|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Radiation Concurrent With Gemcitabine for Locally Advanced Head and Neck Cancer: A Phase I Trial and Intracellular Drug Incorporation StudyFrom the Departments of Radiation Oncology, Pharmacology, Otolaryngology–Head and Neck Surgery; and Medicine, University of Michigan Medical Center, and Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI. Address reprint requests to Avraham Eisbruch, MD, Department of Radiation Oncology, University of Michigan Hospital, Ann Arbor, MI 48109; email: eisbruch{at}umich.edu
PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m2/wk, 150 mg/m2/wk, and 50 mg/m2/wk. No DLT was observed at 10 mg/m2/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m2 (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m2. CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m2, which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.
RADIOTHERAPY (RT) has been the standard treatment for locally advanced, inoperable cancer of the head and neck. Patients with these tumors who receive RT alone have a 5-year survival rate of less than 25%, and most treatment failures occur locally or regionally within the irradiated fields.1 Chemotherapy has been combined with RT in an attempt to improve this outcome.2-12 The most promising approach has been the administration of chemotherapy concurrent with RT, taking advantage of the radiation sensitizing effects of certain chemotherapeutic agents. Several randomized studies have shown improved outcome when RT was combined with concurrent cytotoxic agents, compared with RT alone.3-7,11-12 Many of these studies reported an increased toxicity of the combined treatments, notably hematologic and mucosal toxicities, which limited the ability to deliver full doses of radiation or the chemotherapeutic agents. The optimal drugs, doses, and schedules of concurrent chemotherapy and RT for head and neck cancer are not yet known. Gemcitabine (2’,2’-difluoro-2’-deoxycytidine [dFdCyd]) is a deoxycytidine analog with clinical activity in solid tumors, including head and neck cancer.13-15 It is characterized by relatively low toxicity and a broad spectrum of activity. Investigations of the mechanism of antitumor activity of gemcitabine have demonstrated that it requires intracellular activation by phosphorylation to gemcitabine triphosphate (dFdCTP). This metabolite can then interfere directly with DNA synthesis in tumor cells through the inhibition of DNA polymerization and incorporation of the fraudulent nucleotide into the growing DNA strand. Gemcitabine may also affect DNA synthesis by preventing the de novo biosynthesis of the deoxyribonucleoside triphosphate precursors through inhibition of ribonucleotide reductase.16 A favorable pharmacokinetic characteristic of gemcitabine is the retention of its cytotoxic triphosphate in cells, with terminal elimination rates as long as 72 hours. This permits dosing with gemcitabine on a once- or twice-weekly schedule. Several phase I studies have been conducted in which gemcitabine was delivered in cycles consisting of once-weekly infusions for 3 weeks followed by a 1-week rest. These studies have demonstrated that weekly gemcitabine doses of 1,250 mg/m2 to 2,200 mg/m2 can be safely administered to chemotherapy-naïve patients with good performance status.15 Recent studies have demonstrated that gemcitabine is a potent radiosensitizer in several different solid tumor cell lines in vitro, including head and neck cancer, at noncytotoxic concentrations.16-20 Gemcitabine exposure was required before radiation, and radiosensitization was observed at concentrations of 100 nmol/L or less.16 Current clinical dosing of gemcitabine produces plasma concentrations of 20 µmol/L, which is 200 times higher than the in vitro radiosensitizing concentration for this drug. Short-term (2-hour) exposure to gemcitabine was sufficient to produce radiosensitization when cells were irradiated after 24 or 48 hours, presumably due to the prolonged cellular effects mediated by lengthy retention of dFdCTP.17 This suggests that once- or twice-weekly administration of gemcitabine may effectively sensitize tumor cells during a weekly course of RT. The radiosensitizing properties of gemcitabine at noncytotoxic concentrations, as well as its lack of reported mucositis, make it a candidate for a trial of concurrent radiochemotherapy in head and neck cancer. This phase I study was conducted to find the maximally tolerated dose (MTD) that could be delivered once weekly concurrent with a standard course of radiation. Our preclinical studies suggested that gemcitabine was most effective as a radiosensitizer when administered at least 2 hours before RT.16 Therefore, this study consisted of weekly gemcitabine given during the course of radiation; on the day drug was infused, radiation was delivered 4 hours after the infusion. When this trial began, no data existed on the toxicity of this combination in head and neck cancer. However, data indicated that the accumulation of dFdCTP in mononuclear cells was saturated by a dose rate of 10 mg/m2/min.21 Infusion of 300 mg over 30 minutes (an infusion duration used in most phase I/II studies of weekly gemcitabine alone) was expected to saturate the intracellular active metabolite while delivering 25% or less of the MTD of gemcitabine. Therefore, this dose was selected as the starting dose level. In addition to the standard phase I end point of toxicity, we sought to assess whether the intracellular tumor incorporation levels of the active drug metabolite, dFdCTP, are compatible with levels that cause radiosensitization in vitro. To this end, tumor biopsies were performed in consenting patients after the first infusion of gemcitabine before radiation started, and the intracellular concentrations of dFdCTP were measured.
