Abstract
OBJECTIVE To investigate the relationship between the therapeutic modality and prognostic factors for the patients with T3N0~1M0 nasopharyngeal carcinoma.
METHODS The clinical data from 127 cases of T3N0~1M0 nasopharyngeal carcinoma patients with initial treatment, during the period from January 4th, 2000 to November 12th, 2001, were retrospectively analyzed. The cases were divided into Group A with simple radiotherapy (90) and Group B with the radiation therapy combined with chemotherapy (37), based on various patients' conditions. In group B, inductive chemotherapy was conducted for 18 cases, inductive chemotherapy plus homochronous chemotherapy for 5 and homochronous chemotherapy for 14.
RESULTS The 5-year overall survival (OS) in the groups A and B was 73.4% and 72.3% respectively (P>0.05); the cancer-correlated survival (CCS) in the 2 groups was 76.4% and 72.3% respectively (P>0.05); the disease-free survival (DFS) In group A and B was 65.5% and 71.7% respectively (P<0.05). A multiple analysis showed that the mode of radiation therapy plus chemotherapy was a favorable independent impact factor for DFS.
CONCLUSION Chemotherapy plus radiotherapy can improve the DFS of patients with T3N0~1M0 nasopharyngeal carcinoma, but fails to prolong the survival time of the patients. The modality of chemotherapy plus radiotherapy is not the necessary choice in treatment of patients with T3N0-1M0 nasopharyngeal carcinoma.
keywords
The US South-West Co-operation (Intergroup 0099)[1] first reported that homochronous radiochemotherapy can improve the overall survival rate (OS) of local advanced nasopharyngeal carcinoma. These positive results have brought about a far-reaching influence for the treatment of patients with nasopharyngeal carcinoma of intermediate and advanced stage. In many cancer centers, especially in European and American countries, the mode of homochronous radiochemotherapy plus adjuvant chemotherapy has been applied as the standard therapeutic regimen. However there still exists a lack of agreement on effect of chemotherapy in the treatment of nasopharyngeal carcinoma, i.e., whether or not all patients with local advanced nasopharyngeal carcinoma need radiotherapy plus chemotherapy.[2] It is unclear that what type of patients with local advanced nasopharyngeal carcinoma can improve their long-term survival from the dual therapy. For those with early T3 stage, i.e., N (N0~1), local recurrence w as the main reason for treatment failure. The question as to whether or not the dual therapy is needed in these patients rarely has been reported in China or abroad. Thus in this study, the clinical data from 127 cases with T3N0~1M0 nasopharyngeal carcinoma treated in our center were summarized and analyzed, and the clinical strategy presented for the treatment of the T3N0~1M0 (Fuzhou 92' Staging) nasopharyngeal carcinoma patients.
MATERIALS AND METHODS
General data
The clinical data from 127 cases with T3N0~1M0 (Fuzhou 92’ Staging) nasopharyngeal carcinoma, who had been treated in our center at Sun Yat-sen University, during the period from January 4th, 2000 to November 12th, 2001, were analyzed in this study. The male-female ratio was 5.4:1 with the ages ranging from 16 to 74 (median age, 46). All the cases studied had been diagnosed by pathological examination to be undifferentiated and noncomifying nasopharyngeal carcinoma (WHO type I). The cases were divided into 2 groups: there were 90 cases in Group A (simple radiotherapy), with an median age of 46; in Group B (the dual therapy, i.e. radiotherapy plus chemotherapy), the median age was 47. The Fuzhou 92' Staging was utilized for the clinical staging of the cases. All the cases enrolled in the study received an MRI examination of the nasal pharynx before treatment. The related examinations for staging also included history, physical examination, blood and biochemical tests, chest film or chest CT scanning, and ultrasonic-B examination of the abdomen or abdominal CT scanning, etc. For clinical data from the patients in the 2 groups, see Table 1.
