Phase II trial of gemcitabine concurrent with radiation for locally advanced squamous cell carcinoma of the head and neck

J. Aguilar-Ponce1,*, M. Granados-García2, V. Villavicencio2, A. Poitevin-Chacón3, D. Green4, A. Dueñas-González5, Á. Herrera-Gómez2, K. Luna-Ortiz2, A. Alvarado1, H. Martínez-Said2, C. Castillo-Henkel6, B. Segura-Pacheco5 and J. De la Garza1

Departments of 1 Medical Oncology, 2 Surgery and 3 Radiation, Instituto Nacional de Cancerología, Mexico City; 4 Department of Hematology and Oncology, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Mexico City; 5 Unidad de Investigación Biomédica en Cáncer, Inst. Inv. Biomédicas, UNAM/Instituto Nacional de Cancerología, Mexico City; 6 Postgraduate Medicine Unit Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, México

Received 20 May 2003; revised 28 October 2003; accepted 31 October 2003


    ABSTRACT
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Concurrent chemoradiation is the current standard of treatment for patients with advanced unresectable head and neck squamous cell carcinoma (HNSCC). Due to the potent radiosensitizing properties of gemcitabine, we decided to assess its efficacy and toxicity with concurrent radiation in patients with advanced HNSCC.

Patients and methods:

From January 1997 to December 2001, 27 patients with locally advanced HNSCC (stage III, 37%; stage IV, 63%) were enrolled. All received a course of radiotherapy (70 Gy over 7 weeks) concurrent with weekly infusions of gemcitabine at 100 mg/m2 or 50 mg/m2.

Results:

All patients were assessable for toxicity and 26 for response. Severe mucositis (grade 3–4) was observed in 74% of patients (grade 4, 41%). Severe hematological toxicity was uncommon. Mild and moderate xerostomy was the most common late toxicity in 23 patients (85%). The median radiation dose delivered was 70 Gy (40–80 Gy), 25 patients (93%) received ≥80% of the intended dose. Gemcitabine dose intensity was ≥80% in only 13 (48%) patients. The rate of complete and partial responses were 61% and 27%, respectively, for an overall response rate of 88%. At a median follow-up of 13 months (range 6–62), the actuarial 3-year progression-free survival (PFS) and overall survival (OS) were 37% and 33%, respectively. The only variable associated with prolonged survival (P = 0.0001) was the degree of response. No difference was observed in response or toxicity with either gemcitabine 50 or 100 mg/m2.

Conclusions:

The concurrent use of radiotherapy and gemcitabine is effective but produces manageable severe mucositis in a high percentage of patients.

Key words: chemoradiation, gemcitabine, head and neck cancer, locally advanced


    Introduction
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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Head and neck cancer constitutes a heterogeneous group of malignancies which accounts for approximately 500 000 new cases worldwide each year, representing 3–5% of all cancers [1]. Radiation has been the standard treatment for locally advanced, unresectable cancer of the head and neck. These patients when treated with exclusive radiation have a 5-year survival rate of <25%, and most treatment failures occur locally or regionally within the irradiated fields [2]. Chemotherapy has been combined with radiation in an attempt to improve outcome; the most promising approach being the administration of chemotherapy concurrent with radiation [312]. A number of randomized studies have shown improved results when radiation was combined with concurrent cytotoxic agents compared with radiation alone despite increased toxicity of the combined arm, notably hematological and mucosal toxicities, which limited the ability to deliver full doses of radiation or the chemotherapeutic agents [48, 11, 12]. Although most trials of concurrent chemoradiation have used cisplatin in combination with 5-fluorouracil (5-FU), there is at present no evidence that this combination performs better than cisplatin alone [13]; thus, the optimal drugs, doses and schedules of concurrent chemotherapy and radiotherapy for head and neck cancer are not yet known.