Patients eligible for the study had locally or regionally advanced cancer of the extracranial head and neck without evidence of distant metastases. Patients were judged to be unresectable by the referring surgeon, found to be unresectable at surgery, or had advanced disease (T3/4 or N3 according to the American Joint Committee on Cancer staging) and were medically inoperable or refused surgery. Patients who had experienced prior chemotherapy or radiation were not allowed to participate in the study. Eligibility criteria included Karnofsky performance status score  60, age 18 years, estimated life expectancy of at least 16 weeks, adequate bone marrow reserve (hemoglobin > 9 g/dL, platelet count > 100 x 109/L, granulocyte count > 1.5 x 109/L), adequate renal function (serum creatinine  2.0 mg/dL and blood urea nitrogen 40 mg/dL), and adequate liver function (bilirubin < 2.0 mg/dL, prothrombin and activated partial thromboplastine times 1.5 times control, and ALT and AST elevated to no more than three times normal range). A complete history and physical examination were performed before treatment, including height, weight, performance status, head and neck computed tomography (CT) and/or magnetic resonance imaging scans, and direct endoscopy under anesthesia to assess tumor extent and determine stage. All patients signed an informed consent approved by the institutional review board and were treated at the University of Michigan Hospital (Ann Arbor, MI) and the Ann Arbor Veterans Affairs Research Service.
RT
Gemcitabine
Dose Adjustment and Escalation Criteria
Criteria of Tumor Response
Tumor Phosphorylation of Gemcitabine
Thirty patients were accrued to the study, of which one patient declined treatment after accrual. Twenty-nine patients were treated between May 1995 and January 1999 and are reported in this article. Patient characteristics are summarized in Table 1. All had squamous cell carcinoma except for one patient with medullary thyroid cancer. The trial was primarily aimed at patients with unresectable disease. The reasons for unresectability included involvement of the nasopharynx in six patients (of whom two had advanced primary nasopharyngeal cancer and four had oropharyngeal cancer extending to the nasopharynx), neck metastases that were assessed as unresectable due to fixation and/or radiologic evidence of carotid artery involvement in six patients, neck dissection that was aborted due to intraoperative findings of carotid artery involvement in five patients, and intracranial tumor extension in two patients. In addition, seven patients were believed to require extensive and morbid surgery, and three patients with advanced disease refused surgery. No previous therapy had been delivered to any patient.
Toxicity The commonly observed acute and late toxicities are detailed in Table 2. Due primarily to late mucosal and pharyngeal DLT, successive patient cohorts received de-escalated dose levels of gemcitabine: 300 mg/m2 (eight patients), 150 mg/m2 (12 patients), 50 mg/m2 (six patients), and 10 mg/m2 (three patients). Confluent acute mucositis (RTOG grade 3) was observed in most patients receiving the dose levels of 50 to 300 mg/m2. Confluent mucositis started during the third treatment week in the cohorts receiving 300 and 150 mg/m2 and lasted on average 7 weeks. In the cohort receiving 50 mg/m2, confluent mucositis started at the fourth to the sixth week and lasted on average 3 weeks. Most patients in these cohorts required gastric feeding tubes (all patients receiving 300 mg/m2, 11 of 12 receiving 150 mg/m2, and five of six receiving 50 mg/m2; two of these patients had feeding tubes placed before therapy started). Mucosal/pharyngeal acute DLT consisted of deep mucosal ulcers and was observed in three patients receiving 150 mg/m2. In contrast, none of the patients receiving gemcitabine 10 mg/m2 developed confluent mucositis, none required a feeding tube, and none had an acute DLT. No dose-limiting hematologic or other systemic toxicities were observed in any cohort.
