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
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ABSTRACT |
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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 34) 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 (4080 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 662), 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
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Introduction |
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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.
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Patients and methods |
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Chemotherapy
Gemcitabine was administered intravenously over 30 min once weekly, 12 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 46 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 KaplanMeier method [29].
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Results |
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Radiation dose-intensity was maintained: the median radiation dose delivered was 70 Gy (4080 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%, 6079% 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) 0.700.96] and three patients had no response. The median duration of the response was 21 months (range 256). 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 822). 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 662). PFS and OS are shown in Figure 1. The median PFS was 7 months (range 056) and the median OS was 13 months (range 662). 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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Discussion |
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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 6689% 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 34 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 34 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.
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FOOTNOTES |
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