Abstract
OBJECTIVE To investigate the role of chronochemotherapy in the treatment of nasopharyngeal carcinoma (NPC).
METHODS Sixty NPC patients were randomly designated for induction chrono-chemotherapy plus radiotherapy (CC, 30 patients) or for induction routine-chemotherapy plus radiotherapy (RC, 30 patients). The differences in immediate response, side effects and changes in immunologic parameters between these two groups were analyzed. The chemotherapy regimen of the CC group consisted of cisplatin (DDP) 80 mg/rrPd, at 10:00~22:00 h, 5-flurouracil (5-FU) 750 mg/rrF/d1-3, at 22:00~10:00 on the next day and 5-CHO-FH4 (CF) 200 mg/nf/d starting at 10:00 h, and repeated every 14 days. The regimen of the RC group was the same as the CC group, with the delivery of cisplatin at a conventional rate and the CF via a continuous 24 h venous injection. The radiotherapy regimen was same in the two groups.
RESULTS The complete response rates for the CC and RC groups were 36.7% and 20.0%, respectively(P<0.05)and the response rates (complete response +partial response) were 96.7% and 73.3% respectively. The grade I and II myelosuppression was more serious in the RC group, with rates of 43.3% and 70% in the CC and RC groups (P<0.05) respectively. The differences in CD3, CD4, CD3/CD8, T+B +NK and CD8 cell levels between before and after treatment of the CC group were significant (P< 0.05), but differences in the RC group were not significant.
CONCLUSION The immediate therapeutic response is better with concurrent chronochemotherapy plus radiotherapy and there are fewer side effect compared to concurrent routine-chemotherapy plus radiotherapy.
keywords
The rationale of chronochemotherapy is based on the relationship between the pharmarcokinetics of anti-tumor drugs and the circadian rhythm, with the concept that anti-tumor drug administration can be delivered at the time of minimized cytotoxic side effects. If the anti-tumor drugs are delivered on an individualized chronochemotherapeutic basis, the efficacy of the response may be better with lower side effects. More and more clinical studies have shown that anti-tumor drugs such as oxaliplatin, 5-flurouarcil, Adriamycin, cisplatin and interferon are suitable choices for chronochemotherapy. Cisplatin plus 5-flurouracil rescued by CF (5-CHO-FH4) is the first-line regimen in the treatment of locally advanced nasopharyngeal carcinoma, but the severe toxicities of this regimen will restrict it’s utility in clinical practice. To lower the toxicities and improve the response of this regimen when combined with radiotherapy, we conducted a clinical trial of chronochemotharapy in nasopharyngeal carcinoma patients.
Materials and Methods
Patient characteristics
The criteria for the patients to be included in this study were: ①histologically proven nasopharyngeal carcinoma without previous anti-tumor treatment; ② age less than 70; ③ KPS > 50; ④the anticipated life-time greater than 3 months; ⑤with normal liver and renal function; ⑥ WBC > 4,000/ml and ⑦with no other treatment within 1 month. A total of 60 patients were entered into this study from March 2003 to March 2004. The patients were randomly assigned into an induction chronochemotherapy plus radiotherapy group (CC, 30 patients) or concurrent routine-chemotherapy plus radiotherapy group (RC, 30 patients) with envelop method. The characteristics of the patient cohort are shown in Table 1.
Characteristics of the patient cohort
Treatment
All patients received 2 courses of induction chemoradiotherapy, followed by radical radiotherapy.
The induction chemotherapy regimen was identical for each group, with a difference in delivery time. The regimen consisted of DDP 80 mg/m2dl, 5-FU 750 mg/ m2/d13 and CF 200 mg/m2/di.3, repeated every 14 days for 2 courses. The details for delivery of the chemotherapy drugs in the CC group were as follows: DDP 80 mg/m2, from 10:00 to 22:00 h on d,, 5-FU 750 mg/m2/d13, from 22:00 to 10:00 h on the next day, delivered by a Easypump LT, 5 ml/h (Flow Corporation Lake Forest, CA 92630 USA). CF 200 mg/m2/d].3 was started at 10:00 h with a routine rate. The drug delivery for the RC group was as follows: cisplatin, injected at a routine rate over dl and CF in du, all started at 10:00 h; the 5-FU was delivered by continuously intravenous injection from di to d3.
The radiotherapy treatment in the CC and RC groups was the same, with a regimen consisting of 70 Gy/7 week for the primary site, 60-70 Gy/6~;7 week for the treated neck area, and 50 Gy/5 week for the prophylactic neck area.
Criteria for the response and toxicity
The treatment response and toxicities were evaluated after the completion of 2 courses of induction chemotherapy. The treatment response was defined as complete response (CR), partial response (PR), steady disease (SD), progression disease (PD), according to the 2002 year WHO proposal. The toxicity was evaluated according to the CTC3.0 proposal.
All patients had an examination of immunological parameters before and after induction chemotherapy, including CD3/CD19, CD3/CD4, CD3/CD8, CD3/ CD 16+56 and CD4/CD8 cell levels, assessed by flow cytometry (FACSCalibur, BD Inc, USA).
Statistical analysis
All the data were processed by SPSS 10.0 software. P 0.05 was regarded as a significant difference.
Results
Treatment response
The overall CR rate for the CC and RC groups was 36.7% and 20.0% (P<0.05), respectively (Table 2). For Stage I/II patients, the CR rate for the CC and RC groups was 80.0% and 50.0%, respectively (P>0.05); For stage III/IV patients, The CR rate for the CC and RC groups was 28.0% and 15.4% respectively (P> 0.05); and the CR+PR rate was 96.0% and 69.2%, respectively (P<0.05, Table 3).
