|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Phase I Study of Paclitaxel Given by Seven-Week Continuous Infusion Concurrent With Radiation Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and NeckFrom the University of Pennsylvania Medical Center, Philadelphia; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Texas Southwestern Medical Center, Dallas, TX; University of Maryland Greenebaum Cancer Center, Baltimore, MD; and the Vanderbilt Cancer Center, Nashville, TN. Submitted April 4, 2000; accepted November 8, 2000. Address reprint requests to David I. Rosenthal, MD, Department of Radiation Oncology, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104; email: rosenthal{at}xrt.upenn.edu
PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute–sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks).
RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m2/d with RT for SCCHN.
RADIATION THERAPY (RT) is standard treatment for locally advanced, unresectable squamous cell carcinoma of the head and neck (SCCHN). Local tumor persistence/recurrence is a major problem, and long-term survival is less than 25%.1 There is progressively accumulating evidence that chemotherapy given concurrent with RT can improve local control and survival for many patients with locally advanced SCCHN.2-5 The optimal chemotherapy agents and their dose schedules have yet to be defined. Paclitaxel is one of the most active agents for SCCHN in the metastatic and recurrent setting6 and has been shown to be a radiosensitizer for human SCCHN cell lines.7,8 Paclitaxel promotes the polymerization and stabilization of microtubules, leading to an accumulation of cells at the G2-M boundary, the most relatively radiosensitive phase of the cell cycle.9,10 This suggests an obvious mechanism for radiosensitization, but the reality may be more complex.11 Paclitaxel has also been shown to improve tumor reoxygenation12,13 and to activate apoptosis.14,15 It has also been suggested that exposure to subcytotoxic concentrations of paclitaxel may simply suppress tumor repopulation, as during a course of fractionated RT.16 Several laboratory studies suggest that the dose-response range for radiosensitization by paclitaxel may be relatively narrow, 10 to 50 nmol/L, and that the duration of paclitaxel exposure is more important than peak concentrations for antitumor activity and radiosensitization.17,18 Clinically, paclitaxel administered by 96-hour infusion has led to a response rate of 27% in patients with metastatic breast cancer who had recently progressed during more brief taxane exposure.19 An association has also been found between the duration of exposure above 100 nmol/L paclitaxel and survival in non–small-cell lung cancer but not with peak concentrations.20 Thus prolonged exposure to more modest paclitaxel concentrations may have more activity than a more brief exposure to higher concentration.21-24 Recent trials have also tested paclitaxel given by prolonged infusions of up to 5 days during RT.25,26 A phase I trial evaluating 96-hour infusional paclitaxel during accelerated RT for locally advanced SCCHN found this approach to be feasible and well tolerated up to a dose of 100 mg/m2/96 hours.25 These data suggest that prolonged and continuous exposure to paclitaxel during the entire course of RT is a rational approach for SCCHN. This dose schedule has the potential to sensitize the tumor to each fraction of RT. This phase I study combines once-daily continuous course RT (70 Gy/7 weeks) with a unique continuous-infusion paclitaxel dose-schedule, 24 hours per day, 7 days per week for 7 weeks. The primary objective of this study was to determine the maximum-tolerated dose (MTD) of paclitaxel given on this schedule with RT. The secondary objectives were to determine the dose-limiting toxicities (DLT) and the plasma paclitaxel concentrations achieved.