Gemcitabine [2',2'-difluoro-2'-deoxycytidine (dFdCyd)] is a synthetic pyrimidine antimetabolite that interferes with DNA synthesis by inhibiting ribonucleotide reductase, hence reducing deoxynucleotide pools, competes with deoxycytidine triphosphate (dCTP) for incorporation into elongating DNA strands and halts DNA polymerization [1416]. Moreover, gemcitabine exerts anti-tumor activity in a number of murine solid tumors and human xenografts and frequently increases the levels of deoxycytidine kinase in tumor cells, a process that may enhance the ability of gemcitabine to increase the therapeutic ratio [1719]. This drug, either alone or in combination with cisplatin, has shown activity against head and neck carcinoma [2022]. Moreover, experimental data demonstrate that gemcitabine is among the radiosensitizers, one of the most potent in a number of cancer cell lines, including head and neck cancer cells [2327]. In 1997, Eisbruch et al. reported their preliminary results of a phase I study evaluating low-dose gemcitabine concurrently with standard radiation [28]. At a starting dose of 300 mg/m2/week, they found a remarkably high tumor control rate, although excessive mucosal toxicity led them to reduce the dose. Based on these data, we decided to use a third of the initial dose used by Eisbruch et al. (100 mg/mg2/week) in this study.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
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Patients eligible for the study had locally advanced disease [stages III, IVa and IVb according to the International Union Against Cancer (UICC) classification], histologically proven and measurable squamous cell carcinoma of the head and neck, without evidence of distant metastases at the beginning of the study. Patients were included in the study if they had unresectable disease or refused surgery. Tumors were defined as unresectable when surgical resection was considered technically not feasible or surgical resection with clear margins was estimated to produce significant organ and/or function loss. Patients who had received prior chemotherapy were not excluded. Eligibility criteria included Karnofsky performance status score ≥70%, age 18–75 years, estimated life expectancy of >3 months, adequate liver function tests [bilirubin <1.5 mg/dl and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevated ≤3 x normal range], bone marrow reserve (hemoglobin >10 g/dl, leukocyte count >4000/dl, platelet count >100 000/dl) and renal function (serum creatinine ≤1.5 md/dl and creatinine clearance >60 ml/min). A complete history and physical examination were performed before treatment, including chest radiograph, head and neck computed tomography (CT) and direct endoscopy to assess tumor extent.

Chemotherapy
Gemcitabine was administered intravenously over 30 min once weekly, 1–2 h before radiation, for 7 consecutive weeks at 100 mg/m2, in the first 15 patients and at 50 mg/m2 for the last 12 patients accrued. Dose reduction was decided after patient 15 died from presumed toxicity (gastric perforation) and as a recommendation of the Review Board.

Radiation therapy
Radiotherapy was delivered once daily, 5 days a week as a single 2 Gy fraction. The total dose administered to the macroscopic tumor and to potential sites of microscopic spread was 70 Gy, intended to be delivered over 7 weeks. Radiation was administered using standard lateral opposed 6 MV photon beams and an anterior low-neck field. CT-based treatment planning was performed to assure adequate target coverage and safety. The maximal dose to the spinal cord was restricted to 45 and 54 Gy to the brain stem and optic nerves, respectively.

Toxicity
Toxicity was evaluated weekly according to the World Health Organization (WHO) scoring system: any grade 4 toxicity warranted 1-week delay in the administration of both chemotherapy and radiation. Toxicities were recorded as the worst grade experienced by the patients during treatment.

Response criteria
Assessment of tumor response was performed 4–6 weeks after the end of treatment according to WHO criteria. Tumor response was evaluated by physical examination, head and neck CT and endoscopy with biopsies of the tumor bed. Complete response (CR) was defined as the disappearance of all evidence of disease by physical examination, CT and direct endoscopy. Partial response (PR) status was defined as a reduction of ≥50% of the product of the longest perpendicular diameters of measurable disease, with no progression at other sites of disease and no appearance of new lesions. Patients were considered to have no response if they did not achieve PR status and did not show progressive disease. Tumor progression was considered if there was an increase of ≥25% in the product of the longest perpendicular diameters of tumor lesions, or the appearance of new ones.

Statistical analysis
Data were summarized using frequencies, percentages, means, standard deviations and ranges. Overall survival (OS) and progression-free survival (PFS) time were analyzed using the Kaplan–Meier method [29].


