|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Concurrent Paclitaxel and Radiation in the Treatment of Locally Advanced Head and Neck CancerFrom the Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders; Speech and Language Pathology Section, Rehabilitation Medicine Department, Clinical Center; and Branches of Radiation Oncology, Radiation Biology, Biometric Research, and Medicine, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to Laurie L. Herscher, MD, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm B3B69, Bethesda, MD 20892; email: herscher{at}mail.nih.gov
PURPOSE: To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study. Paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m2, and 17 patients received 120 mg/m2. Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy. RESULTS: Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival. CONCLUSION: Paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC.
HEAD AND NECK cancers comprise 4% of the newly diagnosed malignancies in the United States and are a major problem worldwide.1,2 The majority are locoregionally advanced (stages III and IV) at the time of diagnosis.2 In the past, treatment for patients with advanced disease has involved surgery plus radiation therapy for resectable tumors, or radiation therapy alone for inoperable lesions. Because of both the poor overall survival and functional outcome associated with these therapies, trials using chemotherapy in conjunction with definitive local treatment to try to improve outcome have been conducted.3 It is becoming increasingly clear that the use of chemotherapy concurrent with radiation contributes to improved locoregional control and prolongs survival.4-6 Paclitaxel is an active single agent in head and neck cancer,7 with response rates reported to be as high as 40% when administered as a 24-hour infusion.8 Initial observations that paclitaxel induces a cell cycle blockade at the G2 phase-to-mitosis (G2/M) transition, the most radiosensitive portion of the cell cycle,9-11 led to studies demonstrating a radiation potentiating effect of paclitaxel in a variety of human tumor cell lines, including those derived from head and neck squamous cell carcinoma (HNSCC).12-15 The mechanism accounting for this interaction, however, is not fully understood and has proven to be more complex than simply arresting cells at G2/M. In fact, a G2/M block, although necessary for radiosensitization, is not sufficient.16,17 An additional mechanism seems to involve enhanced tissue oxygenation induced by paclitaxel.18 As little as 10 nmol/L paclitaxel can sensitize cells to radiation, and a 120-hour exposure to paclitaxel provided maximum sensitization in vitro16,17,19. Clinical data, using paclitaxel as a single agent, suggest that prolonged infusions (eg, 96 hours) led to a greater response rate.20 We and others have shown that paclitaxel could be administered safely as a continuous 120-hour infusion and that serum concentrations of greater than 50 nmol/L could be achieved during the infusions.21-23 For these reasons, we chose to examine prolonged continuous infusion of paclitaxel for radiosensitization in head and neck cancer patients. Our initial experience with this dosing schedule came from a phase I study in which patients with mesothelioma and non–small-cell lung cancer were treated with a 120-hour continuous paclitaxel infusion every 3 weeks concurrent with radiation therapy.23 The maximum-tolerated dose of paclitaxel in that trial was 105 mg/m2, with neutropenia being the dose-limiting toxicity. We, therefore, designed a pilot study with a similar paclitaxel dosing schedule concomitant with radiation therapy for patients with locally advanced HNSCC. The objectives of this study were to: (1) assess the feasibility of concurrent paclitaxel and radiotherapy in patients with advanced HNSCC; (2) examine the cell cycle effects and pharmacokinetics of paclitaxel administered as a continuous 120-hour infusion concurrent with radiotherapy; (3) assess speech and swallowing function following therapy; and (4) examine the potential of pretreatment assessments of disease as prognosticators of therapy response.
Patient Eligibility This prospective, nonrandomized clinical study (95-C-0162) was approved by the Institutional Review Board of the Clinical Center, National Cancer Institute, National Institutes of Health. Patients with biopsy-proven HNSCC, American Joint Committee on Cancer (4th edition) stages III and IV tumors for all sites were eligible. Patients must have been either ineligible for curative resection or have refused surgery, and must have had no prior radiotherapy to the head and neck region or chemotherapy. Patients with obvious metastatic disease on diagnostic imaging were excluded from the study. Additional eligibility criteria included the following: (1) Eastern Cooperative Oncology Group (ECOG) performance status  2; (2) age greater than 18 years; (3) absolute granulocyte count greater than 2,000/mm3 and platelet count greater than 100,000/mm3 ; (4) serum bilirubin less than 2.0 mg/dL, SGOT less than four times upper limit of normal, and serum creatinine less than 1.5 mg/dL; (5) no other history of active malignancy other than curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin; (6) no serious medical condition or psychiatric illness that would preclude informed consent. Patients were recruited nationwide and were evaluated by a multidisciplinary team. Pretreatment evaluation included complete history and physical examination and tumor staging. All patients underwent multiple biopsies under anesthesia to determine extent of disease. Other studies included posteroanterior (PA) and lateral chest x-ray, computerized tomography (CT) and/or magnetic resonance imaging (MRI) of the head and neck, CT scan of the chest, complete blood cell count (CBC), serum electrolytes, blood urea nitrogen (BUN), serum creatinine, glucose, total protein, albumin, calcium, phosphate, uric acid, bilirubin, liver function tests (LFT), coagulation studies (PT, PTT), HIV antibody test, and bone scan if clinically indicated. Patients were observed by a multidisciplinary team weekly while receiving treatment and immediately afterward; then monthly for the first year, bimonthly during the second year, and every 3 months thereafter.