Patient Characteristics Patients were enrolled onto this National Cancer Institute (NCI) Cancer Therapy Evaluation Program–sponsored phase I trial (NCI-T92-0248) at the Hospital of the University of Pennsylvania and the University of Texas Southwestern Medical Center. The study was approved by each institutional review board. Patients with previously untreated, histologically proven stage 4A or 4B SCCHN were eligible. Informed consent was obtained from each patient before enrollment. All patients were required to have Eastern Cooperative Oncology Group performance status of 0 to 2 and an expected 5-year disease-free survival rate of 25% or less with conventional therapies. Primary tumor sites were limited to the oral cavity, oropharynx, hypopharynx, and larynx. Patients were required to have adequate hematologic parameters, serum creatinine less than 2 mg/dL, and adequate hepatic function. Exclusion criteria included prior RT except for cutaneous carcinoma, prior chemotherapy, clinical evidence of preexisting grade 2 or greater peripheral neuropathy, clinically significant coronary artery disease, medications that could alter cardiac conduction, and pregnancy. Patients were evaluated in a multidisciplinary clinic for suitability for this trial and treatment coordination. Patients were staged by physical examination, radiographic evaluation, and examination and panendoscopy under anesthesia. A peripherally inserted central catheter or other central indwelling venous catheter was used to facilitate continuous-infusion drug administration. Prophylactic feeding gastrostomy tubes were recommended in patients with preexisting or expected nutritional compromise. Patients were assigned to one of two treatment arms. Arm 1 consisted of patients for whom the morbidity of resection was judged acceptable. They were treated on a preoperative basis with planned radical surgery. Postradiation neck dissection was planned for N2 or N3 disease if the primary site had been controlled. Arm 2 consisted of patients whose tumors were sufficiently advanced and who had poor expected survival. In these patients, the morbidity associated with resection was not felt to be in their best interest. The overall treatment schema is depicted in Fig 1.
Paclitaxel Paclitaxel was administered by outpatient ambulatory continuous-infusion 24 hours per day, 7 days per week for the 7-week duration of RT. The paclitaxel infusion was started 48 hours before the initiation of RT and continued throughout. Patients were premedicated with oral dexamethasone levels and intravenous ranitidine and diphenhydramine before initiation of infusion. Paclitaxel was prepared in 24- or 48-hour infusion bags as a diluted solution of 1.2 mg/mL or less. Administration of paclitaxel was performed via an ambulatory infusion pump at a rate of 5 mL/h. Doses of paclitaxel were escalated according to a modified Fibonacci series as follows: 0.5, 1.0, 1.5, 2.5, 4.0, 6.5, 10.5, 17.0 mg/m2/d. Three patients were entered in each dose level until grade 3 or higher toxicity was observed. Radiation Therapy Oncology Group acute radiation toxicity and NCI common toxicity criteria 1.0 were used. DLT was defined as grade 3 to 4 skin or mucosal reaction requiring more than 1 week interruption of treatment, absolute neutrophil count less than 1,000/µL, or other nonhematologic grade 3 to 4 toxicity. If DLT was noted in any two of three patients, the MTD was exceeded by definition. If DLT was noted in one of the three patients, an additional two patients were accrued at that dose level. If no additional severe toxicity was noted (ie, four of five patients did not have severe or life-threatening toxicity), dose escalation proceeded to the next level. If an additional patient experienced a DLT, then the MTD was exceeded. The prior dose level at which three of three or four of five patients completed without any other DLT was defined as the MTD.
Paclitaxel doses were modified if severe toxicity developed during therapy. Paclitaxel was held until resolution of severe toxicity to
RT and Surgery
Evaluation and Follow-Up
Between April 1994 and May 1998, 27 patients were enrolled onto this phase I trial. Three patients with resectable disease were treated preoperatively on arm 1. The remainder of patients were treated on arm 2 ( Fig 2). In general, patient compliance was excellent, and no patients voluntarily terminated therapy. Dose escalation of paclitaxel proceeded as per protocol, with the exception of the single patient treated at the 1.0 mg/m2/d dose level. Patients were accrued at the next dose level as a result of an agreement with the Cancer Therapy Evaluation Program, as patients on a parallel trial for locally advanced non–small-cell lung cancer tolerated the 1.0 mg/m2/d dose level without excess toxicity.
Patient characteristics are listed in the Table 1. There were 20 male and seven female patients, with a median age of 56 years (range, 42 to 69 years). Twenty-two patients had stage IVA disease, and five patients had stage IVB disease. Fourteen patients had oropharyngeal primaries, the majority originating from the base of the tongue or tonsil. Twenty-six patients (94%) had performance status 0 to 1. All but two patients completed treatment as planned. The median radiation dose for patients on arm 2 was 70 Gy. One patient received 70.2 Gy, and four patients received 72 Gy. The median length of treatment was 51 days, including the 48 hours of preradiation paclitaxel infusion. The median cumulative dose of paclitaxel for patients on arm 2 was 199 mg/m2 (range, 26 to 901 mg/m2), which corresponds to an average weekly dose of 48 mg/m2 during concurrent RT.
