Departments of 1 Clinical Oncology and 2 Diagnostic Radiology and Imaging, Queen Elizabeth Hospital, Hong Kong
Received 10 October 2001; revised 28 January 2002; accepted 26 February 2002
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Abstract |
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To evaluate the efficacy and toxicity of combination gemcitabine plus cisplatin (GC) chemotherapy in metastatic or recurrent nasopharyngeal carcinoma (NPC).
Patients and methods:
Forty-four patients of Chinese ethnicity with metastatic or recurrent NPC received ambulatory GC chemotherapy every 28 days (gemcitabine 1000 mg/m2 days 1, 8 and 15; cisplatin 50 mg/m2 days 1 and 8). There were 40 male and four female patients with a mean age of 47.4 years. More than half (54.5%) of the patients had received either prior platinum-based chemotherapy and/or radiotherapy to target lesions.
Results:
There were nine complete responses and 23 partial responses in the 44 patients, achieving an overall response rate of 73% (78% for the 41 assessable patients). The mean duration of response was 5.3 months. Improved subjective symptom-control scores were found in 78% of patients with pre-existing symptoms, while 64% of patients experienced improved general well-being scores. Toxicity was mainly hematological: grade III/IV anemia, granulocytopenia and thrombocytopenia were found in 11, 37 and 16% of cycles, respectively. With a median follow-up of 17.2 months, 62% survived 1 year while 36% were alive and progression free.
Conclusions:
Gemcitabine plus cisplatin chemotherapy offers a satisfactory overall response rate, subjective patient improvement and safety profile for metastatic and recurrent NPC.
Key words: cisplatin, gemcitabine, phase II, metastasis, nasopharyngeal carcinoma, recurrence
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Introduction |
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Gemcitabine (2'-deoxy-2',2'-difluorocytidine monohydrochloride isomer) is a novel analog of deoxycytidine that inhibits DNA synthesis. Gemcitabine triphosphate, the active metabolite after cellular uptake, competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death. Experimental data, both in vitro and in vivo, suggest that the gemcitabinecisplatin (GC) combination with an appropriate schedule (close sequence or simultaneous exposure of the two compounds) should interact synergistically [16]. The mechanism of this synergism may be due to the ability of gemcitabine to potentiate cisplatin cytotoxicity by inhibition of cisplatin-induced DNA interstrand cross-link removal.
The favorable toxicity profile of the GC combination has recently been confirmed in studies for both non-small-cell lung cancer [17] and bladder cancer [18]. A recent report in combining GC in advanced squamous cell carcinoma of head and neck demonstrated an overall response rate of 22.7% among 22 patients [19]. The scheme used in that particular study was 50 mg/m2 cisplatin on days 1 and 8, with gemcitabine 800 mg/m2 on days 1, 8 and 15 every 4 weeks. Given the encouraging response rate and tolerable toxicity profile, we tested the GC combination in a phase II study for recurrent NPC with either distant metastasis and/or local recurrence to evaluate the end points of response and toxicity. Cisplatin was to be given on two separate days together with gemcitabine to maximize their synergistic effects and to allow the ambulatory delivery of treatment for outpatients.
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Patients and methods |
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Chemotherapy treatment
All patients were treated on an outpatient basis. Gemcitabine was administered at a dose of 1000 mg/m2 by intravenous (i.v.) infusion in 250 ml Normal Saline over 30 min on days 1, 8 and 15 of a 28-day cycle, preceded by bolus i.v. injection of 20 mg metoclopamide and 5 mg dexamethasone. Cisplatin 50 mg/m2 was given i.v. in 1 l Normal Saline over 2 h following gemcitabine infusion on days 1 and 8, again preceded by bolus i.v. injection of metoclopamide 20 mg, dexamethasone 5 mg and frusemide 20 mg. Patients received at least three cycles of chemotherapy before being formally assessed for response to determine whether they should complete a total of six cycles or more. Treatment discontinuation, however, could occur for disease progression or unacceptable drug toxicity or after achievement of best response. In responding patients, treatment could be continued for more than six cycles until there was no further clinical benefit from chemotherapy. Further local treatment, mainly to consolidate the locoregional recurrence by either radiotherapy or even surgery, was allowed if judged by the investigators to be clinically indicated.
The dose of both drugs was reduced to 75% if the WBC count was 2.03.0 x 109/l and/or the platelet count was 5099 x 109/l when chemotherapy was due. Both drugs were omitted if the WBC count was <2 x 109/l or the platelet count was <50 x 109/l. Cisplatin was deferred by 1 week if the creatinine clearance fell below 50 ml/min. Substitution by carboplatin was not encouraged for possibly enhancing myelosuppression. Growth factor support was neither planned nor encouraged. During chemotherapy, blood counts were performed during each visit. Serum biochemistry screening for liver and renal functions and creatinine clearance measurements were done at least once every cycle.