Paclitaxel Dose
Radiation Therapy
Surgery
Toxicity Assessments
Speech and Swallowing Function
Cell Cycle Analysis and Pharmacokinetics Because patients receiving the 120 mg/m2 paclitaxel dose presented with tumors that were not accessible without placing the patient under general anesthesia, tissue cell cycle analysis after therapy was not performed. Paclitaxel plasma concentrations were measured in 13 patients receiving 120 mg/m2 paclitaxel by a modification of a previously published reverse-phase high-performance liquid chromatography method.25 Samples were measured at 1, 12, 24, 48, 72, 120, 121, and 122 hours after the start of a 120-hour infusion.
Statistical Methods
Patient Characteristics and Treatment Thirty-three patients entered this study between October 28, 1995, and June 26, 1999 ( Table 1). The median age was 54 years (range, 25 to 78 years). The majority of the patients were male and had a previous history of smoking and alcohol use. Twenty-two patients were Caucasian, seven were African-American, three were Hispanic, and one was Asian. Twenty-six patients had an ECOG performance status of 1, and seven had a performance status of 2. The median length of follow-up from the completion of radiation therapy was 20 months (range, 1 to 49 months).
Table 2 lists the characteristics of the squamous cell carcinomas treated in this study. The primary sites were as follows: oropharynx (10 patients), hypopharynx (eight patients), oral cavity (five patients), larynx (six patients), nasopharynx (two patients), and paranasal sinuses (two patients). By tumor-node-metastasis staging, 85% of these tumors were classified as stage IV disease, with the remainder being stage III. Nineteen patients had unresectable tumors; the remaining patients declined surgery.
Patients received a 120-hour continuous IV infusion of paclitaxel as an outpatient during weeks 1, 4, and 7 of standard radiation therapy, using a portable IV infusion pump. The dose of paclitaxel was 105 mg/m2 for the first 16 patients enrolled. Because cell cycle blockade was not demonstrated in tumor biopsy specimens (data not shown) and because no dose-limiting toxicity was observed at this level, the dose was increased to 120 mg/m2 in the next 17 patients. The distribution of patients with stages III and IV tumors was similar for the two treatment groups (Table 2). Of the 33 patients, 31 completed all three courses of paclitaxel. In one patient with carotid invasion, paclitaxel treatment was discontinued during the second cycle after he suffered an infarction in the area of a previous cerebrovascular infarction. Another patient received only one cycle of paclitaxel as a result of severe back pain associated with drug infusion, which was unresponsive to premedication for hypersensitivity reactions. An extensive evaluation failed to identify a cause of the back pain, and the development of back pain in conjunction with the administration of taxanes subsequently has been reported.26 All patients completed the planned course of radiotherapy without breaks except one who had tumor infiltration of skin requiring bolus during radiation therapy and who had a 10-day interruption in his course of radiation therapy because of grade 3 radiation dermatitis.
Toxicity The acute toxicities in the radiation field were substantial but tolerable ( Fig 1). The most significant side effects were mucositis and dysphagia. Grade 3 mucositis was identified in 29 (88%) of 33 patients, and grade 3 dysphagia in 31 (94%) of 33 patients. A significant association between paclitaxel dose and duration of mucositis was observed. Patients receiving the higher dose (120 mg/m2) experienced grade 3 mucositis for a significantly longer duration compared with those receiving the lower (105 mg/m2) dose (P = .04, log-rank test). No difference in the time to onset of mucositis was observed between the two groups (P = .44, Wilcoxon rank sum test). Most patients with mucositis required at least 1 month after radiotherapy for the mucositis to subside to a degree that would allow attempts at swallowing. Although the first patient chose not to undergo PEG tube placement, the following 32 patients did in anticipation of severe dysphagia.