The most common DLT in the patient cohorts receiving gemcitabine 50 to 300 mg/m2 was late mucosal/pharyngeal toxicity. This consisted of persistent deep ulceration in nontumor-bearing areas or pharyngeal/upper esophageal obstruction that could not be relieved by trials of esophageal dilation and required persistent gastric tube feeding. This DLT was observed in four, two, and two patients receiving 300, 150, and 50 mg/m2/wk, respectively. One of the patients with late pharyngeal obstruction suffered repeated aspirations and expired without evidence of disease. No late DLT was observed in the patients who had received 10 mg/m2. Therapy was delivered as intended to almost all patients. Of the eight patients receiving 300 mg/m2/wk, one patient had one reduced weekly dose due to transient neutropenia. Of the 12 patients receiving 150 mg/m2/wk, one patient had reduced weekly dose once due to neutropenia and another patient had a delay in drug administration due to stridor. No drug dose modification was made in any patients in the lower doses. Radiation was delivered comprehensively to the neck and primary tumor in all patients and lasted 7 weeks in all patients except for one patient in the 150-mg/m2/wk dose group who had an 8-day treatment break due to skin toxicity.
Disease Status
Five patients died without evidence of disease. This included two patients who died of pneumonia, one patient who suffered pneumothorax during direct laryngoscopy, one patient with probable myocardial infarction 4 months after therapy, and one patient who died of an unknown cause 1 year after therapy.
Intracellular Tumor Incorporation of Gemcitabine
One of the patients who received 150 mg/m2 (patient no. 4) had a second tumor biopsy 24 hours after the first infusion of gemcitabine, in an attempt to estimate the duration of metabolite retention in vivo. No dFdCTP was detectable in this biopsy. It is noted that this patient’s first tumor biopsy had the lowest level of dFdCTP in this dose group.
Our preclinical data suggested that gemcitabine is a potent radiation sensitizer at concentrations well below those required to produce direct cytotoxicity as a chemotherapeutic agent. These preclinical predictions were supported in this study, which demonstrated that the combination of RT and gemcitabine, at doses as low as 5% of those used when this drug is applied as a chemotherapeutic agent, can produce a high complete response rate. However, this combination also caused severe acute mucositis and a high rate of late dysphagia at the dose levels of 50 to 300 mg/m2/wk. These findings suggest that this regimen of gemcitabine and RT does not produce selective sensitization of tumor compared with normal tissue. Severe acute mucositis is a frequent limiting toxicity in studies of chemoradiation for head and neck cancer. This has been observed in trials of RT concurrent with single radiosensitizing agents such as fluorouracil, bleomycin, mitomycin, hydroxyurea, and paclitaxel3,4,8,25 and in trials of radiation concurrent with multiagent chemotherapy.2,6,7 Confluent mucositis causing a transient inability to eat (grade 4 in the WHO grading system) is common in studies of chemoradiation or accelerated radiation alone and may be addressed with aggressive supportive measures, including gastric feeding tubes, adequate pain medication, antifungal agents, and intravenous hydration. We have graded skin and mucosal toxicity according to the RTOG grading system, which better addresses toxicities that are primarily caused by RT. The dose-limiting grade 4 acute mucositis in the RTOG grading system is defined as deep ulceration, hemorrhage, or necrosis, suggesting an unusually severe acute mucosal effect which should limit further dose intensification. We have observed several patients develop such a toxicity. For comparison, studies of a hyperfractionation regimen concurrent with cisplatin and fluorouracil chemotherapy in head and neck cancer reported no acute grade 4 mucosal toxicity (RTOG grading system), despite the high prevalence of confluent mucositis (grade 3).6 Long-term pharyngeal toxicity constituted the majority of the DLT in this study. This toxicity, particularly pharyngeal obstruction that could not be dilated and required permanent gastrostomy feeding, constituted morbidity that profoundly affected patients’ function and quality of life. Late morbidity, uncommon after chemotherapy alone, is frequent and should be detailed in reports of chemoradiation trials. Such details are rarely presented.2 We required a minimal follow-up of 4 months for each patient, to incorporate some of the risk of late toxicity into the decision making regarding dose escalation. While late radiation-related toxicity develops typically within 3 years of therapy, most of the cases with late pharyngeal toxicity in this study were apparent