Outcome measurement
Tumor measurements were obtained before each cycle of therapy in patients with clinically apparent disease and every three cycles in patients who required radiographic studies. The radiological assessment for response was performed by two independent radiologists, and clinical assessment by two independent oncologists. Standard WHO criteria for response assessment were used: (i) CR was defined as the disappearance of all known disease on at least two observations not less than 4 weeks apart; (ii) partial response (PR) was defined as a decrease of 50% or greater in the sum of the products of the perpendicular diameters of measurable bidimensional lesions on at least two observations not less than 4 weeks apart, without any evidence of disease progression; (iii) stable disease was defined as a steady state of disease less than a PR but not regarded as progressive disease as defined below; and (iv) progressive disease was defined as a 25% or greater increase in the overall sum of measurable lesions as described above when compared with baseline, or the appearance of new lesions.
WHO grading for various organ toxicity was recorded in every cycle. In addition, patients were asked to score their subjective sense of general well-being and severity of prevailing symptom(s) such as cough, dyspnea, abdominal distending pain and headache, etc. This was carried out before every cycle and at the conclusion of the chemotherapy by a 10-point visual analog scale (VAS). A maximum score (10 points) on the VAS indicated a perfect subjective sense of general well-being or complete freedom from a specified symptom due to NPC recurrence, which prevailed before study entry, while a low score (zero) indicated the extreme reverse end of the spectrum. These simplified measurements were used as approximate surrogates for quality of life assessment.
Statistical analysis
The primary end point was the objective response rate. The secondary end points were toxicity, progression-free survival, overall survival and VAS scores. Duration of response was measured from the date of the first observed response to date of disease progression or last follow-up. The study was designed to enroll at least 40 patients, based on the null hypothesis H0 with a threshold response proportion of 0.35 and a desired alternative response proportion for rejection of H0 of 0.6. Using two-sided statistical hypothesis testing, the power was 0.9 for a type I error of 0.05. Survival was estimated by the KaplanMeier method and was measured from the date of study entry to the date of event or censor. The analysis was done according to the intention-to-treat principle. The statistical software SPSS for windows (version 9.0) was used for statistical analysis.
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Results |
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Chemotherapy toxicity
Hematological toxicity was the major dose-limiting toxicity as summarized in Table 2. WHO grade 3/4 anemia, neutropenia and thrombocytopenia were encountered in 11, 37 and 16% of all 210 cycles of chemotherapy. Although there was more than one-third incidence of significant neutropenia, only five episodes of neutropenic sepsis were documented (2.4% of the 210 cycles) even when growth factor was never used for marrow support. The median nausea/vomiting grading was 2 when hydroxytryptamine type 3 receptor (HT3) antagonists were also not routinely prescribed. Twenty-eight patients experienced a mean weight loss of 6.4% (range 0.816.3%) while 16 patients (36%) recorded a net gain or no change in body weight after chemotherapy. Twelve patients reported grade 1 and six a grade 2 peripheral neurotoxicity after chemotherapy, while no renal toxicity was recognized. Altogether, 34 hospital admissions were reported among 20 patients. Blood transfusion, fever or infection, and gastrointestional upset represented more than 80% of the indications for the hospitalization. One patient died of suspected reactivation of chronic hepatitis B 7 weeks from the end of chemotherapy.
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Patient scoring of well-being and symptom control
Patients were asked to score their sense of general well-being by a 10-point linear VAS before each cycle of chemotherapy and at the conclusion of all chemotherapy. This was meant to be a surrogate yardstick to measure the subjective impact of chemotherapy on their general well-being upon alleviating the prevailing symptoms and generating associated side-effects. Out of the 43 patients with complete scores, 27 patients (63%) recorded improved end-of-chemotherapy scores over pre-chemotherapy scores. Unchanged and worse scores were found in 11 (26%) and five (12%) patients, respectively. Twelve of the 27 patients with improved scores had at least a 3-point (out of 10) improvement. The symptom severity scores, measured in a similar fashion, were more specific in purely assessing how effective the chemotherapy had controlled the prevailing symptoms. Out of the 58 symptoms complained of by the patients at study entry, 45 (78%), six (10%) and seven (12%) symptoms were scored to become better, unchanged and worse, respectively, after chemotherapy. Twenty-seven of the 45 symptoms with improved scores had at least a 3-point (out of 10) improvement. The 58 symptoms complained of consisted of: cough (13), dyspnea (10), chest pain (3), abdominal discomfort (6), axillary mass discomfort (2), bone pain (6), headache (5), epistaxis (6), facial numbness (4), diplopia (2) and neck mass pain (1).
Survival data
At a median follow-up of 17.2 months (range 6.926.8) from start of chemotherapy, 27 of 44 patients were still alive with the majority having disease. The median overall survival was 15.0 months. The actuarial overall survival at 1 year was 62%, while 36% survived at 1 year progression free. The median time to progression (progression-free survival) was 10.6 months (95% confidence interval 8.512.6 months). The overall survival and progression-free survival curves are presented in Figures 1 and 2, respectively. A Cox regression model was used to examine the relevant prognostic factors mentioned above. Relapse >2 years from the end of primary radiotherapy was shown to be a universally favorable prognostic factor for the two survival end points studied, probably indicating a more slowly progressive disease.