Other toxicities included xerostomia in 26 patients (79%) and grade 3 skin toxicity in nine patients (27%). An association between degree of skin reaction and paclitaxel dose was observed ( Table 3). The maximum skin toxicity grade was significantly higher among the patients receiving the higher paclitaxel dose (P = .0053, Wilcoxon rank sum test).
A number of infections were identified within 3 months after the initiation of treatment. Systemic infections included six episodes of bacteremia and five cases of pneumonia. Local infections included PEG site infections (11 patients, 33%), central line catheter site infections (three patients, 9%), skin infections (three patients, 9%), and tracheitis in two patients, both of whom had tracheotomies (6%). Most acute toxicities were managed on an outpatient basis. During the 3-month period after the initiation of treatment, there were 14 hospitalizations (13 patients) for adverse events. These included dehydration (two patients), thrombosis (one patient), infection (seven patients), fever of unknown origin (three patients), and atrial fibrillation (one patient). Two patients were hospitalized for desensitization protocols during paclitaxel administration for known hypersensitivity reactions to paclitaxel. Long-term or chronic side effects, noted after 3 months from the initiation of treatment, were seen in several patients. There were four cases of ORN among patients with oral cavity or oropharyngeal tumors (one receiving brachytherapy), with one patient sustaining a pathologic fracture of the jaw. Two patients with T4 hypopharyngeal/laryngeal tumors, one involving the hyoid bone and the other involving both the hyoid bone and the thyroid cartilage, developed pharyngocutaneous fistulae. There was a complete response to therapy in both cases, and the development of fistulae was associated with osteo/chondroradionecrosis. All six of these patients developed chronic pain. Wound healing complications were noted in two of six patients undergoing posttreatment neck dissections for resectable N2-3 disease. In each case, dehiscence of a portion of the neck incisions occurred despite 14 days of reinforced closure with skin staples. No incisional or wound infection was observed, and biopsies at the sites did not reveal residual tumor. One patient underwent a second operative procedure to close the wound. This attempt also failed. Finally, development of chemical hypothyroidism during and after treatment was noted in nine patients (27%). The median time to onset was 46 weeks. No association between paclitaxel dose and development of hypothyroidism was observed.
Speech and Swallowing Function
Cell Cycle Analysis and Pharmacokinetics
Response, Survival, and Predictors of Outcome The response rate was assessed by clinical examination and by histopathologic examination of the primary site. At 3 months after completion of therapy, 23 of 29 patients biopsied had histologically confirmed CRs at the primary site, and six had persistent disease. Two patients were not subjected to biopsy at 3 months because metastatic lesions had become apparent, but neither had evidence of disease at their primary sites by clinical examination. The remaining two patients succumbed to their disease before the 3-month timepoint. In summary, 76% (25 of 33) of patients had CRs at the primary site, and 70% (23 of 33) were disease-free overall. There was no statistically significant effect of paclitaxel dose on the CR rate (P = 1, Fisher’s exact test). Pretreatment assessments of disease extent, including bone involvement, resectability, T category dichotomized to T4 v T less than 4, nodal status, and radiographic quantification of tumor volume (TVOL), were examined for potential utility as predictors of response rate. Of those examined, the only variable that was significantly associated with CR rate in a univariate analysis was TVOL (P = .01). There was a trend toward a significant association with resectability (P = .075). After adjusting for resectability in a multivariate analysis, TVOL was still significant (P = .043). Of the 24 patients who initially presented with regional nodal metastases, 75 (71%) had a CR in the neck by clinical and radiographic examination and six (25%) had persistent disease. Of the patients who were disease-free in the neck, four had treatment failures at distant sites and three had progression of disease at the primary site. Patients with N2 or greater nodal disease and who had an overall CR to treatment underwent neck dissections. Of the six who underwent this procedure, two underwent bilateral neck dissections. None was found to have residual tumor in the neck by histopathologic examination. Estimates of LR control, overall survival, and DF-survival were computed using the Kaplan-Meier Estimator ( Fig 3). At 36 months, LR control of tumor progression was 55.7% (95% confidence interval, 39.4% to 78.7%). Similarly, the estimated 36-month rate for overall survival was 57.8% (95% confidence interval, 40.6% to 82.2%), and that for DF-survival was 51.1% (95% confidence interval, 35.5% to 73.7%). The median survival duration for the entire group was greater than 50 months.
Overall, 15 patients eventually had progression and/or recurrence of their disease after treatment. Patterns of failure are represented in Table 4. Of these, six were treatment failures within the radiation field, four had disease outside of the radiation field, and five had disease both within and outside of the radiation field. One patient who developed distant metastases to the lung previously had a suspicious but nondiagnostic lesion on a chest CT scan on entry to the study.