Toxicity Profile All 27 patients were assessable for toxicity. Two patients died during treatment as a result of complications from aspiration pneumonia and nonneutropenic sepsis. The first event was unrelated to treatment and occurred during the first week of radiation at the 4 mg/m2/d dose level of paclitaxel. The second occurred in the sixth week of treatment at the 6.5 mg/m2/d dose level of paclitaxel, at which time mucositis was present. There were no significant allergic reactions to the continuous infusion of paclitaxel. Two patients developed reversible grade 1 peripheral neuropathy. Abnormalities in serum transaminases and renal function were rare, not dose-limiting, and reversible. Gastrointestinal toxicities, including nausea and vomiting, were minimal and generally responded to antiemetics. A summary of maximum toxicities is included in Table 2.
The maximum hematologic, mucocutaneous, and gastrointestinal toxicities are shown for each dose level in Tables 3 and 4. This trial was initiated using the Radiation Therapy Oncology Group acute toxicity and the original NCI common toxicity criteria scoring. Nonfebrile grade 3 neutropenia occurred in one patient at a dose level of 17 mg/m2/d, and only three other patients had grade 1 neutropenia. Severe lymphopenia was recorded at a range of dose levels but did not seem clinically significant. All patients at the 10.5 and 17 mg/m2/d dose levels had grade 3 mucosal reactions—a diffuse, confluent, gray, edematous mucositis with fibrinous exudate associated with copious, tenacious oropharyngeal secretions. Grade 2 mucositis was seen in 10 (56%) of 18 patients at lower (0.5 to 6.5 mg/m2/d) paclitaxel dose levels. The majority of patients maintained enteral feeding tubes, thereby limiting significant weight loss to four patients (15%). If mucosal toxicity were reclassified by NCI common toxicity criteria 2.0, all patients treated at the 6.5 mg/m2/d paclitaxel dose level or higher would have had grade 3 mucositis. One patient at the 10.5 mg/m2/d dose level had grade 3 mucositis, required a 1-week break, and developed recurrent grade 3 mucositis after restarting treatment with a dose reduction of paclitaxel. This patient was restarted on and completed RT alone. Grade 3 mucositis was not dose-limiting in the other five patients at the 10.5 mg/m2/d dose level. All three patients at the 17 mg/m2/d dose level had grade 3 confluent, moist skin desquamation in the entire radiation field, requiring a 2-week treatment interruption. This skin reaction represented DLT as defined. All patients healed, and there were no consequential late effects. Five of six patients completed treatment on schedule at the next lower dose level, 10.5 mg/m2/d, with only a single DLT. Therefore, a continuous paclitaxel dose of 10.5 mg/m2/d with concurrent RT represents the MTD.
All grade 3 mucositis and skin toxicity resolved within 8 weeks of treatment discontinuation. There was no grade 4 mucositis, possibly due to the dose-limiting effect of skin toxicity at the highest dose level of paclitaxel. One patient with bilateral N3 neck disease developed significant neck edema after bilateral neck dissection. This patient remained gastrostomy-dependent for 8 months until the edema resolved but is now swallowing normally. None of the long-term survivors are dependent on feeding tubes. At all dose levels, there were instances of central venous access device obstruction. This often required either line flushing, injection of urokinase into the catheter, or placement of a new line. Some instances may have resulted from precipitation of drug crystals at low flow rates. The use of a dual-channel infusion pump also infusing normal saline at 40 mL/h with paclitaxel via the same venous access device reduced line obstruction and provided welcome hydration.
