease at the primary site or neck after completion of chemoradiotherapy. For patients initially staged as N2 or N3, modified neck resection also was recommended, even in the absence of overt residual tumor. Surgery at the primary site was omitted in patients who achieved complete remission confirmed by physical examination, radiographic imaging, and/or a negative biopsy.
Chemotherapy and Radiation.
Before initiating therapy, patients were randomized to receive or not receive r-HuEpo (Procrit; Ortho-Biotech, New York) during chemoradiotherapy. All patients were admitted to the inpatient unit and treatment started on day 0 (usually Sunday evenings) with hydroxyurea administered at 500 mg p.o. every 12 h for 11 doses. The first daily dose of hydroxyurea on days 1 through 5 was given 2 h before the first fraction of daily radiotherapy. Continuous infusion 5FU was also started day 0 in the evening at 600 mg/m2 and continued for 5 days (120 h). Paclitaxel was administered i.v. over 1 h at 100 mg/m2 on day 1 after the first dose of radiation. Premedication for paclitaxel included dexamethasone 10 mg p.o. at 12 h and 1 h before paclitaxel and benadryl 25 mg i.v. push 30 min before paclitaxel. Radiation therapy was administered twice daily with a minimum of 6 h between fractions at 1.5 Gy/fraction with concomitant chemoradiotherapy during days 1 through 5 (total dosage 15 Gy/cycle). No chemoradiotherapy was administered on days 6 through 13; cycles were administered every other week. For patients randomized to r-HuEpo (Procrit; Ortho Biotech) 40,000 IU was administered once weekly for 14 weeks, starting with the first treatment week of cycle 1 and continued for 4 weeks after treatment finished. Patients randomized to r-HuEpo also received concomitant oral iron therapy (ferrous sulfate 325 mg three times daily) beginning day 1 and continued throughout administration of Procrit (Fig. 1)
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Treatment cycles were not postponed for mucositis, dermatitis, or diarrhea. For grade 4 mucositis, dermatitis, or diarrhea exceeding 7 days duration or that persisted on day 1 of a subsequent cycle, 5FU was decreased to 500 mg/m2/day and paclitaxel decreased to 75% of the calculated dose. For WBC count of 1000–1999 cells/µl or platelet count of 50,000–74,999 cells/µl, paclitaxel was decreased 75% of the calculated dose, and hydroxyurea was decreased to 50% of the full dose. For WBC count of <1000 cells/µl or platelet count < 50,000 platelet/µl on days 0 through 5 of any cycle, paclitaxel and oral hydroxyurea were withheld, whereas 5FU and radiotherapy were continued. In the presence of a persisting fever that exceeded 38°C or other clinically apparent infections, a cycle could be postponed for 1 week or interrupted if this was judged to be necessary in the opinion of treating medical and radiation oncologist. G-CSF was not routinely administered in between cycles, however, in patients who developed grade 3 neutropenia at any time or grade 2 neutropenia on day 0 of any cycle, G-CSF (5 µg/kg) was administered on days 6 through 12 at a minimum of 12 h after completion of 5FU. In these patients, G-CSF was used in all subsequent cycles.
Radiotherapy Guidelines.
Patients underwent dental evaluation and treatment as soon as possible during the initial evaluation. Patients underwent CT-based simulation and field arrangements determined with plans to treat gross disease and areas of potential microscopic involvement. Opposed lateral fields were used initially to treat the primary site and neck lymph nodes. The anterior and posterior triangle nodes and the base of skull were included in the initial treatment volume in most cases. In selected cases, a three-field technique or wedged pair was used. Three-dimensional conformal planning and tissue compensators were used when appropriate. If indicated, a separate field was used to treat the supraclavicular fossa. Custom cerrobend blocks were used to shield areas that were not considered at risk of containing disease or to block critical structures such as spinal cord to avoid exceeding tissue tolerance. Each cycle of chemoradiation consisted of 5 consecutive days of concomitant chemoradiotherapy. Patients received 150 cGy twice daily (300 cGy/day and 1500 cGy/week) on the alternate week schedule. There was a minimum of 6 h between fractions. Total radiation dose for presumed microscopic disease was 4500–6300 cGy. Areas of gross disease were boosted after appropriate field reduction to total dose of 7000–7500 cGy.