Survival analyses were performed with patients stratified by paclitaxel dose levels and by pretreatment assessments of the disease extent. As with CR, no statistically significant effect of paclitaxel dose on overall survival or DF-survival was observed (P = .77 and .51, respectively, log-rank test). When we examined potential predictors of outcome by univariate analysis ( Table 5), we found the following statistically significant measures: tumor resectability, dichotomized T category, nodal status, and TVOL. The effects of TVOL on survival were assessed first by grouping patients above and below the median tumor volume (79 cm3); log-rank tests showed that patients with tumors above the median had a poorer prognosis (P = .032, for overall survival; P = .111, for DF-survival). The prognostic significance of TVOL was confirmed in a proportional hazards model, treating TVOL as a continuous covariate (P < .001 for overall survival; P = .0017 for DF-survival). When we examined only patients with stage IV disease, we found that there was still a significant association between TVOL measured radiographically and poor prognosis (P < .001, for overall survival; P = .005, for DF-survival), suggesting that, in these patients with advanced tumors, radiographic quantification of TVOL was able to add to the predictive power of the current tumor-node-metastasis staging system. In a multivariate analysis ( Table 6), taking into account all of the variables found to be associated with survival in the univariate analyses, only TVOL was statistically significant for predicting overall survival (P = .009) and was the variable that most closely approached significance when considering specifically DF-survival (P = .084). These results suggest that radiographic quantification of TVOL is an independent predictor of clinical outcome in patients with advanced head and neck SCC treated with this regimen.
In this study, we have shown that a 120-hour continuous infusion of paclitaxel administered as an outpatient during weeks 1, 4, and 7 of standard radiation therapy is a promising and well-tolerated regimen. A 70% overall CR was achieved in patients with highly advanced HNSCC, and no dose-limiting toxicities were encountered at paclitaxel administrations of 120 mg/m2. This response rate is comparable to those achieved using concurrent cisplatin, fluorouracil, and radiation.27-29 The 55.7% locoregional control rate achieved with our regimen at 36 months was greater than a 35% rate achieved with concomitant radiation and cisplatin/fluorouracil in another study of unresectable stages III and IV HNSCC tumors.30 Survival rates at 36 months in our study were comparable to those reported using regimens of concurrent cisplatin/fluorouracil/radiation.29,30 Of note, unlike the administration of high-dose cisplatin and fluorouracil, the regimen used in this study can easily be administered to outpatients. Although some patients in our study sustained significant local toxicities, two of these—mucositis with dysphagia and radiation dermatitis—are known side effects of radiotherapy. The degree of these toxicities seemed to be greater than historical experience with radiation alone30 but were comparable to the use of concurrent cisplatin, fluorouracil, and radiation.27,29 Studies examining the radiation-potentiating activity of taxanes have indicated that the effects on normal tissue are less pronounced than those on tumor.12 The fact that we found local toxicities to be greater with the higher paclitaxel dose and no significant difference in local control between the two groups suggests that the higher dose (120 mg/m2) may not be necessary. Although no dose-limiting systemic toxicity was encountered in our study, 18% of patients experienced grade 3 neutropenia, which is consistent with previous reports of myelosuppression with prolonged infusions of paclitaxel.8,31,32 The clinically insignificant grade 4 lymphopenia, seen in the majority of patients, is also consistent with other studies examining combined paclitaxel and radiotherapy.33-36 Severe long-term toxicities related to concurrent therapy included ORN, pharyngocutaneous fistulae, impaired wound healing, and hypothyroidism. The development of ORN and pharyngocutaneous fistulae seemed to relate to the site of the primary tumor and bone/cartilage involvement, and the observed incidence of ORN after radiation was within the range reported in the literature.37-39 The delayed wound healing that was observed in two patients may have been related to nutritional causes. Even though there is experimental evidence from others that paclitaxel affects wound healing capacity,40 the incidence of wound healing complications was well below the incidence reported to be associated with organ preservation therapy.41,42 Although hypothyroidism can result from direct exposure of the thyroid gland to radiation, we saw a greater incidence and earlier onset with concomitant radiation than that reported to be associated with radiation alone. Tell et al43 found that 6% of patients who received external beam radiation to the neck developed elevated thyroid stimulating hormone (TSH) levels and depressed free thyroxine levels and that 22% had elevated