The clinical data from the patients with nasopharyngeal carcinoma in the two groups
Methods of treatment
Methods of radiotherapy
The methods of radiotherapy applied to groups A and B were the same. The radioactive source: The 60Co (1.25 mev) or a linear accelerator (6 mev) was used for external irradiation and an 129Ir brachytherapy afterloading device with a high dose rate was used for intracavitary irradiation. The methods of irradiation were as follows: the conventional fractionated radiation therapy was applied in both groups, with 2 Gy each time and 5 times each week. The range of irradiation included the nasal pharynx, base of the skull and neck. The pyrolytic of plastic face mask was applied for fixing the body position. The irradiation field was set up using the localization tomogram based on the CT scanning image, with the lead backup for protection of the normal tissue around the target area. The irradiation at the joint field of the bilateral faciocervix plus the anterior field of the inferior cervix, with a dose of 36 Gy, was applied in stage I of radiotherapy; in stage II, irradiation at the bilateral preauricular field with 34 Gy and the anterior field of cervix, with a dose of 14 to 24 Gy, were applied based on involvement of lymph nodes in the oropharynx and neck; or moved forward to the posterior boundary of the joint field of the faciocervix to avoid spinal irradiation, with 14 to 24 Gy, used the electronic boost irradiation at the hind neck with 14 to 24 Gy, then conducted irradiation at the anterior field of bilateral ears with 10 to 20 Gy. The exposure doses were as follows: the exposure dose at the nasopharynx was 67 to 80 Gy in the group A, with an average dose of 72.0 Gy, and the exposure dose at the neck was 50Gy to 74 Gy, with an average dose of 58.9 Gy; in group B, the nasopharyngeal irradiation dose was 68 Gy to 80 Gy, with an average of 72.7 Gy and the cervical exposure dose was 46 Gy to 76 Gy, with an average of 61.6 Gy. For the distribution of irradiation source, the exposure dose and time for radiotherapy in the two groups, see Table 2.
Comparison of radiotherapy and first therapeutic effect between the cases of the two groups
Chemotherapy
In group B cases, inductive chemotherapy was conducted in 18 cases (48.6%), the inductive plus homochronous chemotherapy in 5 (3.6% ) and homochronous chemotherapy in 14 (47.8%). The course of treatment for chemotherapy was as follows: 2 courses of treatment were used in 20 cases, 3 in 15 cases and 4 in 2 cases. The methods of chemotherapy included the PF regimen for combined chemotherapy which was adopted for all cases and the chemicals used included 5-FU 750 mg/m2 dl~5, DDP 20 mg~30 mg/m2 and q3W.
Evaluation of tumor residue
MRI/CT checkups on the nasopharyngeal and cervical areas were conducted for 101 patients at 3 months after completion of the radiotherapy and for 14 patients 4 to 5 months after radiotherapy. Rechecks using MRI/CT were conducted in 6 patients at 6 months after radiotherapy and a simple nasopharyngeal fiberscopic examination was performed on only 6 patients after radiotherapy. Based on physical examinations, nasopharyngeal fiberscopy and MRI/CT checkups, evaluation of the condition for the tumor residue in the nasopharyngeal and cervical areas were conducted 3 to 6 months after completion of radiotherapy.
Follow-up and statistical analysis
The ending date of our observations was March 20, 2006. During the period from January 4th, 2000 to November 12th, 2001, 127 cases with T3N0~1M0 nasopharyngeal carcinoma were treated in our center here. At 1,4, and 5 years after treatment, 4, 1 and 1 cases respectively failed follow-up. The overall follow-up rate was 95%. The follow-up time was 12 to 74.3 months and the median was 60.3 months. The follow-up time in the group A was 12 to 73 months and the median was 60.8 months, while in group B, the follow-up time was 14 to 74.3 months and the median 60 months. There was no statistical difference between the follow-up times of the groups by t test (P> 0.05). The total survival time was based on the last date of follow-up and the ending date of observation from the start of treatment to death by any disease. The cancer-correlated survival rate (CCS) time was based on the last date of follow-up and the ending date of observation from the start of treatment to death from this disease. The disease-free survival rate (DFS) time was based on the last date of follow up or ending date of observation from the start of treatment to the recurrence, metastasis and progression of tumors. The Kaplan-Meier method was used to calculate the survival rate, the Log-rank test was employed to compare the survival rates between the groups and Cox multiple-factor regression analysis was used for effects of various clinical factors on the CCS and DFS. SPSS 11.0 soft ware was applied to complete the statistical analysis.
RESULTS
Comparison of dinical data between the two groups
The clinical data included the age, sex, invasion of the carotid sheath, invasion of the hinder margin of the clivus, invasion of back cranial nerves, stage N and distribution of cervical glands, as well as naught difference between the distribution of the two groups (P> 0.05), see Table 1.