a few months after the completion of treatment. Had late toxicity been ignored, a higher dose level of gemcitabine than the dose we have reported could have been declared tolerable. A somewhat higher dose of gemcitabine might be tolerable compared with the doses reported here, using a regimen that incorporates periodic treatment breaks in both chemotherapy and RT.26 Few studies of gemcitabine concurrent with RT in sites other than the head and neck have been reported and few of these studies are ongoing. They include an early study in lung cancer in which full doses of radiation and weekly gemcitabine (1,000 mg/m2) were used, resulting in unacceptable pulmonary toxicity.27 Careful phase I studies in pancreatic cancer suggest that higher doses of gemcitabine may be delivered concurrent with RT at this site, compared with our experience in head and neck malignancies. Blackstock et al28 reported an MTD of gemcitabine 40 mg/m2 delivered twice weekly concurrent with radiation (50.4 Gy). Our group’s experience suggests that gemcitabine 600 mg/m2 delivered once weekly concurrent with 50.4 Gy RT is tolerable in pancreatic cancer29 (C. McGinn, personal communication, June 2000). It is unclear whether the duodenal mucosa has a higher tolerance to the radiosensitizing effects of gemcitabine compared with the oral/pharyngeal mucosa, which would allow the delivery of a higher drug dose. The rate of endoscopy and biopsy-proven CR was 67% to 87% in the patient cohorts that received gemcitabine 50 to 300 mg/m2/wk. This rate compares favorably with a CR rate of 42% to 47% reported in trials of radiation concurrent with multiagent chemotherapy for unresectable head and neck cancer, in which similar tumor response assessment methods were used.30,31 Acknowledging the small number of patients in this study, the heterogeneous populations, and lack of uniformity in the definition of unresectable disease, this response rate suggests significant clinical antitumor radiosensitization. However, taking into account the high rate of acute and late mucosal toxicity, it becomes apparent that the therapeutic ratio of the regimen that was used was not high. The doses in which significant clinical radiosensitization occurred, 50 to 300 mg/m2/wk, represent 5% to 30% or less of the MTD of gemcitabine when the drug is being delivered alone. This suggests that gemcitabine is one of the most potent radiosensitizers and confirms our preclinical data that showed that gemcitabine caused radiosensitization at concentrations that were well below cytotoxic levels.16 Recent reports of radiation recall reactions observed when gemcitabine was delivered soon after the completion of radiation32,33 underscore the radiosensitizing properties and suggest that caution should be practiced when RT and gemcitabine are delivered sequentially. To our knowledge, this is the first report of metabolite levels in tumor biopsy specimens from patients treated with gemcitabine. The nucleotide analog was identified in all biopsy specimens except for one of the two from patients receiving gemcitabine 10 mg/m2. Although the data suggest a trend of lower accumulation of dFdCTP as the dose of gemcitabine was decreased from 300 mg/m2 to 50 mg/m2, there were no significant differences between the nucleotide levels in patients treated at those dose levels. The levels of dFdCTP in the patients treated at 10 mg/m2 were considerably lower than the levels accumulated at higher doses. The levels of intratumoral dFdCTP seemed to correlate with the clinical results, in which significant radiosensitization was observed at gemcitabine dose levels of 50 to 300 mg/m2/wk, but no enhanced mucosal toxicity was observed at the dose level of 10 mg/m2/wk. The lack of significant difference in dFdCTP among tumors of patients receiving gemcitabine doses of 50 to 300 mg/m2 reflects in part the broad range of values for dFdCTP accumulation among patients receiving these doses, as well as the small number of patients studied. Considering the low doses used, the rapid deamination of gemcitabine in vivo, and the expected variability among patients in the anabolic and catabolic pathways for gemcitabine, such variation in dFdCTP accumulation is expected. Another possible explanation of these findings is that a saturation in gemcitabine phosphorylation occurs in tumor cells in vivo at relatively low doses. A saturation of dFdCTP in mononuclear cells of patients receiving various doses of gemcitabine was found when a dose of 350 mg/m2 was reached,21 and a saturation of dFdCTP accumulation was reported in leukemia and solid tumors in vitro.34,35 However, it is also possible that higher doses of infused gemcitabine may result in significantly higher intracellular dFdCTP concentrations. A study of tumor biopsies after a high dose of gemcitabine may address these possibilities.