TSH levels with normal thyroxine levels. The median time to onset was 60 weeks in both cases. In our study, 27% of patients were found to have elevated TSH and depressed thyroxine levels with the median time to onset being 46 weeks. This suggests that paclitaxel has a radiation potentiating effect on the thyroid gland and that patients receiving this combined therapy should be closely monitored for this delayed toxicity. Several studies have recently been reported that explore various dosing schedules of (concurrent) paclitaxel and similar total radiation dose and fractionation in the treatment of HNSCC. Although the total dose of paclitaxel received per 3 weeks of radiation therapy was similar in these studies to ours (see dose/3 weeks below), the comparison of biologic effectiveness and radiation sensitization of different schedules is more difficult to make without a randomized study. Hoffmann et al44 administered weekly 1-hour infusions of paclitaxel concomitant with standard radiotherapy (daily fractionation to total doses of 60 to 70 Gy) to 18 patients with unresectable or incompletely resected head and neck cancer. The dose-limiting toxicity in their study was mucositis with a maximum tolerated paclitaxel dose of 30 mg/m2/wk as 1-hour infusions (dose-intensity = 90 mg/m2/3 weeks). Of the seven patients who had undergone prior surgery, four (57%) had a CR after a median observation time of 8.2 months (range, 5 to 12 months). Of the 11 patients treated primarily with Taxol and radiation, four (36%) had a CR after a median observation time of 9.4 months (range, 1 to 15 months). Tishler et al45 reported a study in which 14 patients with stages III and IV HNSCC were treated with paclitaxel administered at a dose of 100 mg/m2 over 3 hours every 3 weeks (dose-intensity = 100 mg/m2/3 weeks), in combination with external beam radiation (daily fractionation to total doses of 60 to 70 Gy). Of these 14 patients, 10 had received prior cisplatin, fluorouracil, and leucovorin. Overall, the concurrent therapy achieved a CR in 13 (92%) of the 14 patients. Three of the 13 went on to develop recurrent disease (one with distant metastasis and two with local/regional disease). The major toxicities included grade 3 mucositis in 11 patients and grade 4 mucositis in two patients. A PEG tube was required in 12 patients, with two patients experiencing prolonged PEG dependence (greater than 20 months). Steinberg et al46 described a study in which 24 patients with stages III and IV HNSCC were administered radiotherapy (daily fractionation to total doses of 66 to 72 Gy) in combination with paclitaxel given as 24-hour continuous infusions on days 1, 22, and 43. Dose escalations of 75, 90, and 105 mg/m2 were given (dose-intensity = 75 to 105 mg/m2/3 weeks). This regimen achieved a CR of 72% at the primary site. The maximum-tolerated dose was retrospectively determined to be less than 75 mg/m2, because more than 50% of the patients developed febrile granulocytopenia at that dose. Significant local toxicities also were reported. Most notable of these were grade 3 mucositis, necessitating enteral feeding tubes, and skin toxicity. Finally, Rosenthal et al47 reported a study in which patients with stages III and IV HNSCC were treated with standard radiotherapy in combination with paclitaxel administered as a continuous infusion 24 hours/d, 7 days/wk, for the 7-week duration of radiotherapy (daily fractionation to total doses of 50 Gy). Their rationale for this dosing schedule is based on preclinical and clinical data that suggest that direct antitumor activity and radiosensitization are more dependent on the duration of paclitaxel exposure than on the peak serum concentrations.16,20,48 At the time of their report, dose escalation was ongoing, and no limiting toxicity was noted at doses up to 6.5 mg/m2/d (dose-intensity = 136.5 mg/m2/3 weeks). The trial reported here used a prolonged continuous infusion of paclitaxel to lengthen the duration of drug exposure and maximize radiosensitization. The 70% CR achieved in our study is comparable to those achieved with the regimens employed by Hoffmann et al44 and by Steinberg et al.46 Although the CR reported by Tishler et al45 was higher, comparisons of efficacy are difficult to interpret because 67% of those patients with a CR had received prior therapy. Although no conclusions can be drawn as to the optimal regimen based on this comparison of our study with the ones above, the schedule of paclitaxel infusion as well as the dose-intensity is likely to modulate the efficacy of the drug. An example of this can be seen in the study by Steinberg et al46 (24-hour paclitaxel). They found an unacceptably high incidence of hematologic toxicity, yet their dose-intensity at the maximally tolerated dose was the lowest (< 75 mg/m2/3 weeks) of all the paclitaxel/radiation studies in head and neck cancer. Similarly, in a recent randomized study of paclitaxel (without radiation) in breast cancer, Smith et al49 found that for the same dose of paclitaxel, a 24-hour infusion was associated with both a higher response rate and greater incidence of febrile neutropenia than a 3-hour infusion. The most common major local toxicity associated