    Results
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 Introduction
 Patients and methods
 Results
 Discussion
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Patient population
From January 1997 to December 2001, 27 patients were enrolled. Patient and tumor characteristics are summarized in Tables 1 and 2. All patients had squamous cell carcinoma and most tumors (93%) were well or moderately differentiated. All patients were staged as III (10 patients, 37%) or IV-a and IV-b (17 patients, 63%); no patient had IV-c disease. The most commonly involved primary sites were larynx in 12 patients (44%) and paranasal sinuses in 7 patients (26%). Sixteen patients (60%) had unresectable disease: the main reason for this was fixation or involvement of the carotid artery and/or trachea (nine patients); the remaining 11 patients either refused surgery or were believed to require extensive and morbid surgery. Radiotherapy was not previously delivered to any patient; moreover, two patients had previously received cisplatin-based chemotherapy without response.


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Table 1. Patient characteristics
 

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Table 2. Tumor characteristics
 
Toxicity
All 27 patients were assessable for toxicity; acute toxicities were common but manageable (Table 3). One death during chemoradiation was recorded—a gastric perforation 8 weeks after the initiation of treatment (gemcitabine 100 mg/m2). Mucositis and nausea/vomiting were the most common acute and serious side-effects; dysphagia and pain commonly were grade 2 (Table 3). Hematological toxicity was uncommon with grade 3–4 neutropenia occurring in 11% of patients; however, lymphopenia grades 3–4 was observed in 74% of patients. No events of thrombocytopenia and febrile neutropenia were recorded and no red blood cell transfusions were required. Allergic skin rash was observed in three patients, grade 1 radiodermatitis was observed in four patients and grade 2 in nine patients (Table 3). Gastric feeding tubes were required in seven cases due to inability to maintain nutrition orally.


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Table 3. Acute toxicity expressed as toxicity per patient
 
Acute toxicity was manageable in most cases; however, after 15 patients were treated, the high incidence of grade 3–4 mucositis (11/15 patients), resulting in radiotherapy interruption and one toxic death, prompted us to lower the dose of gemcitabine to 50 mg/m2.

Radiation dose-intensity was maintained: the median radiation dose delivered was 70 Gy (40–80 Gy). Twenty-five (93%) patients received ≥80% of the prescribed total dose of radiotherapy and most of them underwent the 7-week combined treatment with no interruptions; however, in eight patients (29%) radiotherapy was delayed, due to mucositis, for between 2 and 6 weeks, although no difference in response rates or survival was observed among them. In contrast, chemotherapy dose intensity was ≥80%, 60–79% and <60% in 13 (48%), seven (26%) and seven (26%) patients, respectively.

Late toxicity consisted of mild and moderate xerostomy observed in 16 (59%) and seven patients (26%), respectively. The patient who died from a second primary tumor (papillary thyroid cancer) developed a symptomatic esophageal stricture; however, it should be stated that no objective evaluation of swallowing function was performed.

Response to treatment
Only one patient was not assessable for response due to early toxic death. Sixteen of 26 evaluable patients (61%) achieved a complete response confirmed by CT and direct endoscopy, PR was observed in seven (27%) cases, for an objective response rate of 88% [95% confidence intervals (CI) 0.70–0.96] and three patients had no response. The median duration of the response was 21 months (range 2–56). Four of 16 patients who had achieved CR relapsed, three locally and one with pulmonary metastases. All seven patients with evidence of PR and the three patients with no response progressed locoregionally. The mean time to relapse or progression was 13.6 months (range 8–22). There was no correlation of response with tumor grade, nodal status, stage or primary site.

