GETICS, Yerba Buena, Tucumán, Argentina
Received 6 January 2003; revised 12 March 2003; accepted 28 April 2003
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Abstract |
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The purpose of this study was to determine the maximum-tolerated dose (MTD) and the antitumor activity of gemcitabine when administered in combination with concurrent cisplatin and radiotherapy in locally advanced cervical carcinoma (LACC).
Patients and methods:
Patients with histologically confirmed LACC (International Federation of Gynecology and Obstetrics IIBIVA), previously untreated, were eligible for entry in the study to receive radiotherapy and concomitant weekly chemotherapy with cisplatin 40 mg/m2 and gemcitabine at increasing doses levels until the MTD was found.
Results:
Thirty-six patients were included. Sixteen patients were entered at four dose levels. The MTD was 150 mg/m2 and the recommended dose of gemcitabine for phase II was 125 mg/m2. Twenty additional patients were entered at this level. Toxicity at the recommended dose was acceptable with grade 3/4 toxicity in <20% of patients. Thirty-five of thirty-six patients (97.3%) achieved an objective response, 32 (88.8%) a complete response (CR) three a (8.3%) partial response and one (2.7%) stable disease. At a median follow-up of 26 months, 28 of 36 patients (77.7%) are in sustained complete remission and seven of 36 (19.4%) have relapsed. The 3-year disease-free and overall survival rates are 67% and 72%, respectively.
Conclusion:
The association of cisplatin and gemcitabine with concurrent radiotherapy is active and well-tolerated in untreated LACC.
Key words: cervical cancer, cisplatin, concurrent chemoradiotherapy, gemcitabine
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Introduction |
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Radiotherapy and concurrent chemotherapy were shown to improve the control of pelvic disease and significantly increased overall survival (OS) rates in five randomized trial [26] and are the currently recommended treatment in locally advanced cervical cancer, following a National Cancer Institute (NCI) clinical announcement [7]. Cisplatin-based chemotherapy is the most widely used, but as yet no single drug or schedule is accepted as standard.
Among the schedules used in randomized trials, weekly cisplatin 40 mg/m2 with concurrent radiotherapy seems to have the better therapeutic ratio.
Gemcitabine is a drug with a modest single-agent activity in metastatic or recurrent cervical carcinoma [8, 9], but has shown definite radiosensitizing properties in preclinical trials [10, 11] including in human cervical carcinoma cell lines [12]. Gemcitabine has been tested with concurrent radiotherapy as a single agent in cervical cancer in two studies. In a phase I study gemcitabine was escalated until 150 mg/m2 with mild toxicity; the study was stopped and the maximum-tolerated dose (MTD) was not established [13]. In the second study, 19 patients with locally advanced disease were treated with a fixed dose of gemcitabine (300 mg/m2 weekly) and concurrent radiotherapy. Toxicity was mild and a complete response rate of 89% was reported [14].
Several preclinical and clinical studies have proven the synergy between cisplatin and gemcitabine [15, 16], and there are phase I studies testing the combination of cisplatin and gemcitabine with concurrent radiotherapy in pancreatic cancer and in non-small-cell lung cancer (NSCLC) that show different MTDs [1719].
The current study was designed to determine whether the addition of gemcitabine to a standard combination of weekly cisplatin 40 mg/m2 and concurrent radiotherapy is safe and feasible and to evaluate the efficacy of the two-drug combination in locally advanced cervical carcinoma.
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Patients and methods |
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Other eligibility criteria were as follows: leukocyte count >3.0 x 109/l; platelet count >100 x 109/l; hemoglobin 10 g/dl (after transfusion if necessary); serum creatinine level <2.0 mg/dl (177 µmol/l); serum bilirubin level <1.5 x upper normal limit at the institution where it was measured; and serum aspartate aminotransferase level <3 x upper normal limit at the institute where it was measured. All patients gave their written informed consent.
A complete physical examination with pelvic examination (PE) performed by a multidisciplinary team was required to determine the clinical stage according to the FIGO classification. Patients underwent chest X-ray, intravenous pyelography, computed tomography scan or ultrasonography of the abdomen and pelvis, sigmoidoscopy and cystoscopy.
Radiotherapy
Radiotherapy was administered to the whole pelvic region in 28 fractions for a total of 50.4 Gy followed 1 or 2 weeks later by intracavitary brachytherapy.
Pelvic radiotherapy was delivered by a four-field box technique (anteroposterior and posteroanterior parallel and two lateral fields) using a cobalt-60 unit at a skin source distance of 80 cm. Intracavitary radiation was delivered by tandem and ovoid applicators using afterloading cesium-137 sources in one application. The point A (a reference location 2 cm lateral and 2 cm superior to cervical external orifice) target dose was 3035 Gy to achieve a minimum of 80 Gy to point A combined external and intracavitary radiation. The irradiated volume was to include the whole uterus, the paracervical, parametrial and uterosacral regions, as well as the external iliac, hypogastric and obturator lymph nodes. The usual field borders for anterior and posterior fields were superior at the L5S1 interspace, inferiorly at the bottom of the obturator foramen or the lower extension of the disease and laterally 1 cm beyond the lateral margins of the bony pelvic wall. Lateral fields had the anterior border at the anterior edge of the symphysis pubis and the posterior border at the S2S3 interspace.