with these various regimens of concurrent paclitaxel and radiation has been mucositis. Although we found an association between duration of mucositis and paclitaxel dose, return of swallowing function was essentially the same between the two dose groups. All patients required enteral feeding tubes during and immediately after treatment to maintain adequate nutrition in the setting of dysphagia/odynophagia secondary to mucositis. We found that most patients gained weight while on treatment and that the placement of PEG tubes should be a routine component of the preparation for this type of therapy. Speech and swallowing functions of the patients after treatment are similar to those of patients in other organ preservation protocols.50 Our patients retained communication skills adequate for their activities of daily living throughout treatment. Although swallowing function was compromised for many, the ability to regain some degree of swallowing function was promising. Further analysis of swallowing physiology, which is currently being conducted, will assist in more precisely defining swallowing function and the longitudinal effects of treatment and may yield additional rehabilitation interventions. The lack of significant G2/M block on DNA cell cycle analysis in biopsies taken 48 hours after the beginning of infusion led us to examine whether significant plasma concentrations of paclitaxel were achieved over the 120-hour infusion at an increased dose of 120 mg/m2. By 48 hours, the mean plasma concentration at the 120 mg/m2 dose attained concentrations in the range associated with G2/M block and radiosensitization in vitro16,17,19. Although it was unfortunate that none of these patients had tumors accessible to biopsy without a general anesthetic, plasma concentration profiling indicated that the highest concentrations of paclitaxel were not achieved until 120 hours after infusion, after the start of radiation, and therefore, it is possible that the biopsies taken from the subset of patients receiving the 105 mg/m2 dose of paclitaxel may have demonstrated a G2/M block had they been obtained later in the 120-hour cycle. Although there was no evidence to suggest differences in overall response or survival between the two dose groups, we acknowledge that the two groups of patients had some differences, most notably in the representation of oral cavity tumors. The failure to achieve a CSS of paclitaxel in the study reported here was unexpected. Although the nonlinear pharmacokinetics of paclitaxel are well-documented with saturable distribution and elimination,51,52 this nonlinear pharmacokinetic behavior has been described as being less pronounced at low dosages and with longer infusion durations. Hudes et al53 found that paclitaxel concentrations reach steady-state levels by 48 to 72 hours for regimens of 105 or 120 mg/m2 using a 96-hour infusion schedule. A steady-state level was not achieved at a higher dose (140 mg/m2, 96-hour infusion) in three of four patients whom they treated; however, drug interactions could not be excluded. To explain the pharmacokinetic behavior that we observed, we considered the potential role of concomitantly administered medications, but no medications were regularly taken during the initial course of therapy. We did not observe an association with CYP-3A4, -2A6, and -2C isozyme inhibitors (data not shown). In addition, no significant abnormalities in liver function tests explained this phenomenon. Because a CSS seemed to be developing during the 48 hours of infusion before the initiation of radiotherapy, we suspect that radiation may play an important role in the continuous increase of plasma paclitaxel concentrations. Further experimental studies are warranted to investigate this phenomenon. Prediction of treatment response and clinical outcome of patients treated by radiotherapy for head and neck cancer has traditionally relied on the tumor-node-metastasis staging system. In this study of patients with predominantly stage IV tumors, we found that the radiographic quantification of TVOL adds to the predictive power of the current tumor-node-metastasis staging system. This variable was significantly associated with both CR at the primary site and survival. It also provided a stratification of patients with respect to outcome within a single tumor-node-metastasis group stage. It is not surprising that TVOL correlates with response to radiotherapy because larger tumors are more likely than smaller ones to have a subpopulation of cells that are resistant to therapy and because larger tumors have more cells in a hypoxic environment. These findings are consistent with other studies examining the use of radiographic TVOL in the prediction of local control by radiotherapy.54-56 In summary, we have demonstrated that paclitaxel can be safely administered with concomitant radiotherapy using a continuous 120-hour infusion schedule in patients with HNSCC. Both systemic and local toxicities were encountered, but none was dose-limiting. We have also demonstrated the prognostic utility of radiographic quantification of TVOL in patients receiving this combined therapy.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999
2.