Pharmacokinetic Data
Response and Survival Response to treatment was assessed in all patients in arm 2 and for those considered assessable for response, defined as having received a minimum radiation dose of 70 Gy. Nineteen (79%) of the 24 patients treated on arm 2 were assessable for treatment response (Fig 2). Five patients were not assessable for response: two patients died during treatment, one patient died shortly after therapy from a cerebrovascular event, and two developed distant metastatic disease during treatment. Complete tumor clearance was documented in 14 (74%) of 19 assessable patients receiving full-dose RT or 58% of all patients enrolled on arm 2. Three additional patients had partial responses, for an overall response rate of 71% (17 of 24 patients on arm 2). The response rate in patients who received 4.0 mg/m2/d or less of paclitaxel was similar to that in patients who received higher doses of paclitaxel. One patient had stable disease locoregionally, and another patient had progressive disease at distant sites. Twelve patients underwent postradiation neck dissection after a complete response at the primary site and negative rebiopsy. Five (42%) of these patients had neck dissection specimens with no viable tumor. A summary of response data for each paclitaxel dose level is listed in Table 5.
Among 14 patients with a CR, four later developed locoregional recurrence and five developed distant metastases. Durable locoregional control persisted in nine (47%) of 19 assessable patients or 38% of all patients enrolled on arm 2. Two patients with locoregional recurrence underwent salvage surgery, and one patient remains without evidence of disease. This one patient who was successfully salvaged and four other patients who have not developed locoregional recurrence are currently without evidence of disease at 20 to 54 months after completing therapy. All patients who went off study or had less than a CR ultimately died during therapy or from progressive disease. The median time to progression was approximately 5 months from completion of therapy. Three patients treated on a preoperative basis were not included in the assessment of response because they underwent gross total resection. Interestingly, two patients had a complete pathologic response at the primary site, and two patients had no viable tumor in the neck dissection specimens. All three patients in arm 1 were treated at a paclitaxel dose level of 0.5 mg/m2/d and 50 Gy of radiation. Two patients developed metastatic disease and eventually died, and the third patient died postoperatively from pulmonary embolism unrelated to preoperative treatment. The median follow-up times for the entire cohort and for assessable patients were 13 months and 17 months (range, 6 to 56 months), respectively. Median follow-up time for surviving patients was 28 months. As shown in Fig 4, overall survival for all patients was 52% at 1 year and 32% at 2 years. Overall survival for 19 assessable patients was 63% at 1 year and 47% at 2 years. Twenty patients (74%) have died during the follow-up period. Two patients died during chemoradiation, and a third patient in the preoperative arm died from sepsis four months after surgery. One patient died of causes not clearly related to progressive cancer (cerebrovascular accident). The other 16 patients died of progressive locoregional or distant disease.
Because of the poor survivorship resulting from the high frequency of locoregional persistence/recurrence despite aggressive standard RT for advanced SCCHN, clinical research has concentrated on methods of improving local tumor control. Moderate improvements in locoregional control have been demonstrated with intensification of RT alone, but these efforts have not been sufficient to translate into a reproducible survival advantage.29,30 Chemotherapy may be added as an induction regimen; however, concurrent chemotherapy and RT holds the most promise,31 as gains in local control have been shown to be sufficiently large to impart an improvement in survival.2-5,32 The feasibility and tolerability of continuous-infusion paclitaxel throughout a 7-week course of conventional RT for locally advanced SCCHN has been demonstrated by this trial. The major toxicities encountered in this study were the exacerbation of the local acute mucosal and skin reactions within the radiation fields. Grade 3 mucositis, dermatitis, and resulting dysphagia became prominent at 10.5 mg/m2/d; specifically the skin reaction became dose-limiting at 17 mg/m2/d. At this level, confluent moist skin desquamation developed by approximately 45 Gy and required treatment breaks for 2 weeks, thereby becoming dose-limiting by definition. All patients re-epithelialized and were able to complete planned treatment. We did not observe consequential late effects in any patient. Most patients required temporary feeding gastrostomy, and some required temporary tracheostomy. Ultimately, all patients became able to swallow, had adequate laryngeal airways, and were happy with the quality of their speech. Preliminary response and survival data are reported, as all assessable patients were treated with definitive RT. Many patients in the earlier cohorts probably had subtherapeutic paclitaxel exposure. All 24 patients in the definitive arm had stage 4 A/B, large-volume disease and poor expected local control and survival. Despite the fact that most patients were treated at paclitaxel dose levels that did not produce measurable paclitaxel concentrations in serum, 14 (74%) of 19 assessable patients achieved initial complete tumor clearance, and five of these patients have had no recurrence at last follow-up. Furthermore, two of three primary tumor specimens in patients treated preoperatively and seven (50%) of 14 neck dissection specimens in patients contained no viable tumor. The 2-year survival rate was 32%, with four long-term survivors now beyond 3 years with no evidence of disease. Two of these patients had T3 and 4 hypopharyngeal cancers with N2-3 nodal disease, one had T3N3 tonsil cancer, and the other had T3N3 base-of-tongue cancer. Two others are without evidence of disease and one patient is controlled locoregionally with greater than 18 month follow-up. These results are encouraging given the traditionally poor outcome for patients with these specific diagnoses.