Outcome
The median follow-up time was 13 months (range 6–62). PFS and OS are shown in Figure 1. The median PFS was 7 months (range 0–56) and the median OS was 13 months (range 6–62). Local control was good, among the 16 patients with complete response, 13 (81%) remained free of local recurrent disease (recurrence at 8, 11 and 22 months). The only patient who developed distant metastases was free of local and regional relapse for 11 months. Currently, at a maximum follow-up of 62 months (median 1), nine patients (33%) were still alive and free of disease. Eighteen patients have died: 14 of disease recurrence or progression (including the one toxic death), two from unrelated intercurrent illnesses and two from a second primary (soft-tissue sarcoma and thyroid cancer, respectively). There was no significant difference in PFS and OS according to primary tumor site, stage or nodal status; however, a trend towards better survival was observed for stage: 50% of stage III patients were alive at 36 months compared with 28% for those in stage IV. The only variable that demonstrated a statistically significant association with longer survival was the response: median survival time for patients with CR, PR and NR was 40, 9 and 5 months, respectively (P = 0.0001) (data not shown).



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Figure 1. Progression-free survival (PFS) and overall survival (OS) at a median follow-up time of 13 months (range 6–62).

 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Although concurrent chemoradiation has become the standard of care for advanced and/or unresectable head and neck carcinoma patients, the best drug and schedule of chemoradiation remains to be determined. This trial was designed to test the efficacy and toxicity of a regimen of weekly gemcitabine concurrent with radiation in a group of patients with advanced HNSCC. Most of the patients were stage IV and considered unresectable by the referring surgeon: 60% had fixation of the primary tumor to the cervical spine or invasion to the trachea or common carotid artery and nine of them had N2 or N3 nodes. Despite these unfavorable patient characteristics, this regimen showed an encouraging tumor response rate and acceptable survival results. The efficacy of this schedule of gemcitabine, in which less than one-tenth of the usual systemic dose was administered, confirms its potent radiosensitization effect, which is further supported from pharmacokinetic data from Eisbruch et al. showing that a dose as low as 50 mg/m2/week is able to achieve adequate intracellular concentrations of the active drug metabolite, dFdCTP [30].

The results of this study in both efficacy and toxicity are comparable to those recently reported by Eisbruch et al. [30], a chemoradiation trial in which gemcitabine was administered at 300 mg/m2; however, due to late mucosal and pharyngeal toxicity, successive patient cohorts received de-escalated dose levels of gemcitabine at 150, 50 and 10 mg/m2. The most important finding emerging from that study was that the combination of radiotherapy and gemcitabine, even at doses 5% of those administered when the drug is used as a cytotoxic agent, produced a high response rate of 66–89% among the different cohorts. In our study, using gemcitabine at two dose levels (100 and 50 mg/m2), we achieved an overall response rate of 88%. This slightly different response rate could stem from the fact that we accrued a significant number of patients with primary tumors of the paranasal sinuses, which may carry a poorer prognosis [31].

A second trial, by Benasso et al. [32], used the combination of cisplatin, gemcitabine and radiation therapy. In this study, the incidence and severity of toxicity led the authors to stop accrual after 14 patients were treated; the chemotherapy regimen used was based on typical ‘systemic’ doses of both cisplatin and gemcitabine, explaining the development of severe hematological toxicity and mucositis in >80% of patients. Despite the unacceptable toxicity profile, this combination demonstrated high activity and good local control; however, only 21% of patients received the planned dose of gemcitabine, which supports its use in HNSCC as a radiation sensitizer rather than as a cytotoxic agent.

Severe acute mucositis is the most frequent limiting toxicity in studies of chemoradiation for HNSCC. We observed a significant rate of grade 3–4 mucositis (74%); however, it is lower than the one observed in most novel and more aggressive chemoradiation schedules and comparable with most previously reported studies [68, 33, 34]. Because a toxic death occurred, we intended to decrease mucosal toxicity by reducing gemcitabine dose to 50 mg/m2, as Eisbruch et al. suggested [30]. The rationale for this reduction was the earlier development and longer duration of acute mucositis in the cohorts receiving gemcitabine 300 and 150 mg/m2 as compared with the cohorts receiving 50 and 10 mg/m2, apparently with no negative effect on tissue radiosensitization. However, we observed no significant lessening of the toxicity profile or significant difference in response or local control with the lower dose. A possible explanation for this finding is that the concentration at which gemcitabine produces radiosensitization, and more specifically ribonucleotide reductase inhibition, is >1000-fold lower than the typical plasma concentrations of the drug, and there seems to be, in a phase I trial, no significant difference in plasma concentrations between 50, 150 and even 300 mg/m2 [35].