Statistical Analysis.
After completion of chemoradiotherapy, patients were evaluated for response status using bidimensional measurements as described previously (8
, 9)
. Data were summarized using frequencies, percentages, means, SDs, and ranges. Survival time, progression-free survival time, time to locoregional progression, and time to distant progression were analyzed using Kaplan-Meier product limit curves. The term locoregional is used to describe disease in the primary tumor region and/or neck. In the progression-free survival analysis, progression was defined to be the occurrence of at least one of the following events: locoregional progression; distant progression; treatment-related (including late toxicity at any time of follow-up) death; or death from disease. All deaths within 3 months of completion of treatment were reported as treatment related. The log-rank test was used to compare curves between subgroups, in particular, to compare groups receiving or not receiving r-HuEpo.
According to initial study design, 60 patients were to be enrolled with half assigned randomly to receive r-HuEPO based on an expected total response rate (complete response and partial response) among these patients to be 
90%. A 90% response rate among 60 patients would yield a 95% confidence interval for the true response rate of 79–96%. On the basis of data from prior Phase II study, the average change in hematocrit from baseline to end of treatment was -6.3 percentage points. On the basis of the assumption that the addition of r-HuEPO would reduce the mean change to -3.0, then 30 patients in each group would provide > 80% power to detect a difference significant at the 0.05 level. The investigators decided to accrue an additional 30 patients after the initial goal of 60 was met based on early data indicating favorable response and survival rates. These additional patients continued to be randomized to receive r-HuEPO.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2
. Staging information is listed in Table 3
. Stage IV, T4, and N2/N3 were encountered in 96, 61, and 66% of patients, respectively.
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Toxicities and Organ Function.
Acute toxicities were severe but manageable in the majority of patients (Table 4)
. As in our previous study of T-FHX with 120-h infusion of paclitaxel, mucositis, dermatitis, and pain were the most commonly reported serious nonhematological side effects. Leukopenia and anemia were the most common serious hematological side effects. Fifty-three percent of patients on treatment experienced >10% weight loss. Patients frequently required intensive supportive care, including daily dressing changes for dermatitis and feeding support devices and narcotic analgesia for mucositis and treatment-related odynophagia. As a result, the planned dose intensity was maintained (Table 5)
with 86% of patients receiving all planned cycles of chemoradiotherapy and 10 (11%) patients received four of five planned cycles. (All of these were planned to have five cycles, or some were postoperative and planned for only four cycles.)
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Five patients died of treatment-related toxicity in the absence of documented disease progression. Only one of these, a pulmonary embolism, occurred before completion of therapy. Three events were from unknown causes at 2.5, 3 and 5.5 months after the start of therapy, respectively, and one was from bacterial endocarditis 4.5 months after the start of therapy. Two patients died of late toxicity after apparent hemorrhage from the head and neck region but without definitive evidence of local recurrence 7 and 20 months after the start of therapy.
Surgery.
Nineteen patients underwent surgery before chemoradiotherapy, including a neck dissection in 14 patients and surgery at the primary site in 12 patients (Table 6)
. Primary site surgeries included 4 tonsillectomies, 2 base of tongue resections, 2 partial maxillectomies, 1 local excision of an anterior tongue primary, and 1 floor of mouth resection, respectively. Two patients underwent laser debulking of a base of tongue and a pyriform sinus primary. Two patients with unknown primary site underwent neck dissections as initial treatment before chemoradiotherapy, one of which also included an ipsilateral tonsillectomy. Of 32 patients who underwent neck dissection after completion of chemoradiotherapy, only 10 were found to have pathologic evidence of residual disease. Radiographic response before neck dissection correlated poorly to pathologic response (Fig. 2)
. Two patients with partial responses at the primary site successfully underwent salvage total laryngectomies. In a third patient, salvage surgery was unsuccessful because of unresectable disease.