Radiotherapy was withheld if the leukocyte count was <2000/mm3, the platelet count <100 000/mm3 or in the event of severe (grade 4) radiation-related gastrointestinal or genitourinary toxicity. Blood transfusions were indicated any time during treatment if hemoglobin level decreased to <10 g/dl.
Chemotherapy
Cisplatin was administered as a 1-h i.v. infusion, once a week, at a fixed dose of 40 mg/m2 of body surface area. Then, gemcitabine was administrated in a 30-min i.v. infusion starting at 75 mg/m2 and escalated with a 25 mg/m2 increment in successive cohorts of three patients.
Chemotherapy was started on day 1 of radiotherapy and administrated 2 h before radiation weekly for 5 weeks.
Dose escalations and definitions of MTD and dose-limiting toxicity
Cohorts of three patients were evaluated at each dose level, and sequential dose levels were studied in the absence of dose-limiting toxicity (DLT). If one of three patients at any level developed treatment-related DLT, three additional patients were enrolled at that level before escalation. If no further cases of DLT were seen in the additional patients, then the dose level was escalated for the next cohort. Otherwise the escalation was stopped. If the incidence of DLT was >33% (two or three of three patients) at a given level, then dose escalation was stopped. There was no dose escalation in individual patients. The MTD was defined as the dose level below that which produced DLT in more than one-third of treated patients. Because this was a multi-institutional trial, additional patients could be entered at a different dose level only after the cohort of patients from the previous dose level had completed the treatment without experiencing DLT. Once the MTD was defined, additional patients were included at this level as a recommended dose, to validate the safety profile of the combination.
The DLT was defined as grade 4 hematological toxicity, grade 3 neutropenia with fever, grade 4 diarrhea, cystitis, rectitis and skin toxicity inside the radiotherapy field, any grade 3 non-hematological toxicity and any toxicity lasting >2 weeks, except for alopecia, nausea and vomiting.
Dose modifications
Toxicity was evaluated weekly during treatment and every 3 months thereafter according to NCI and Radiation Therapy Oncology Group grading scales.
Each course of chemotherapy was delayed until patients achieved an absolute neutrophil count 1.5 x 109/l and platelet count
100 x 109/l and had resolution of non-hematological toxicities to grade
1.
Patient evaluation
Patients were evaluated for response 4 weeks and 3 months after completion of radiotherapy and brachytherapy. The evaluation of responses consisted of physical examination and PE performed by the same multidisciplinary team who staged the patient. Additional tests and biopsies were performed if persistent disease was found on PE or this was non-conclusive. Complete response was defined as the disappearance of all gross lesions for 1 month after completion of radiotherapy. Partial response was defined as a >50% reduction of tumor size for 1 month after completion of radiotherapy and absence of new lesions. Stable disease was defined as the presence of tumor with <50% reduction of tumor size. Progressive disease was defined as the appearance of any new lesion during treatment or a >25% increase in size of local tumor. Once treatment ended, patients were evaluated for disease status and late toxicity every 3 months for the first 3 years and every 6 months for an additional 2 years.
Secondary therapy
Patients who had persistent tumor on completion of treatment were considered for salvage surgery if resectable. Surgery consisted of radical abdominal hysterectomy or pelvic exenteration. Patient with unresectable bulky disease underwent palliative treatment.
Statistics
Patient characteristics, the safety profile of the combined modality treatment, treatment administration and response rate by baseline patients characteristics were characterized with descriptive methods. The 95% confidence intervals (CIs) for the estimated response rate and survival rate were calculated by using the binomial distribution. Disease-free survival (DFS) and OS curves were calculated according to the KaplanMeier method.
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Results |
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Grade 3/4 non-hematological toxicity was not seen at the first two levels. At level III a grade 3 local toxicity (diarrhea, local mucositis and skin toxicity) was observed in two out of six patients, with no grade 4 toxicity at this level. At level IV all three patients had severe non-hematological toxicity, one developed grade 3 and two grade 4 diarrhea, one grade 3 skin toxicity and two grade 3 asthenia. All three patients required hospitalization at the end of treatment. There were no toxic deaths (Tables 2 and 3)
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Phase II study. The toxicity observed in the 20 additional patients was added to data of the other six patients included at that level in the first part of the study. Among the 26 patients (six from part I and 20 from part II) who were treated with 125 mg/m2 gemcitabine, only one patient had grade 4 neutropenia. Grade 3/4 nonhematological toxicity was observed in <20% of patients: diarrhea in five, local mucositis in three and skin toxicity in three patients (Table 4).