This study provides information regarding the biochemical mechanism of gemcitabine radiosensitization. Our previous in vitro data suggest that radiosensitization with gemcitabine is due to depletion of deoxyadenosine triphosphate (dATP) through the inhibition of ribonucleotide reductase by the diphosphate metabolite, dFdCDP.16 Due to the small size of the biopsies, neither dATP nor dFdCDP, whose concentration is Locoregional failure is the most common pattern of failure after therapy of locally advanced head and neck cancer. A regimen of radiation and low-dose radiosensitizer such as gemcitabine has the potential to improve locoregional control without the systemic toxicity of full-dose chemotherapy. However, the combination of gemcitabine and RT will be effective and acceptable in the treatment of head and neck cancer only if a regimen with an improved therapeutic ratio can be found. Several promising preclinical studies can serve as the basis for better strategies of drug and radiation combinations, aiming at a more selective radiosensitization of the tumor. Examples include a preclinical model that suggests prolonged infusion, compared with bolus infusion of gemcitabine, might provide better antitumor effect and less toxicity.36 Fields et al37 reported a higher therapeutic ratio of twice weekly compared with once-weekly infusions of gemcitabine, in mice bearing murine oral squamous cell carcinoma receiving radiation concurrent with the drug. Milas et al38 have reported that maximal enhancement of murine sarcoma response was obtained when gemcitabine preceded RT by at least 24 hours, while the cellular radioresponse of the normal gastrointestinal epithelium was slightly protected when gemcitabine and RT were separated by 24 hours. The differential response created a time frame within which therapeutic gain could be maximized. This hypothesis was verified in a murine model, in which the highest therapeutic gain was achieved by administering gemcitabine 24 hours before the start of RT.39 A clinical study based on some of these preclinical models is underway at our institution.
Supported in part by National Institutes of Health grant no. CA 78554 and Eli Lilly Co.
1. De Vita VT,(ed): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, 1993, pp 574-630
2.
Vokes E, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18: 1652-1661, 2000
3.
Fu KK, Phillips TL, Silverberg IJ, et al: Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer. J Clin Oncol 5: 1410-1418, 1987 4. Gupta NK, Pointon RC, Wilkinson PM: A randomized clinical trial to compare radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol 38: 575-581, 1987[Medline] 5. 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]
6.
Brizel DM, Albers ME, Fisher RS, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338: 1798-1804, 1998
7.
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 8. Stefani S, et al: Hydroxyurea and radiation in head and neck cancer: Results of a randomized study. Int J Radiat Oncol Biol Physics 6: 1398, 1980 9. Haselow RE, et al: Radiation alone versus radiation with weekly low dose cis-platinum in unresectable cancer of the head and neck, in Fee WE, et al (eds): Head and Neck Cancer ( vol II ). Philadelphia, PA, BC Decker, 1990, p 279 10. Shanta V, Krishnamurthi S: Combined bleomycin and radiotherapy in oral cancer. Clin Radiol 31: 617-620, 1980[Medline]
11.
Hafty BG, Son YH, Papac R, et al: Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: Results of the Yale mitomycin randomized trials. J Clin Oncol 15: 268-276, 1997
12.
Wendt TG, Grabenbauer GC, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter trial. J Clin Oncol 16: 1318-1324, 1998
13.
Heinemann V, Hertel LW, Grindey GB, et al: Comparison of the cellular pharmacokinetics and toxicity of 2’,2’-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 48: 4024-4031, 1988 14. Heinemann V, Xu YZ, Chubb S, et al: Inhibition of ribonucleotide reduction in CCRF-CEM cells by gemcitabine. Mol Pharmacol 38: 567-572, 1990[Abstract] 15. Abbruzzese JL: Phase I studies with the novel nucleoside analog gemcitabine. Semin Oncol 23: 25-31, 1996 (suppl 10)
16.