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and 4
). Twenty-eight patients (31%) have progressed locoregionally and/or distantly (Fig. 5)
. Eleven patients (12%) progressed locoregionally and 15 patients (17%) distantly. In 2 patients (2%), initial progression was simultaneously locoregional and distant. Fourteen of 17 patients progressing with distant disease were initially staged N2 (9 patients) or N3 (5 patients). Three of 10 patients with positive neck dissections eventually developed disease progression, 1 with local progression and 2 with distant progression. Of the 22 patients with negative neck dissections, 7 eventually progressed, 6 progressed distantly, and 1 progressed locally and distantly. There was no difference in survival between patients with negative and positive neck dissections. There have been 41 deaths, including 26 (64%) related to disease, 5 (12%) related to toxicities, 2 (5%) from possible late complication, 6 (15%) from unrelated illnesses, and 1 from a second primary (lung cancer). The cause of death in 1 patient could not be determined.
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]. However, randomization to erythropoietin did not statistically significantly alter the number of patients requiring transfusion [19 (40%) versus 24 (56%); P = 0.20] nor the mean (median) number of transfusions required [1.28 (0) versus 1.79 (1)
; P = 0.25] to maintain a hemoglobin of 10. Lack of benefit was independent of baseline hemoglobin. As expected, the addition of erythropoietin had no effect on other hematological toxicities such as leukopenia or thrombocytopenia, and the groups did not differ on any QOL, side effect, or performance parameter. The addition of erythropoietin had no significant effect on disease progression, overall survival or response rates (Figs. 7
and 8
). The number of transfusions required to maintain a hemoglobin of 10 had no effect on overall survival. However, a baseline hemoglobin level of 14 g/dl in 16 patients (18%) was associated with improved overall survival (P = 0.05). No patients maintained hemoglobin levels > 14 during treatment (only 2 patients maintained hemoglobin > 12 during treatment). There was no survival benefit at any other hemoglobin level either before or during treatment.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Despite the elimination of routine administration of G-CSF between cycles of 1-h T-FHX, grade 3/4 leukopenia was nearly identical to that seen with T-FHX using 120-h infusion, implying that the 1-h schedule is less myelosuppressive. The addition of paclitaxel to FHX had less hematological toxicity and similar nonhematological toxicity compared with the addition of cisplatin to FHX. Although mucositis appears increased in the latter trials, this toxicity is difficult to quantify, and interobserver differences may be partially responsible for this observation. A recent trial by Adelstein et al. (13)
using a more traditional cisplatin/5FU regimen with hyperfractionated radiotherapy schedule and a trial by Sunwoo et al. (14)
using three cycles of 120-h continuous infusion paclitaxel, and standard fractionated radiotherapy are also included in Table 7
. Given the similar outcome data and consistent failure rates and patterns, it appears that paclitaxel can be substituted for cisplatin as a systemically active, radiation-enhancing agent without the subjective side effects and with less myelosuppression associated with cisplatin. Although the Sunwoo trial, using a less intensive chemoradiotherapy schedule, achieves similar overall survival with arguably less toxicity, it is a small trial (n = 33) with a higher percentage of stage 3 patients (15%) than the other trials.
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There has been debate concerning the surgical management of the neck after completing chemoradiotherapy. In this multicenter study, there was some variance from one site to another, but in general, neck dissection was encouraged for N2 or N3 disease regardless of clinical or radiographic response to T-FHX. Approximately one-third of patients (10 of 32) who underwent neck dissection after chemoradiotherapy had residual disease. This percentage is consistent with that found in our two previous studies and by other investigators (13 , 15 , 16) . Posttreatment CT scan was not a reliable way to access for residual disease with 50% of patients with negative neck dissections having positive CT scans and 40% of patients with positive neck dissections having negative CT scans.
Restaging was done within a 4–6-week window after treatment during which time treatment-related edema could interfere with CT scan interpretation. Of interest, the rate of residual disease in the neck is much lower in our more recent trial that added two cycles of induction chemotherapy to the T-FHX regimen (17) .
There was no clear benefit derived from erythropoietin as used in this study. Although there was a significant decrease in grade 2/3 hemoglobin toxicity, this did not translate clinically to a decreased need for supplemental transfusion of RBCs to maintain hemoglobin of 10 g/dl. Similarly, there was no survival benefit associated with the use of erythropoietin. A hemoglobin level of >14 at baseline, observed in only 16 patients enrolled in the study, was associated with improved survival (P = 0.05). The lack of a benefit from r-HuEpo may be attributable to the short overall treatment duration (9 weeks) and the absence of a platinating agent in our regimen. For these reasons, the study may have been underpowered to detect a small but statistically significant difference.