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Seven patients relapsed or progressed after treatment. Two partial responders progressed locally and five complete responders relapsed (two inside the radiation field, one in the lungs and two in the bones). One patient had a stroke 11 months after a complete remission and died with no evidence of disease.
At a median follow-up of 26 months, median DFS and OS were not reached. The 3-year DFS rate is 67% (95% CI 48% to 86%) and OS rate is 72% (95% CI 54% to 90%).
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Discussion |
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Five randomized phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiotherapy [26]. The patient population of these studies included women with FIGO stage IB2IVA cervical cancer treated with primary radiation therapy and women with FIGO stage IIIA disease found to have poor prognostic factors at the time of primary surgery. Although the trials vary in terms of stage of disease, dose of radiation and schedule of cisplatin and radiation, they all demonstrated significant survival benefit for the combined treatment, decreasing the risk of death by 3050%.
Three of these trials included patients with locally advanced disease [35]. Local control, DFS and OS were better in the combined treatment arms in all of them. Even though toxicity was significantly higher in the combination, there were no significant differences in the length of radiotherapy between combination arms and radiotherapy alone. Although the pelvic disease control was superior in the combined treatment arms, the local recurrence rate is still high (between 19% and 24%).
Gemcitabine has radiosensitizing properties but the exact mechanism of radiosensitization is not completely understood. Based on preclinical studies, several mechanisms have been proposed. Gemcitabine may inhibit repair of the DNA damage caused by radiation leading to increased cell death, it may also induce cell cycle redistribution, causing cells to accumulate in a more radiosensitive phase of the cell cycle. Finally, exposure to gemcitabine produces a dNTP (deoxynucleotriphosphate) pool perturbation (particularly dATP depletion) in the cell that in combination with cell cycle redistribution into the S phase impairs the repair of DNA damage caused by radiation [2025].
The interaction between gemcitabine and radiotherapy has been studied in pancreatic cancer [2634], NSCLC [3538], cervical cancer [13, 14], and head and neck cancer [3941]. Using standard doses of radiation, the MTD of gemcitabine was 300 mg/m2 weekly for cancer of the pancreas, lung and cervix and 75 mg/m2 once a week for head and neck tumors.
The combination of gemcitabine and cisplatin has been studied extensively and has shown a synergic interaction in several in vitro studies, although the mechanism remains unclear [16].
Concomitant radiation and gemcitabine have been tested in combination with cisplatin in pancreatic cancer [17], where MTDs were 400 mg/m2 for gemcitabine and 20 mg/m2 for cisplatin. This combined modality treatment was also analyzed in two phase I studies in NSCLC where MTDs were 100 mg/m2 and 12 mg/m2 for gemcitabine and cisplatin, respectively, in one study [18] and 150 mg/m2 and 20 mg/m2 for gemcitabine and cisplatin in the other [19].
In our study we have shown that the combination of cisplatin and gemcitabine can be safely administered with concurrent radiation.
In the first part of this study, we found the MTD of gemcitabine to be 125 mg/m2/week and the DLT to be due to both local and hematological toxicities. These phase I results were validated in the second part of the study where there was <20% of severe (grade 3/4) toxicity in 20 additional patients. This toxicity pattern seems to be the expected toxicity for a concurrent treatment (according to toxicity data from the combined treatment arms in randomized trials).
We obtained a high response rate, with 32 of 36 patients achieving a complete remission according to the clinical evaluation. This response rate is comparable with the one observed in other phase II studies of cisplatin and concurrent radiotherapy [42, 43]. However, only 33% of patients in these trials were FIGO stages IIIB or IVA.
This response rate was not reported in the five randomized trials mentioned above.
If we consider only the three randomized trials that included patients with locally advanced disease, our results are at least equivalents in terms of survival but the populations were different (Table 5). In the study by Rose et al. [3], the OS rate in the combination arms was 70% at 24 months; 46% of patients were FIGO stages IIIB or IVA. In the trial by Morris et al. [4], which included patients with FIGO stage IBIVA, the OS with a median follow-up of 43 months was 73% in the combination arm, but considering only patients with FIGO stages IIIB or IVA (30% of patients) the OS was 58%. Whitney et al. [5], with a longer follow-up (8.7 years), showed an OS rate of 55% in the chemoradiotherapy arm in a population of 38% of patients with FIGO stages IIIB or IVA.
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As in other trials, we observed that almost 50% of recurrences were outside the radiation field. In the study by Morris et al. [4] the local and distance recurrence rate were 19% and 14% in the combined modality arm. Whitney et al. [5] reported a local and distant recurrence rate of 24% and 17%, respectively. These data support the rationale for adjuvant chemotherapy after complete remission following chemoradiation in patients with locally advanced disease.
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Footnotes |
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References |
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