Comparison of the method of radiotherapy and initial curative effects between Ihe groups
There were 9 cases with residue of tumors in the 127 selected patients after initial treatment, among which 7 were those with nasopharyngeal residues and 2 with residues in the cervical glands. The total recurrence number was 28 cases during the follow-up period with a recurrence rate of 22%, among which 19 cases were those with recurrence in the nasopharynx and 9 with a recurrence in the cervical glands. The number of recurrent cases was 21 in group A (accounting for 23.3% the inter-group ratio) and there were 7 cases with recurrence in group B (accounting for 18.9% of the inter-group ratio). Nineteen cases with metastasis occurred during the follow-up period and the total rate of metastasis was 15%, among which 11 were osseous métastasés, 8 were métastasés in the liver, lung and other organs. Metastasis were found in 17.8% in group A and 8.1% in group B. In the cases with recurrent métastasés, the time of recurrent metastasis was 2 to 54 months and the median 21 months, among which the cases of recurrent metastasis within 2 years accounted for 78.6% and that within 3 years amounted to 88.4%. There was no statistical difference in the radioactive source, exposure dose, time of radiotherapy, the residual rate, relapse and metastasis, etc. of tumors after initial treatment between the two groups (P> 0.05), see Table 2.
The survival rate and the prognostic influencing factors
Comparison of survival between the groups
The 5-year overall survival rate (OS) in groups A and B was 73.4% and 72.3%, respectively (Fig.l) and the 5-year CCS rate in the two groups was 76.4% and 72.3% respectively (Fig.2). There was no statistical difference in comparison of the 5-year OS and CCS between the two groups (P>0.05). The DFS rate in groups A and B was 65.5% and 71.7% respectively (Fig.3). There was a significant difference in the DFS between the two groups (P=0.045).
The overall survival curve of the cases with stage T3N0~1M0 nasopharyngeal carcinoma in the two groups.
. The cancer specific survival curve of the cases with stage T3N0~1M0 nasopharyngeal carcinoma in the two groups.
The disease-free survival curve of the cases with nasopharyngeal carcinoma in the two groups.
Multiplicity influencing CCS
The clinical data including the age, sex, invasion of the carotid sheath, invasion of the hinder margin of the clivus, invasion of back cranial nerves, stage N, radioactive source, exposure dose and time and the methods and course of chemotherapy, etc., were examined by Cox regression analysis. The results showed that combined application of radiotherapy with chemotherapy was not the independent factor affecting the CCS, see Table 3.
Multivariate analysis by Cox regression of disease-free survival in 127 patients
Multiplicity affecting DFS
The clinical data, such as the age, sex, invasion of the carotid sheath, invasion of the hinder margin of the clivus, invasion of back cranial nerves, stage N, radioactive source, exposure dose and time, etc., were examined by Cox regression analysis, suggesting that combined application of radiotherapy with chemotherapy was a favorable independent factor affecting the DFS, see Table 4.
Multivariate analysis by Cox regression of disease-free survival in 127 patients
DISCUSSION
Although results produced from meta analysis and 6 centers based on clinical tests confirmed that synchronous radiochemotherapy did enhance the overall survival and disease-free survival rate of the patients with local advanced nasopharyngeal carcinoma,[3-6] no hierarchical analysis for local advanced nasopharyngeal carcinoma was conducted in these studies. To what degree did the synchronous radiochemotherapy improve the survival rate in the end? Recently results of a meta-analysis [6] from France showed that chemotherapy along with radiotherapy can improve the 5-year overall survival of patients with local advanced nasopharyngeal carcinoma by 6% (ascending from 56% to 62%) and can enhance the 5-year disease-free survival by 10% (ascending from 42% to 52%). The answer for whether or not synchronous radiochemotherapy is really needed for all the patients with stage III and IV nasopharyngeal carcinoma was negative,[7] and at present no positive answer has been obtained as to which patients can benefit from the therapeutic regimen. So it is still not clear whether the survival rate of the T3N0~1M0 nasopharyngeal-carcinoma patients would be improved with chemotherapy. Radiotherapy is the fundamental modality for treatment of non-distant nasopharyngeal carcinoma metastasis, and satisfactory results have been obtained in the patients with stage I and II nasopharyngeal carcinoma. With the rapid development of the technology of imaging, radiobiology and radiology, simple radiotherapy can significantly improve the local control and survival rate in patients with local advanced nasopharyngeal carcinoma. Recently a report of a meta-analy-sis from France and a summary from Hong Kong[6,8] showed that after simple radiotherapy of patients with stage III~IV nasopharyngeal carcinoma, the 5-year overall survival of the patients amounted to 56 to 58%. A special report on stage III nasopharyngeal carcinoma with MRI staging was issued in Hong Kong showing that the 5-year survival by simple radiotherapy was 76%. In addition, research on synchronous radiochemotherapy demonstrated that enhancement of the survival rate mainly relied on improvement of the local control rate and that the rate of distant métastasés was not obviously decreased. Thus the ability for chemotherapy to convert the increased local control rate into a beneficial survival rate was decreased.[7] These results suggested that radiotherapy can improve survival rates for localized intermediate and advanced nasopharyngeal carcinoma patients (N0/N1), especially for those with T3N0~1M0 tumors.
