Japanese Journal of Clinical Oncology Advance Access originally published online on October 7, 2008
Japanese Journal of Clinical Oncology 2008 38(12):803-809; doi:10.1093/jjco/hyn104
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© The Author (2008). Published by Oxford University Press. All rights reserved
Chemoradiotherapy for Locally Recurrent Nasopharyngeal Carcinoma: Treatment Outcome and Prognostic Factors
Department of Radiation Oncology, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Japan
For reprints and all correspondence: Tatsuya Nakamura, Department of Radiation Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusaku, Nagoya 464-8681, Japan. E-mail: tatsuya.nakamura{at}nifty.com
Received July 22, 2008; accepted September 4, 2008
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Abstract |
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Objective: To evaluate the treatment outcome of patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with re-irradiation and chemotherapy.
Methods: Between 1991 and 2004, 36 patients with locally recurrent NPC received re-irradiation and chemotherapy. The median re-irradiation dose was 37.9 Gy; the median total dose of prior irradiation and re-irradiation was 104.4 Gy. The outcome is studied retrospectively and also evaluated the prognostic factors and toxicities.
Results: With a median follow-up of 40 months, 3-year overall survival (OS) was 58.3% and 3-year progression-free survival (PFS) was 25.0%. Patients aged <50 and of early stage at recurrence had a significantly better OS and PFS. Over Grade 3 of late toxicities were seen in patients received a total dose of >110 Gy.
Conclusions: Age and stage at recurrence were identified as prognostic factors for OS and PFS. Patients received external beam radiation therapy at a total dose of more than 110 Gy should be careful for severe late toxicities, and it is thought to be the optimal dose for recurrent tumor.
Key Words: re-treatment • locally recurrent • nasopharyngeal carcinoma • treatment outcome • prognostic factors
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Nasopharyngeal carcinoma (NPC) is generally sensitive to radiation; thus, radiotherapy is the first choice of treatment. With the advent of conformal radiotherapy and the use of combined chemoradiotherapy, the incidence of local failure after primary treatment of NPC has been decreasing. However, 15–58% of cases still develop local failures after primary radiotherapy (1–8). Several modalities have been reported to be useful for the treatment of locally recurrent NPC, including nasopharyngectomy (9), brachytherapy (10,11), radiosurgery, stereotactic radiotherapy (SRT) (12,13), intensity-modulated radiotherapy technique (IMRT) (14) or combinations of these methods. Re-irradiation still remains the most effective modality for salvaging nasopharyngeal recurrence. Based on the presence of certain prognostic factors, it is possible to identify the group of patients who has a high chance of local salvage. If this group of patients is treated curatively and local control is obtained, improvements in long-term survival can be expected. The current report presents the outcomes of re-treatment of recurrent NPC using chemoradiotherapy and examines the prognostic factors related to local control and long-term survival.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Between 1991 and 2004, 36 NPC patients (29 men, 7 women) with local recurrence after radical radiotherapy treated at Aichi Cancer Center Hospital were studied retrospectively. The patients’ median age was 55 years, with a range from 27 to 75 years. Histologically, 18 tumors were World Health Organization (WHO) I (squamous cell carcinoma or keratinizing carcinoma) and 18 tumors were WHO II or III (nonkeratinizing carcinoma or undifferentiated carcinoma). Patients were staged using nasopharyngoscopy, physical and neurologic examination, computed tomography (CT) scan or magnetic resonance imaging (MRI) of the nasopharynx and neck, chest X-ray and biochemical profile, including renal and hepatic function. From 2002 onwards, positron emission tomography (PET) has also been used for re-staging such patients. The disease at recurrence was staged according to the 2002 TNM staging system of the International Union Against Cancer (UICC) and is reported as rTxNx in this paper.
Twenty-three patients had recurrence at the primary site, six had recurrence in the regional neck nodes and seven had recurrence both at the primary site and the regional neck nodes. In case of the patients who had recurrence in the regional neck nodes, we recommended salvage operation at first but they refused. The median duration period between two irradiation treatments was 18 months (range, 4.2–182.3 months). The patients’ performance status was 0–2. The patient and disease characteristics are summarized in Table 1.