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Discussion |
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Despite an initially satisfactory overall response rate and a rather high CR rate, the mean duration of response for responders was brief (5.3 months). Therefore, it may not be illogical to give consolidation or maintenance therapy to those who respond after the planned six cycles. This is especially beneficial to (i) patients with only locoregional recurrence, in whom additional aggressive local therapy may serve to eradicate the drug-resistant clones, and (ii) those with limited thoracic disease whose long disease-free survival after aggressive combined therapy has been reported [21]. Indeed, four of the nine patients with locoregional recurrence alone received a second course of radiation after chemotherapy. Two other similar patients underwent surgery (nasopharyngectomy and radical neck dissection, respectively) for residual disease after chemotherapy that had reduced the initial extensive recurrence to an operable status. On the other hand, four patients had received more than six cycles of chemotherapy (three patients received seven cycles and one patient eight cycles) upon documentation of response. Whether continuation of similar chemotherapy for two or three more cycles beyond the planned six will improve the duration of response remains to be investigated in view of possible cumulative toxicity and patients diminishing tolerance.
Apart from achieving a high percentage of responses, the other advantage of this regimen is the ease of administration in the outpatient setting. The chemotherapy schedule was designed such that it could be given as outpatient treatment, thus obviating the costs and stress of hospital stay for the patient. The close sequential infusion of gemcitabine followed by cisplatin is based on experimental evidence of synergism [16] obtained with such a schedule and the clinical observation of satisfactory results in the treatment of various solid tumors. This synergism was taken advantage of fully by fractionating the cisplatin dose to allow two occasions of such sequential infusion of the two drugs within one cycle of chemotherapy. Such scheduling of sequential infusion proved to be successful, as omission of day 1 or 8 infusions occurred in <10% of all cycles, although attenuation of the dose was inevitable in some of the cycles, leading to a mean RTD of cisplatin of 87%. The somewhat lower figure of 78% for the mean RTD of gemcitabine, due mainly to the 35% omission of the day-15 gemcitabine-alone infusion, can still be regarded as acceptable. In redesigning the strategy, one may consider giving a 21-day cycle consisting of only day 1 and 8 sequential infusion of GC but escalating the gemcitabine dose from 1000 mg/m2 to 1250 mg/m2. The possibility of continuing further chemotherapy as maintenance therapy beyond six cycles for responders should also be explored in future studies.
Finally, the fact that prior exposure (>6 months ago) to cisplatin-based chemotherapy did not adversely affect the probability of response may suggest the possibility of employing this combination regimen as second-line salvage chemotherapy for patients in whom first-line cisplatin-based chemotherapy has failed. The ease of administration and lack of significant toxicity positions itself favorably when compared with other second-line regimens such as ifosfamide5-fluorouracilleucovorin [22].
There was negligible neutropenic sepsis despite a 37% grade 3/4 neutropenia without growth factor support. Stringent follow-up, strict adherence to guidelines on antibiotic prophylaxis and appropriate dose reduction were the keys to achieving such a low morbidity rate. Routine prescription of potent antiemetics, which was not enforced mainly for economic reasons, might have further improved the emesis grading and possibly subjective general well-being. Other non-hematological toxicities of cisplatin, such as neurotoxicity or renal toxicity, were not significant problems with such a fractionated schedule. The mortality from suspected hepatitis B reactivation should have been prevented with the routinely available lamivudine prophylaxis [23] for all hepatitis B carriers to cover the chemotherapy period up to 6 weeks after chemotherapy.
Since chemotherapy for metastatic or recurrent NPC is still essentially a palliative treatment for the majority of cases, quality of life measurement besides response and survival is an important end point. Unfortunately, this was not documented in any of the NPC chemotherapy reports in the literature. Due to the absence of a fully validated Chinese version of such a tool for evaluation, attempts were made to use approximate surrogates. A 10-point VAS was used firstly to assess the severity of symptom(s) that prevailed at study entry, and this was tracked throughout the chemotherapy till the end. A separate assessment was performed to assess the patients own subjective rating of his/her general well-being before each cycle of chemotherapy, which was supposedly a rating discounted by the individuals chemotherapy side-effects. It was not surprising, therefore, to find a smaller proportion of patients feeling better (63% better scores) at completion of chemotherapy than the number of symptoms felt to be less disturbing to the patients (78% better scores). By the same token, the magnitude of absolute scores gained in symptom control was also higher: 60% of symptoms with improved scores had at least a 3-point increase while 43% of patients with improved well-being scores had such an increase. With all the inherent shortcomings of such an unrefined and unvalidated tool, the encouraging impression from the score profiles indicated that the chemotherapy generally conferred clinical benefits to the symptomatic patients and the chemotherapy side-effects had not negated a significant subjective gain in symptom control.
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Conclusion |
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Footnotes |
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References |
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