Both efficacy and DLT of paclitaxel are dose-schedule dependent. Preclinical data suggest that there may be a relatively narrow dose-response range between 10 to 50 nmol/L for paclitaxel17,21,22 and that duration of paclitaxel exposure is more a determinant of response than the maximum concentration to which cells are exposed. This response range is orders of magnitude less than peak serum concentrations of 10 µg/mL (11.7 µmol/L) achieved after standard infusions of 175 to 250 mg/m2 over 1 to 3 hours.33 More prolonged exposure to paclitaxel was shown to be the determinant of clinical response in breast and lung cancer trials.19,20 With respect to toxicity, neutropenia is dose-limiting for paclitaxel at doses > 135 to 170 mg/m2 given by 24-hour infusion.34 The duration of exposure to paclitaxel concentrations Pharmacokinetic data demonstrate that prolonged paclitaxel exposure to concentrations > 50 nmol/L is associated with neutropenia.35 The data from the current study suggest that plasma paclitaxel concentrations could be maintained for 7 weeks above levels associated with antitumor activity but below those associated with neutropenia. Such a target concentration might be amenable to pharmacokinetically guided dose modification. These levels, which are maintained for 7 weeks, may be sufficient for direct cytotoxicity against the primary tumor and sensitization of the tumor to each fraction of RT.
Among the 13 patients treated at dose levels sufficient to produce measurable plasma paclitaxel concentrations ( Paclitaxel and RT have been combined in numerous phase I and II studies for locally advanced SCCHN ( Table 6).25,26,37-42 In addition, an analog of paclitaxel and docetaxel is also being tested with RT for advanced SCCHN, thereby increasing chemotherapy combination options.43 A number of studies have demonstrated the tolerability and efficacy of RT and weekly paclitaxel 1- or 3-hour infusions alone or with platinum agents at various dose levels.38,41,42 Weekly paclitaxel infusions are a convenient outpatient schedule and may allow several radiation fractions to occur with sensitizing levels of chemotherapy.44 In two separate phase I trials of continual weekly paclitaxel and RT to doses of 60 to 70 Gy for SCCHN, the MTD was determined to be 30 mg/m2/d once weekly without requiring dose reduction. Higher doses caused unacceptable mucositis.41,45 Suntharalingam et al42 administered a 50% higher weekly dose of paclitaxel and added carboplatin with RT at 1.8 Gy/d for locally advanced SCCHN. In this trial, however, approximately two thirds of patients required treatment breaks, 26% of patients had 50% dose reductions in chemotherapy, and the median number of cycles administered was six of the possible eight.42
Other investigators have tested higher-dose paclitaxel given every 3 to 4 weeks with RT, with MTD found to be in the range of 75 to 100 mg/m2 depending on the duration of infusion.25,39,40 NCI tested standard fractionation RT (1.8 Gy/d) with three courses of paclitaxel given as an infusion of 105 mg/m2, each over 120 hours.26 In a phase I trial at the University of Pennsylvania, the MTD of paclitaxel was 100 mg/m2 over 96 hours for two cycles in conjunction with accelerated concomitant-boost RT to 72 Gy over 6 weeks.25 The final 32 Gy was delivered as a boost using 1.6 Gy fractions twice a day and represented one of the most intense continuous-course chemoradiation schedules reported. The cumulative paclitaxel doses given during 7 weeks of continuous-course RT in this study exceed those reported by others by a factor of 1.5 to 3 ( Table 7). At the dose levels of 10.5 and 17 mg/m2/d, the cumulative 7-week doses of paclitaxel of 515 mg/m2 and 833 mg/m2, respectively, are the most dose-dense reported. These correspond to weekly doses of 73.5 mg/m2 and 119 mg/m2, respectively, which exceed the once-weekly MTD of 30 mg/m2 by factors of 2.5 to 4.41,45 The MTD of paclitaxel in the current study, allowing uninterrupted RT in the regimen, is 10.5 mg/m2/d. The 17 mg/m2/d dose level delivered 70% more drug but required a 2-week rest, thus rendering it dose-limiting by definition. Although time-factor analysis suggests that single-agent RT should be completed as expeditiously as possible,46 the time factor may be less important when radiation is combined with concurrent chemotherapy.1,35,47