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Re-treatment
All 36 patients were also received chemotherapy. Usually, two or three courses of chemotherapy were given with re-irradiation. The first course of chemotherapy was given in the first day of re-radiotherapy, the second course was performed in 3–4 weeks and the third course was added as adjuvant chemotherapy. Figure 1 showed the schedule used for combining chemotherapy with radiotherapy. Informed consent about the schedule of chemoradiation and the merit and risk of this re-treatment including the possibilities of late toxicities was obtained from all patients.
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One course of chemotherapy consisted of continuous infusion of 5-fluorouracil (5-FU) at a dose of 700 mg/m2/24 h for 5 days (Days 1–5) and cisplatin (CDDP) at a dose of 50 mg/m2/24 h for 2 days (Days 6–7) from 1991 to 1996. Since 1997, nedaplatin (NDP) has been given at a dose of 130 mg/m2/6 h for 1 day (Day 6) instead of CDDP; patients with renal dysfunction were given carboplatin (CBDCA) instead of CDDP or NDP. In general, chemotherapy was performed at 4-week intervals. However, it was not given when serum creatinine levels were >1.5 mg/dl on the scheduled date of drug administration. When the white blood cell (WBC) count was <3000/mm2 or the platelet count was <100 000/mm2 on the scheduled date of drug administration, chemotherapy was postponed and radiotherapy was given instead. When the hematological data obtained 2 weeks after radiotherapy did not meet the inclusion criteria (WBC count
3000/mm2 and platelet count 100 000/mm2), chemotherapy was abandoned. When the WBC count decreased to <1000/mm2 or the platelet count decreased to <25 000/mm2 after chemotherapy, the doses of 5-FU and CDDP or NDP were decreased by 25% at the time of the next drug administration. When serum creatinine levels were >1.5 mg/dl after chemotherapy, the dose of CDDP or NDP was decreased by 25% at the time of the next scheduled drug administration. External beam radiation therapy (EBRT) was delivered with 6–10 MV linear accelerators. Until 1997, re-irradiation was performed by 2-dimensional plan, since 1998 we use 3-dimensional conformal radiotherapy. Gross tumor volume (GTV) was defined as any visible evidence of disease on physical examination or on any imaging modality, including CT, MRI and/or PET scans. The clinical target volume (CTV) was defined as the GTV plus a margin to cover microscopic disease, and the planning target volume was defined as the CTV plus a margin of 5–10 mm, depending on the proximity of critical structures, in order to compensate for set-up errors. All target volumes and their surrounding organs at risk were contoured by a clinician.
In most patients, the EBRT involved the dynamic rotational arc technique. A daily EBRT dose of 1.8–2 Gy was prescribed five times per week. In selected cases, additional boosts were planned using the non-coplanar beam method with multiple arc setting or an intracavitary brachytherapy boost through an original centering catheter using iridium (192Ir) thin wire; the details have been previously reported (15,16). The irradiation dose of brachytherapy was evaluated at the mucosal surface of tumor as the reference point, and a dose of 4–6 Gy per fraction was delivered, one to two fractions per week.
Twenty-six patients were treated by coplanar EBRT: the dynamic rotational conformal technique was used in 17 patients, the oblique opposing portal beam technique was used in eight patients and the electron beam alone was used in one patient. One patient was treated using a combination of EBRT (dynamic rotational conformal technique) and a gamma knife session, which was performed at another institute. In addition to EBRT, nine patients were also treated with a non-coplanar beam technique, using stereotactic multiple arc radiotherapy (SMART) (17). The dose of EBRT before SMART ranged from 0 to 40 Gy (median 21.6 Gy), and the dose of SMART ranged from 8 to 40 Gy (median 14.4 Gy). After EBRT, five patients received brachytherapy using 192Ir thin wire (15,16). The dose of EBRT before brachytherapy ranged from 24 to 40 Gy (median 34.2 Gy), and the dose of brachytherapy ranged from 10.3 to 23.6 Gy (median 15.6 Gy).