Vokes EE, Weichselbaum RR, Lippman SM, et al: Head and neck cancer. N Engl J Med 328: 184-194, 1993 3. Vokes EE: Combined-modality therapy of head and neck cancer. Oncology (Huntingt) 11: 27-30, 1997 4. Adelstein DJ: Recent randomized trials of chemoradiation in the management of locally advanced head and neck cancer. Curr Opin Oncol 10: 213-218, 1998[Medline] 5. Haffty BG: Concurrent chemoradiation in the treatment of head and neck cancer. Hematol Oncol Clin North Am 13: 719-742, 1999 6. Bourhis J, Pignon JP: Meta-analyses in head and neck squamous cell carcinoma. What is the role of chemotherapy? Hematol Oncol Clin North Am 13: 769-775, 1999[Medline] 7. Smith RE, Thornton DE, Allen J: A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies. Semin Oncol 22: 41-46, 1995[Medline] 8. 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 82: 2270-2274, 1998[Medline] 9. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by Taxol. Nature 277: 665-667, 1979[Medline]
10.
Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 77: 1561-1565, 1980
11.
Terasima R, Tolmach LJ: X-ray sensitivity and DNA synthesis in synchronous populations of HeLa cells. Science 140: 490-492, 1963 12. Milas L, Milas MM, Mason KA: Combination of taxanes with radiation: Preclinical studies. Semin Radiat Oncol 9: 12-26, 1999[Medline] 13. Elomaa L, Joensuu H, Kulmala J, et al: Squamous cell carcinoma is highly sensitive to Taxol, a possible new radiation sensitizer. Acta Otolaryngol (Stockh) 115: 340-344, 1995[Medline]
14.
Leonard CE, Chan DC, Chou TC, et al: Paclitaxel enhances in vitro radiosensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res 56: 5198-5204, 1996 15. Rosenthal DI, Carbone DP: Taxol plus radiation for head and neck cancer. J Infus Chemother 5: 46-54, 1995[Medline]
16.
Liebmann J, Cook JA, Fisher J, et al: In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 86: 441-446, 1994
17.
Milas L, Hunter NR, Mason KA, et al: Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel. Cancer Res 54: 3506-3510, 1994
18.
Milas L, Hunter NR, Mason KA, et al: Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res 55: 3564-3568, 1995 19. Geard CR, Jones JM, Schiff PB: Taxol and radiation. J Natl Cancer Inst Monogr ( 15): 89-94, 1993
20.
Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14: 1877-1884, 1996 21. Spriggs DR, Tondini C: Taxol administered as a 120 hour infusion. Invest New Drugs 10: 275-278, 1992[Medline]
22.
Wilson WH, Chabner BA, Bryant G, et al: Phase II study of paclitaxel in relapsed non-Hodgkin’s lymphomas. J Clin Oncol 13: 381-386, 1995 23. Herscher LL, Hahn SM, Kroog G, et al: Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer. J Clin Oncol 16: 635-641, 1998[Abstract] 24. Sonies B, Sheppard J, Arvedson J, et al: Dysphagia Functional Outcomes: Adult Scale—Summary Matrix. Rockville, MD, American Speech Hearing Association Task Force Document, 1997 25. Willey TA, Bekos EJ, Gaver RC, et al: High-performance liquid chromatographic procedure for the quantitative determination of paclitaxel (Taxol) in human plasma. J Chromatogr 621: 231-238, 1993[Medline]
26.
Seibel NL, Blaney SM, O’Brien M, et al: Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: A collaborative Pediatric Oncology Branch. National Cancer Institute and Children’s Cancer Group trial. Clin Cancer Res 5: 733-737, 1999
27.
Adelstein DJ, Kalish LA, Adams GL, et al: Concurrent radiation therapy and chemotherapy for locally unresectable squamous cell head and neck cancer: An Eastern Cooperative Oncology Group pilot study. J Clin Oncol 11: 2136-2142, 1993 28. Clayman GL, Weber RS, Guillamondegui O, et al: Laryngeal preservation for advanced laryngeal and hypopharyngeal cancers. Arch Otolaryngol Head Neck Surg 121: 219-223, 1995 29. Adelstein DJ, Saxton JP, Lavertu P, et al: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results. Head Neck 19: 567-575, 1997[Medline]
30.
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 16: 1318-1324, 1998
31.
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12: 2654-2666, 1994 32. Ohtsu T, Sasaki Y, Tamura T, et al: Clinical pharmacokinetics and pharmacodynamics of paclitaxel: A 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 1: 599-606, 1995[Abstract]
33.