Shewach D, Hahn TM, Chang E, et al: Metabolism of 2’,2’-difluoro-2’-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 54: 3218-3223, 1994 17. Shewach DS, Lawrence TS: Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 23: 65-71, 1996 (suppl 10) 18. Lawrence TS, Chang EY, Hahn TM, et al: Radiosensitization of pancreatic cells by 2’,2’-difluoro-2’-deoxycytidine. Int J Radiat Oncol Biol Phys 34: 867-872, 1996[Medline] 19. Lawrence TS, Eisbruch A, Shewach DS: Gemcitabine-mediated radiosensitization. Semin Oncol 24: 24, 1997 (suppl 7) 20. Rockwell S, Grindey GB: Effect of 2’,2’-difluorodeoxycytidine on the viability and radiosensitivity of EMT6 cells in vitro. Oncol Res 4: 151-155, 1992[Medline] 21. Abbruzzese JL, Grunewald R, Weeks EA: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9: 491-501, 1991[Abstract] 22. World Health Organization: Handbook for Reporting Results of Cancer Treatment (WHO Publication No. 48). Geneva, Switzerland, World Health Organization, 1979 23. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31: 1341-1346, 1995[Medline] 24. Schewach DS: Quantitation of deoxyribonucleoside 5’-triphosphate by sequential boronate and anion exchange high-pressure liquid chromatographic procedure. Anal Biochem 206: 178-172, 1992[Medline] 25. Hoffman W, Belka C, Schmidberger H, et al: Radiotherapy and concomitant weekly 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] 26. Humerickhouse R, Haraf D, Brockstein B, et al: Gemcitabine, 5-FU and paclitaxel with concomitant radiotherapy in recurrent or advanced head and neck cancer. Cancer Invest 18:32-33 (abstr) (suppl 1) 27. Vokes EE, Gregor A, Turrisi AT: Gemcitabine and radiation therapy for non-small cell lung cancer. Semin Oncol 25: 66-69, 1998 (suppl 9)
28.
Blackstock AW, Bernard SA, Richards F, et al: Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 17: 2208-2212, 1999 29. McGuinn CJ, Smith DC, Szarca CE, et al: A phase I study of gemcitabine in combination with radiation therapy in patients with localized, unresectable pancreatic cancer. Proc Am Soc Clin Oncol 17: 264a, 1998 (abstr)
30.
Wibault P, Bensmaine M, de Forni M, et al: Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous cell carcinoma of the head and neck: A phase II study of radiotherapy with cisplatin and continuous infusion fluorouracil. J Clin Oncol 14: 1192-1200, 1996 31. Chougule P, Wanebo H, Akhtar M, et al: Concurrent paclitaxel, carboplatin and radiotherapy in advanced head and neck cancer: A phase I study. Proc Am Soc Clin Oncol 17: 381a, 1998 (abstr)
32.
Burstein HJ: Side effects of chemotherapy: Case 1. Radiation recall dermatitis from gemcitabine. J Clin Oncol 18: 693-694, 2000
33.
Castellano D, Hitt R, Cortes-Funes H, et al: Side effects of chemotherapy: Case 2. Radiation recall reaction induced by gemcitabine. J Clin Oncol 18: 695-696, 2000 34. Van Haperen V, Veerman G, Boven E, et al: Schedule dependence of sensitivity to gemcitabine in relation to accumulation and retention of its triphosphate in solid tumor cell lines and solid tumors. Biochem Pharmacol 48: 1327-1339, 1994[Medline]
35.
Gandhi V, Plunkett W: Modulatory activity of gemcitabine on the phosphorylation and cytotoxicity of arabynosyl nucleotides. Cancer Res 50: 3675-3680, 1990 36. Veerman G, van Haperen R, Vermorken JB: Antitumor activity of prolonged as compared with bolus administration of gemcitabine in vivo against murine colon tumors. Cancer Chemother Pharmacol 38: 335-342, 1996[Medline] 37. Fields MT, Eisbruch A, Normolle D, et al: Radiosensitization produced by once versus twice daily gemcitabine. Int J Radiat Oncol Biol Phys 47: 785-791, 2000[Medline]
38.
Milas L, Fuji T, Hunter N: Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res 59: 107-114, 1999 39. Mason KA, Milas L, Hunter NR, et al: Maximizing therapeutic gain with gemcitabine and fractionated radiation. Int J Radiat Oncol Biol Phys 44: 1125-1135, 1999[Medline] Submitted June 19, 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