There have been several recent trials that report pretreatment hemoglobin associated with improved response to chemoradiation in head and neck cancer. Dubray, in a prospective study, demonstrated that anemia was associated with lower locoregional control and survival after radiation therapy for head and neck cancer (18) . Haddad et al. (19) and Budach et al. (20) reported that hemoglobin levels >12 and 14, respectively, were associated with improved locoregional control and overall survival. Staar et al. (21) have also reported on initial hemoglobin level as a significant factor for survival in patients treated with hyperfractionated radiotherapy with or without chemotherapy. Contrary to our findings Dunphy et al. (22) report in a study, which included induction chemotherapy, that the addition of erythropoietin significantly reduced anemia and the need for transfusions. Glaser et al. (23) report both correction of anemia and improved efficacy in patients receiving erythropoietin during neoadjuvant chemoradiotherapy. On the basis of these trials, a hemoglobin between 12 and 14 g/dl rather than 10 g/dl may be necessary to significantly improve response, survival, and decrease need for transfusion.
One-h T-FHX has a high complete response rate, and overall survival is as good as or better than regimens currently being evaluated in randomized trials. Toxicity remains severe but manageable, and although patients report significant functional and QOL declines during treatment, the majority of these resolve to pretreatment levels by 12 months. On the other hand, even 2–4 years posttreatment completion, a subgroup of patients continue to have significant problems eating with up to 22% remaining tube dependent (24) . Clearly QOL and functional parameters must be included in the design and analysis of aggressive chemoradiotherapy regimens, with the additional goal of identifying baseline parameters that might place patients at risk for long-term impairment. Treatment strategies such as alternating weeks of chemotherapy and radiotherapy or single agent chemoradiotherapy in the recently reported Head and Neck Intergroup Trial have generally proved less toxic but with lower survival in comparison to the intensified multiagent chemoradiotherapy regimens (25 , 26) .
As in prior trials from our group, as well as others using intensified chemoradiotherapy regimens, a reversal of the usual pattern of disease progression has emerged (8
, 9
, 13)
. With locoregional control rate of 83%, distant disease failure has become more common than locoregional failure (Fig. 5)
. Although trials of induction chemotherapy have failed to consistently demonstrate a survival benefit over radiation alone in advanced head and neck cancer, several trials have demonstrated a decrease in distant metastases (27, 28, 29, 30)
. Neoadjuvant chemotherapy significantly improved survival in the Groupe d’Etude de Tumeurs de la Tête et du Cou trial, although 73% of patients had stage II and III disease, as well as in subgroup analysis of patients with resectable disease in the Paccagnella trial (29
, 31)
. Posner et al. (32)
in a recent series of Phase II trials has achieved high complete response rates with intensive induction chemotherapy followed by chemoradiotherapy. Therefore, the current focus of our group is to integrate a brief, active induction regimen to precede 1-h T-FHX with the expectation of maintaining a high rate of locoregional control and decreasing distant disease failure. A secondary objective will be to select patients, based on their local response to induction chemotherapy, who might be safely treated with a lower total dose of radiotherapy and thus decrease toxicity from the regimen (17)
.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported, in part, by the University of Chicago/Northwestern University Oral Cancer Research Center Grant P50 DE11921, University of Chicago Cancer Research Center Grant P30 CA14599, The Francis Lederer Foundation, The Geraldi Norton Memorial Corporation, The Robert and Valda Svendsen Memorial, Bristol-Myers Squibb, Princeton, New Jersey, and Ortho Biotech, Raritan, New Jersey. 
2 To whom requests for reprints should be addressed, at University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637-1470. Phone: (773) 834-3093; Fax: (773) 702-3002; E-mail: evokes{at}medicine.bsd.uchicago.edu
3 The abbreviations used are: FHX, fluorouracil, hydroxyurea, and radiotherapy; C-FHX, addition of cisplatin to FHX; T-FHX, addition of paclitaxel to FHX; r-HuEpo, recombinant human erythropoietin; CT, computed tomography; 5FU, 5-fluorouracil; G-CSF, granulocyte colony-stimulating factor; QOL, quality of life.
Received 8/14/02; revised 12/26/02; accepted 12/31/02.
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REFERENCES |
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