The treatment response in both groups (%)
The treatment response analysis according the stage
Changes in immune parameters
The changes in immunological parameters before and after treatment in each group are shown in Table 4. It shows that the immune function was improved after chemotherapy in the CC group, while there was no change in RC group.
The immunological parameters before and after chemotherapy in both groups (x±s)
Toxicity
Leucopenia was the most common blood toxic side effect, with an incidence of 43.3% in the CC group (all were grade I-II); this toxicity was more severe in the RC group, with an overall incidence of 80% (70% in grade I-II, 10.0% in grade III, P<0.05). The other blood toxic effects were also more severe in the RC group compared to the CC group (Table 5).
The blood toxic effects in both groups (n/%)
Other toxic responses seen in this study were alopecia, liver and renal dysfunction and phlebitis, with the incidence rate being higher in the RC group (Table 6).
Other toxicities in this study
DISCUSSION
The aim of chronochemotherapy is to deliver the antitumor drugs at a time when they have minimal toxicity to normal tissue, based on the relationship of the drug pharmarcokinetics and circadian rhythm. According to chronobiological and chronopharmacological theories, the circadian rhythm will influence the antitumor drug effects and the tolerance of normal tissue.™ Some studies have shown that the tolerated dose of normal tissue would increase 40% if the anti-tumor drugs were delivered under the guidance of the circadian rhythm, and therefore improve the treatment response. The largest multi-center clinical trial of chronochemotherapy was conducted by EORTC, which included 36 institutes in 10 countries. The results showed that a regimen consisting of 5-flurouracil, oxaliplatin and CF delivered based on chronochemo-therapeutic theory reached a good prognosis for metastatic colorectal cancer patients.[2]
Dihydropyrimidine dehydrogenase(DPD) is the rate-limiting enzyme in the pathway of catabolism of flurouracil. Therefore the activity of DPD impacts on the normal tissue toxicities of flurouracil and its analogs. The data from Kobayashi et al.[3] showed that there was a circadian rhythm in the activity of DPD in mouse liver with a peak at 16:00 and nadir at 04:00 h. The ratio of activity between peak and nadir times was about 7. Hecquet et al.[4] reported that the activity peak of DPD in human blood was at 22:00 to 02:00 h. The activities of cisplatin and various alkylating agents were associated with the level of glutathione (GSH). Several studies showed that the peak of GSH concentration in the blood of nasopharyngeal carcinoma patients was at 13:00 h; Hecquet’s study also indicated that the binding of cisplatin to plasma proteins also had its own circadian rhythm, with the peak time at 16:00 h. The concentration of free cisplatin would be lower if cispaltin was delivered at this time period and therefore caused less toxicity.[3]
Nasopharyngeal carcinoma is one of the most common head and neck cancers in China. The results from the literature [5,6) have confirmed that DNA synthesis in the nasopharyngeal carcinoma cells has a specific circadian rhythm, with a significant difference between the peak and nadir points. Also, some studies have shown that the interval between DNA synthesis in tumor and marrow cells of tumor-loaded nude mice was about 10 h. These data all indicate that nasopharyngeal carcinoma is a suitable candidate for chronochemo-therapy. To examine this hypothesis, we conducted this study. Our results showed that the total response rate was high in the CC group (P<0.05), but, in stage III/IV patients, this difference not significant, perhaps because of the small sample size. Our results are somewhat different from those of Yang et al.[7] Our findings indicate that, for nasopharyngeal carcinoma, the response rate with chronochemotherapy has some advantages over routine chemotherapy.
Chemotherapy, as well as radiotherapy, is a two-edged sword, i.e. it will kill normal blood lymphocytes along with the anti-tumor effect. Qu et al. [8]showed that the CD4, CD4/CD8, and CD56 cell levels were decreased after chemotherapy in locally advanced lung cancer, and this may be one of the main causes for poor prognosis, frequent recurrence and distant metastasis. Similar results were found by Hu et al.[9] in treating patients with head and neck squamous cell carcinomas. Zhou et al.[10] found that the T lymphocyte subsets changed after induction chemotherapy. These authors suggested that induction chemotherapy may reo cover the patients immune function which was inhibited by the tumor before treatment, whereas Li et al.[11] proposed that chemotherapy may play a double role on patient immune function, namely it may recover the immune function by killing tumor cells, or weaken the immune function by selectively killing the proliferating lymphocytes. Therefore, the immune function after chemotherapy was determined by the predominant effect of induction chemotherapy. Our data showed that, following chronochemotherapy, the immunological parameters of CD3, CD4, CD4/CD8 and T+B+NK were increased. This means that chronochemotherapy relieved the immune function inhibition, with an evident improvement in T lymphocyte function.
As to the toxicity, chronochemotherapy provides some advantages over routine chemotherapy, with a grade I~II blood-toxic rate of 43%, whereas with routine chemotherapy, the overall incidence was 80%, and 10% in grade III. Other toxicities were also more severe in the RC group, similar to the data of Price et al. [12] in treatment of locally advanced colorectal cancer.
Our study showed that, chronochemotherapy in the treatment of nasopharyngeal carcinoma, when compared to routine-chemotherapy, produced a better response with less toxicity and improved the patient’s immune function. The role of chronochemotherapy deserves further large-sample clinical studies.
- Received August 1, 2006.
- Accepted November 22, 2006.
- Copyright © 2006 by Tianjin Medical University Cancer Institute & Hospital and Springer
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