Localized recurrence was the major reason for failure in the treatment of early N (N0~1) patients with stage-T3 nasopharyngeal carcinoma. Hong, et al.[9] reported that the rate of local recurrence in patients with T3N0~1M0 nasopharyngeal carcinoma was 42% and the distant-metastasis rate was 19.7%. Therefore highdose external irradiation or hyperffactionated radiotherapy was applicable to increase the local control rate. In these patients, the local invasion by stage-T3 nasopharyngeal carcinoma was extensive but no, or very limited metastasis could be found. It is therefore of extreme importance to enhance the local control rate for these patients.
There were also some negative results in the combined radiochemotherapy. One was aggravation of the economic burden and venenous and adverse reaction. Also the long-term toxicity for the combined therapy was still uncertain. So the corresponding clinical strategy against various risk factors was needed, thus to reduce unnecessary over-treatment. This was the focus of our study.
Our results showed that local recurrence and distant métastasés occurred in the 127 cases. Local recurrence in the patients after simple radiotherapy was 23.3%, with a metastatic rate of 17.8%; the local recurrence of the patients after the combined chemoradiotherapy was 18.9%, with a metastatic rate of 8.1%. There was no statistical difference between the two treatment groups, although the metastatic rate in the combined radiochemotherapy group was somewhat lower than that in the group treated only with radiotherapy. These results suggest that chemotherapy on the base of radiotherapy can not effectively lower the rate of recurrence and métastasés, and thus improve the survival rate of these patients with T3N0~1M0 nasopharyngheal carcinoma.
It was shown from this study that the 5-year DFS was statistically higher (P=0.045) in the group with combined therapy compared to the simple-radiotherapy group (71.7% vs. 65.5% ). This suggests that chemotherapy can extend the DFS time for the patients with T3N0~1M0 nasopharyngeal carcinoma, which is in accordance with overseas reports.[10-14] However, the predominance of DFS fails to change into a predominance for improvement of the cancer-correlated survival and a decrease of the recurrence and distant métastasés. It was shown in this study that there was no statistical difference between the two groups in comparing the metastatic rate or the 5-year cancer specific survival rate. Possible reasons are as follows: a) The number of cases studied with synchronous chemotherapy was quite small (19 cases, among which 5 were the inducing chemotherapy plus synchronous chemotherapy and 14 synchronous chemotherapy), but the cases with inducing chemotherapy nearly accounted for a half of the totals (18 cases). The role of inducing chemotherapy on local advanced nasopharyngeal carcinoma was not confirmed at present. The only one report of inducing chemotherapy on improvement of the overall survival rate was reported by the Korean National University, other reports on effects of inducing chemotherapy on the overall survival rate were negative; b) T3N0~1M0 nasopharyngeal carcinoma belongs to a limited local advanced nasopharyngeal carcinoma, so these patients might fail to benefit from the modality of combined therapy. Therefore, the authors suggest hat the modality of chemotherapy plus radiotherapy is not the pre-requisite one for treatment of the T3N0~1M0 nasopahryngeal carcinoma. It should be noted that this study is only a retrospective analysis and further clinical prospective studies with random controls will still be needed for therapeutic decision-making for the patients with T3N0~1M0 nasopharyngeal carcinoma.
- Received June 19, 2006.
- Accepted July 17, 2006.
- Copyright © 2006 by Tianjin Medical University Cancer Institute & Hospital and Springer
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.