Most combined schedules of chemoradiation are associated with a high, sometimes unacceptable, systemic toxicity, particularly hematological toxicity, such as febrile neutropenia and sepsis [36, 37]. The most important theoretical advantage of using ‘low’ dose gemcitabine is maintaining a high response rate and radiosensitization with low systemic toxicity. In our study, and as also reported by Eisbruch et al. [30], hematological toxicity was mild, severe neutropenia was found only in 11% of patients and no events of febrile neutropenia were recorded. Likewise, grade 3–4 thrombocytopenia was not observed and no red blood cell transfusions were required. On the other hand, despite mucosal toxicity-induced delays, radiotherapy dose intensity could be maintained. An interesting observation was the presence of severe lymphopenia observed in 74% of patients. Radiation-induced lymphopenia and its possible deleterious effect on cancer patients should be addressed in future studies; in this regard, recent work from our institution demonstrates long-term immune dysfunction after radiotherapy to the head and neck area [38].

At a median follow-up of 13 months and a maximum of 62 months, the projected survival was 33%. Considering the advanced stage and poor prognosis of the enrolled patients, the concurrent use of radiotherapy and gemcitabine demonstrated an encouraging survival as compared to other chemoradiation trials, which range from 24% to 49% [39]. It is noteworthy that the low frequency of second primary neoplasms observed could be the result of the large proportion of patients with sinus carcinomas accrued, as this tumor type is characterized by its low ability to give rise to distant metastases.

In summary, gemcitabine at relatively low doses is a potent radiosensitizer effective in HNSCC patients; however, at the schedule used it produces a high incidence of mucositis and xerostomy. Further studies are needed to optimize the administration of gemcitabine with radiation. In particular, intensity-modulated radiation seems promising as it could improve the therapeutic index of this combination.


    FOOTNOTES
 
* Correspondence to: Dr J.-L. Aguilar-Ponce, Department of Medical Oncology, Instituto Nacional de Cancerología, San Fernando 22, Tlalpan 14080, México D.F., México. Tel/Fax: +52-5628-0435; E-mail: subedu{at}hotmail.com Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533–543.[CrossRef][Medline]

2. De Vita VT (ed.): Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott 1993; 574–630.

3. Vokes E, Kies MS, Haraf DJ et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000; 18: 1652–1661.[Abstract/Free Full Text]

4. 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 1987; 5: 1410–1418.[Abstract]

5. 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 1987; 38: 575–581.[ISI][Medline]

6. 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 1992; 327: 1115–1121.[Abstract]

7. 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 1998; 338: 1798–1804.[Abstract/Free Full Text]

8. 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 1999; 91: 2081–2086.[Abstract/Free Full Text]

9. Stefani S, Eells RW, Abbate J. Hydroxyurea and radiotherapy in head and neck cancer. Results of a prospective controlled study in 126 patients. Radiology 1971; 101: 391–396.[ISI][Medline]

10. Haselow RE. Radiation alone versus radiation with weekly low dose cisplatinum in unresectable cancer of the head and neck. In Fee WE et al. (eds): Head and Neck Cancer, volume II. Philadelphia, PA: BC Decker 1990; 279.

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 1997; 15: 268–276.[Abstract]

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 1998; 16: 1318–1324.[Abstract]

13. Adelstein DJ, Adams GL, Li Y et al. A phase III comparison of standard radiation therapy versus split course RT plus concurrent cisplatin versus RT plus concurrent cisplatin and 5-fluorouracil in patients with unresectable squamous cell head and neck cancer: an intergroup study. Proc Am Soc Clin Oncol 2000; 19: 1624.

14. Plunkett W, Gandhi V, Chubb S et al. 2',2'-Difluorodeoxycytidine metabolism and mechanism of action in human leukemia cells. Nucleosides Nucleotides 1989; 8: 775–785.[ISI]

15. Plunkett W, Huang P, Xu Y-Z et al. Gemcitabine: metabolism, mechanisms of actions, and self-potentiation. Semin Oncol 1995; 22 (Suppl 11): 3–10.

16. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anti-Cancer Drugs 1995; 6 (Suppl 6): 7–13.[Medline]

17. Hertel LW, Boder GB, Kroin JS et al. Evaluation of antitumor activity of 2',2'-difluoro-2'-deoxycytidine. Cancer Res 1990; 50: 4417–4422.[Abstract]

18. Braakhuis BJ, van Dongem AMS, Vermorken JB, Snow GB. Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (gemcitabine) against head and neck cancer. Cancer Res 1991; 51: 211–214.[Abstract]

19. Braakhuis BJM, Ruiz van Haperen VWT, Welters MJP et al. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur J Cancer 1995; 31A: 2335–2340.[CrossRef][ISI][Medline]

20. Guchelaar HJ, Richel DJ, van Knapen A. Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat Rev 1996; 22: 15–31.[ISI][Medline]

21. Catimel G, Vermorken JB, Clavel M et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994; 5: 543–547.[Abstract]

22. Garcia-Carbonero R, Hitt R, Castellano D et al. Phase II trial of cisplatin (C) and gemcitabine (G) in advanced squamous cell carcinoma of the head and neck (AHNC). Proc Am Soc Clin Oncol 1998; 17: 392a (Abstr 1511).

23. Lawrence TS, Chang EY, Hahn TM et al. Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys 1996; 34: 867–872.[ISI][Medline]

24. Hernandez P, Olivera P, Duenas-Gonzalez A et al. Gemcitabine activity in cervical cancer cell lines. Cancer Chemother Pharmacol 2001; 48: 488–492.[CrossRef][ISI][Medline]

25. Shewach DS, Hahn TM, Chang E et al. Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 1994; 54: 3218–3223.[Abstract]

26. Braakhuis BJ, van Dongem AMS, Vermoken JB et al. Preclinical in vivo activity of 2'2'-difluorodeoxycytidine against head and neck cancer. Cancer Res 1991; 51: 211–214.[Abstract]

27. Joschko MA, Webster LK, Groves J et al. Enhancement of radiation-induced regrowth delay by gemcitabine in a human tumor xenograft model. Radiat Oncol Invest 1997; 5: 62–71. [CrossRef][Medline]

28. Eisbruch A, Shewach DS, Urba S et al. Phase I trial of radiation concurrent with low-dose gemcitabine for head and neck cancer: high mucosal and pharyngeal toxicity. Proc Am Soc Clin Oncol 1997; 16: 386a (Abstr 1377).

29. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

30. Eisbruch A, Shewach DS, Bradford CR et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 2001; 19: 792–799.[Abstract/Free Full Text]

31. Fonseca E, Cruz JJ, Duenas A et al. Do the conventional clinicopathologic parameters predict for response and survival in head and neck cancer patients undergoing neoadjuvant chemotherapy? Tumori 1996; 82: 560–566.[ISI][Medline]

32. Benasso M, Merlano M, Sanguineti G et al. Gemcitabine, cisplatin, and radiation in advanced unresectable squamous cell carcinoma of the head and neck. Am J Clin Oncol 2001; 24: 618–622.[CrossRef][ISI][Medline]

33. Jeremic B, Shibamoto Y, Stanisavljevic B et al. Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol 1997; 43: 29–37.[CrossRef][ISI][Medline]

34. Adelstein DJ, Saxton JP, Lavertu P et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 2002; 20: 1405–1410.[Abstract/Free Full Text]

35. Shewach DS, Lawrence TS. Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 1996; 23 (Suppl 10): 65–71.

36. Urba SG, Forastiere AA, Wolf GT et al. Intensive induction chemotherapy and radiation for organ preservation in patients with advanced resectable head and neck carcinoma. J Clin Oncol 1994; 12: 946–953.[Abstract]

37. Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14: 838–847.[Abstract]

38. Verastegui EL, Morales RB, Barrera-Franco JL et al. Long-term immune dysfunction after radiotherapy to the head and neck area. Int Immunopharmacol 2003; 3: 1093–1104.[CrossRef][ISI][Medline]

39. Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control 2002; 9: 387–399.[Medline]