Reckzeh B, Merte H, Pfluger KH, et al: Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer. J Clin Oncol 14: 1071-1076, 1996 34. Kirkbride P, Gelmon K, Eisenhauer E, et al: A phase I/II study of paclitaxel (TAXOL) and concurrent radiotherapy in advanced nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 39: 1107-1111, 1997[Medline] 35. Robert F, Childs HA, Spencer SA, et al: Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer: Analysis of early and late pulmonary morbidity. Semin Radiat Oncol 9: 136-147, 1999[Medline] 36. Koukourakis MI, Bahlitzanakis N, Froudarakis M, et al: Concurrent conventionally factionated radiotherapy and weekly docetaxel in the treatment of stage IIIb non-small-cell lung carcinoma. Br J Cancer 80: 1792-1796, 1999[Medline] 37. Curi MM, Dib LL: Osteoradionecrosis of the jaws: A retrospective study of the background factors and treatment in 104 cases. J Oral Maxillofac Surg 55:540-544; discussion 545-546, 1997 38. Turner SL, Slevin NJ, Gupta NK, et al: Radical external beam radiotherapy for 333 squamous carcinomas of the oral cavity: Evaluation of late morbidity and a watch policy for the clinically negative neck. Radiother Oncol 41: 21-29, 1996[Medline] 39. Tong AC, Leung AC, Cheng JC, et al: Incidence of complicated healing and osteoradionecrosis following tooth extraction in patients receiving radiotherapy for treatment of nasopharyngeal carcinoma. Aust Dent J 44: 187-194, 1999[Medline] 40. Hopkins MP, von Gruenigen VE, Holda S, et al: The effect of intermittent-release intraperitoneal chemotherapy on wound healing. Am J Obstet Gynecol 176:819-823; discussion 823-825, 1997 41. Sassler AM, Esclamado RM, Wolf GT: Surgery after organ preservation therapy. Analysis of wound complications. Arch Otolaryngol Head Neck Surg 121: 162-165, 1995 42. Smith RV, Krevitt L, Yi SM, et al: Early wound complications in advanced head and neck cancer treated with surgery and Ir 192 brachytherapy. Laryngoscope 110: 8-12, 2000[Medline] 43. Tell R, Sjodin H, Lundell G, et al: Hypothyroidism after external radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 39: 303-308, 1997[Medline] 44. Hoffmann W, Belka C, Schmidberger H, et al: Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer: Results from a phase I trial. Int J Radiat Oncol Biol Phys 38: 691-696, 1997[Medline] 45. Tishler RB, Busse PM, Norris CM Jr, et al: An initial experience using concurrent paclitaxel and radiation in the treatment of head and neck malignancies. Int J Radiat Oncol Biol Phys 43: 1001-1008, 1999[Medline] 46. Steinberg L, Hassan M, Olmsted L, et al: A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma. Semin Oncol 24: S19-51-S19-56, 1997 47. Rosenthal DI, Sinard RJ, Okani O, et al: Seven-week continuous-infusion paclitaxel with concurrent radiotherapy for locally advanced head and neck squamous cell cancer: A phase I study. Semin Oncol 24: S19-67-S19-71, 1997 48. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell cycle effects of Taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 32: 235-242, 1993[Medline]
49.
Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17: 3403-3411, 1999 50. Hillman RE, Walsh MJ, Wolf GT, et al: Functional outcomes following treatment for advanced laryngeal cancer. Part I: Voice preservation in advanced laryngeal cancer. Part II: Laryngectomy rehabilitation: The state of the art in the VA System. Research Speech-Language Pathologists. Department of Veterans Affairs Laryngeal Cancer Study Group. Ann Otol Rhinol Laryngol Suppl 172: 1-27, 1998[Medline] 51. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22: 16-23, 1995[Medline]
52.
Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13: 180-190, 1995 53. Hudes GR, Obasaju C, Chapman A, et al: Phase I study of paclitaxel and estramustine: Preliminary activity in hormone-refractory prostate cancer. Semin Oncol 22: 6-11, 1995 54. Gilbert RW, Birt D, Shulman H, et al: Correlation of tumor volume with local control in laryngeal carcinoma treated by radiotherapy. Ann Otol Rhinol Laryngol 96: 514-518, 1987[Medline] 55. Freeman DE, Mancuso AA, Parsons JT, et al: Irradiation alone for supraglottic larynx carcinoma: Can CT findings predict treatment results? Int J Radiat Oncol Biol Phys 19: 485-490, 1990[Medline] 56. Pameijer FA, Mancuso AA, Mendenhall WM, et al: Evaluation of pretreatment computed tomography as a predictor of local control in T1/T2 pyriform sinus carcinoma treated with definitive radiotherapy. Head Neck 20: 159-168, 1998[Medline] Submitted April 28, 2000; accepted September 22, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
10 nmol/L, the concentration at which radiosensitization was observed in vitro