A 7-week infusion of paclitaxel was relatively convenient for patients. This route of administration can be performed entirely in an outpatient setting. In this current trial, patients were required to get daily or every-other-day cassette changes for a renewed supply of drug during their RT. The adoption of 72-hour cassettes would eliminate the need for weekend nursing visits. Paclitaxel seems to be stable for at least this period of time after reconstitution.48 The routine use of dual-channel pump devices with saline infusion also reduces line obstruction, which was problematic at lower flow rates, and gives desirable hydration. Daily intravenous bolus49 or the potential for liposomal and/or oral delivery of taxanes might closely mimic a prolonged infusion and obviate the need for dedicated venous access and a pump, as well as the associated risks.
There are two major differences between the 7-week continuous infusion used herein and the common alternative of once-weekly 1 to 3 hour paclitaxel infusion. The first difference is the cumulative dose of paclitaxel that can be administered with acceptable toxicity (at least 2.5 times greater with 7-week infusion). There may be an association between radiosensitization and the absolute amount of drug given. The second difference is the number of radiation fractions given with paclitaxel serum concentrations associated with radiosensitization. Preclinical data demonstrate that tumor cells must be incubated with paclitaxel for 18 to 24 hours before radiosensitization is produced,10,17 and the radiosensitizing effect is lost very quickly in vitro when paclitaxel is removed after 24-hour incubation.21 This was the rationale for starting the 7-week paclitaxel infusion 48 hours before starting RT in the current trial. A previous publication on paclitaxel pharmacokinetics simulated the paclitaxel concentrations resulting from weekly 1- and 3-hour infusions of 30 mg/m2,35 suggesting that paclitaxel concentrations of In conclusion, concurrent RT and paclitaxel by 7-week continuous infusion is feasible and tolerable, with encouraging initial rates of response and tumor control. The recommended phase II dose for continuous therapy is 10.5 mg/m2/d, with confluent moist skin desquamation representing DLT. The associated toxicities are the local skin and mucosal reactions of RT, limited in scope to the radiation portals. The systemic toxicities of myelosuppression or peripheral neuropathy associated with infusions of 24- to 120-hour duration are not significant. Paclitaxel concentrations achieved by prolonged continuous infusion can be maintained in the range associated with tumor sensitization for each and every fraction of RT, and the cumulative paclitaxel doses delivered during RT are the highest reported. Preliminary data on treatment efficacy suggest that this unique schedule of paclitaxel administration has led to responses sufficient to indicate evaluation in subsequent studies.
Supported in part by an unrestricted grant from Bristol-Myers Squibb Corporation, Princeton, NJ, General Clinical Research Center, grant nos. M01-RR00633 and MO1-RR00095, and the National Cancer Institute Cancer Therapy Evaluation Program grant no. NCI T92-0248.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, May 15-18, 1999, Atlanta, GA.
1. Merlano M, Vitale V, Rosso R, et al: Treatment of advanced squamous cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 327: 1115-1121, 1992[Abstract]
2.
Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced stage oropharynx carcinoma. J Natl Cancer Inst 91: 2081-2086, 1999 3. Brizel DM, Albers MA, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 328: 1798-1804, 1998 4. Bachaud J-M, Cohen-Jonathan E, Alzieu C, et al: Combined postoperative radiotherapy and weekly cisplatin for locally advanced head and neck carcinoma: Final report of a randomized trial. Int J Radiat Oncol Biol Phys 36: 999-1004, 1996[Medline]
5.
Wendt TG, Grabenbauer GG, Rödel 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 6. 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]
7.
Leonard CE, Chan DC, Chou T-C, et al: Paclitaxel enhances in vitro radiosensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res 56: 5198-5204, 1996 8. 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] 9. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by Taxol. Nature 22: 665-667, 1979 10. Tishler RB, Schiff PB, Geard CR, et al: Taxol: A novel radiation sensitizer. Int J Radiat Oncol Biol Phys 22: 613-617, 1992[Medline] 11. Rosenthal DI, Carbone DP: Taxol plus radiation for head and neck cancer. J Infus Chemother 5: 46-54, 1995[Medline]
12.
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 13. Milas L, Hunter N, Mason KA, et al: Tumor reoxygenation as a mechanism of Taxol-induced enhancement of tumor radioresponse. Acta Oncol 34: 409-412, 1995[Medline] 14. Moos PJ, Fitzpatrick FA: Taxanes propagate apoptosis via two cell populations with distinctive cytological and molecular traits. Cell Growth Differentiation 9: 687-697, 1998[Abstract]
15.
Scatena CD, Stewart ZA, Mays D, et al: Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest. J Biol Chem 273: 30777-30784, 1998 16. van Rijn J, van den Berg J, Meijer OW: Proliferation and clonal survival of human lung cancer cells treated with fractionated irradiation in combination with paclitaxel. Int J Radiat Oncol Biol Phys 33: 635-639, 1995[Medline] 17. 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]
18.
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
19.
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
20.
Huizing MT, Giaccone G, Vanwarmerdam LJC, et al: Pharmacokinetics of paclitaxel and carboplatin dose-escalating and dose-sequencing study in with non-small-cell long cancer. J Clin Oncol 15: 317-329, 1997 21. Zanelli GD, Quaia M, Robieux I, et al: Paclitaxel as a radiosensitizer: A proposed schedule of administration based on in vitro data and pharmacokinetic calculations. Eur J Cancer 33: 486-492, 1997 22. Liebmann JE, Cook JA, Lipschultz C, et al: Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines. Br J Cancer 68: 1104-1109, 1993[Medline] 23. Geard CR, Jones JM, Schiff PB: Taxol and radiation. J Natl Cancer Inst Monogr 15: 89-94, 1993 24. Gupta N, Hu LJ, Deen DF: Cytotoxicity and cell-cycle effects of paclitaxel when used as a single agent and in combination with ionizing radiation. Int J Radiat Oncol Biol Phys 37: 885-895, 1997[Medline] 25. Machtay M, Aviles V, Kligerman MM, et al: A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy for unresectable head and neck cancer. Int J Radiat Oncol Biol Phys 44: 311-315, 1999[Medline] 26. Kroog GS, Van Waes C, Thomas G, et al: A pilot study of 120-hour paclitaxel with radiation therapy for locally advanced head and neck cancer. Proc Am Soc Clin Oncol 17: 396, 1998 (abstr 1528) 27. Longnecker SM, Donehower RC, Cates AE, et al: High-performance liquid chromatographic assay for Taxol in human plasma and urine and pharmacokinetics in a phase I trial [published erratum appears in Cancer Treat Rep 71: 340, 1987]. Cancer Treat Rep 71: 53-59, 1987[Medline] 28. Jamis-Dow CA, Klecker RW, Sarosy G, et al: Steady-state plasma concentrations and effects of taxol for a 250 mg/m2 dose in combination with granulocyte-colony stimulating factor in patients with ovarian cancer. Cancer Chemother Pharmacol 33: 48-52, 1993[Medline] 29. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: Preliminary results of RTOG 9003. Int J Radiat Oncol Biol Phys 45:145, 1999 (suppl) (abstr 1) 30. Ang KK: Altered fractionation trials in head and neck cancer. Semin Radiat Oncol 8: 230-236, 1998[Medline] 31. Rosenthal DI, Pistenmaa DA, Glatstein E: A review of neoadjuvant chemotherapy for head and neck cancer: Partially shrunken tumors may be both leaner and meaner. Int J Radiat Oncol Biol Phys 28: 315-320, 1994[Medline]
32.
Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16: 1310-1317, 1998 33. Hainsworth JD, Meluch AA, Greco FA: Paclitaxel, carboplatin, and long-term continuous infusion 5-fluorouracil in the treatment of upper aerodigestive malignancies: Preliminary results of a phase II trial. Semin Oncol 24: S19-38-S19-42, 1997 (suppl 19) 34. Donehower RC, Rowinsky EK, Groichow LB, et al: Phase I trial of Taxol in patients with advanced cancer. Cancer Treat Rep 71: 1171-1177, 1987[Medline] 35. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22: 16-23, 1995 (suppl 6)[Medline]
36.
Rowinsky EK, Chaudhry V, Forastiere AA, et al: Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: Neuromuscular toxicity is dose-limiting. J Clin Oncol 11: 2010-2020, 1993 37. Brockstein B, Kies M, Rosen F, et al: Concomitant chemoradiotherapy (CRT) with paclitaxel (T), 5-fluorouracil (F), hydroxyurea (H), and twice daily (BID) radiotherapy (RT) for locoregionally advanced head and neck cancer (HNC). Proc Am Soc Clin Oncol 18: 390, 1999 (abstr 1507) 38. Chougule PB, Akhtar MS, Akerley W, et al: Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study. Semin Radiat Oncol 9: 58-63, 1999 (suppl 1)[Medline] 39. Tischler 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] 40. 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 (suppl 19) 41. Hoffman 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] 42. Sunthraralingam M, Haas ML, Conley BA, et al: The use of carboplatin and paclitaxel with daily radiotherapy with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 47: 49-56, 2000[Medline] 43. Tischer RB, Posner MR, Colevas AD, et al: Phase I study of concurrent Taxotere/radiation (TRT) after induction chemotherapy in patients with squamous cell cancer of the head and neck. Proc Am Soc Clin Oncol 18: 400, 1999 (abstr 1547) 44. Choy H, Safran H, Akerley W, et al: Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Clin Cancer Res 4: 1931-1936, 1998[Abstract] 45. Flood W, Lee DJ, Trotti A, et al: Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: Preliminary results of two pilot trials using paclitaxel and cisplatin. Semin Radiat Oncol 9: 64-69, 1999 (suppl 1)[Medline] 46. Mendenhall WM, Parsons JT, Million RR, Fletcher GH: T1-2 squamous cell carcinoma of the glottic larynx treated with radiation therapy: Relationship of dose-fractionation factors to local control and complications. Int J Radiat Oncol Biol Phys 15: 1267-1273, 1988[Medline] 47. 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 13: 876-883, 1995[Abstract] 48. Xu Q, Trissel L, Martinez JF: Stability of paclitaxel in 5% dextrose injection or 0.9% sodium chloride injection at 4, 22, or 32 degrees Celsius. Am J Hosp Pharm 51: 3058-3060, 1994[Medline] 49. Rathmann J, Leopold KA, Rigas JR: Daily paclitaxel and thoracic radiation therapy for non-small cell lung cancer: Preliminary results. Semin Rad Oncol 9: 130-135, 1999 (suppl 1)[Medline]
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
70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m2/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m2/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels 
grade 2 and could be restarted at either full-dose or a 25% reduced dose. Patients with greater than 2 weeks’ delay or with recurrence of severe toxicity were taken off the study. RT could continue if it was considered unlikely that the toxicity would be worsened by continued radiation (ie, neutropenia or generalized rash). No prophylactic colony-stimulating factor was used in this study. Plasma paclitaxel concentrations were drawn weekly in selected patients for pharmacokinetic analysis during the continuous infusion and assayed using high-performance liquid chromatography.