Three courses of chemotherapy were given to 10 patients, two courses were given to 23 patients and one course was given to three patients. Eight patients received 5-FU+CDDP, 23 patients received 5-FU+NDP and three patients received 5-FU+CBDCA.
The toxicity of giving this chemoradiotherapy was evaluated using the National Cancer Institute common toxicity criteria (NCI-CTC), version 3. During the treatment period, complete cell counts were measured at least twice per week and hematological and biochemical examinations were performed once per week. The total dose of irradiation was judged if there is no evident residual tumor by an ocular inspection, or the irradiation was stopped if over Grade 4 acute toxicities are seen.
The treatment response to this protocol was evaluated based on the results of pharyngeal fiber-optic endoscopy and CT or MRI performed 1 month after the completion of treatment. The effects of treatment on the cervical lymph nodes were also evaluated based on the results of CT, MRI or palpation according to the New Guidelines to Evaluate the Response to Treatment in Solid Tumors (RECIST) (18). After completion of the whole treatment protocol, the patients were followed every 4 weeks and during the first post-treatment year, every 2 months during the second and third post-treatment years, and once every 3 months after the third post-treatment year. Nasopharyngoscopy was performed at every visit to the outpatient clinic; CT or MRI was performed once every 3 months between the completion of treatment and the second post-treatment year and then once every 6 months. Furthermore, chest X-ray, liver ultrasonography, CT and bone scintigraphy were done to check distant metastases once every 6 months.
Several prognostic factors were evaluated on univariate and multivariate analyses. These factors included age (<50 versus 50 years), histological type, stage at recurrence, interval to recurrence (
18 versus >18 months) and re-irradiation dose of external beam radiotherapy (38 versus <38 Gy). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan–Meier method. The differences between the survival curves of both groups were analyzed using the log-rank test. The survival period was calculated from the initial day of chemoradiotherapy. OS was calculated from the initial day to the day of death. All relapses or deaths of any cause were defined as events related to PFS. The multivariate analyses of prognostic factors were performed using a Cox-regression model.
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RESULTS |
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The period of follow-up was ranged from 3.8 to 187 months (median: 40 months, average: 55 months), 12 of 36 patients remain alive. The scheduled radiotherapy course was completed in all patients. The re-irradiation dose ranged from 20 to 50 Gy (median: 38 Gy) to the nasopharynx, and from 18 to 55 Gy (median: 40 Gy) to the metastatic cervical lymph nodes. The sum of the initial and re-treatment radiation doses ranged from 86.4 to 160 Gy (median 104.4 Gy) to the nasopharynx, and from 89 to 110 Gy (median 117.2 Gy) to metastatic cervical lymph nodes.
The entire duration of chemoradiotherapy ranged from 22 to 78 days (median: 47.5 days). All patients completed radiotherapy. In three patients, chemotherapy was discontinued after the end of the first course due to bone marrow toxicity; 33 patients (91.7%) received more than two courses of chemotherapy. As the initial response to this protocol, 23 patients achieved complete response (CR), nine patients had a partial response (PR) and four patients had stable disease (SD). The response rate was 88.9% and the CR rate was 63.9%.
Survival and Local Control
Figure 2 shows the OS curve. The 3-year OS was 58.3%. Figure 3 shows the PFS curve. The 3-year PFS was 25.0%.
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Table 2 shows the site of subsequent recurrence after re-treatment. The number of patients with the tumor in nasopharynx alone was 23. Six (23%) patients were under control, 10 (43.5%) patients developed re-recurrence of nasopharynx, five (21.8%) patients developed neck lymph nodes metastases and distant metastases were seen in two patients.
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Prognostic Factors
The univariate analysis results dealing with prognostic factors are shown in Table 3. On univariate analysis, patients aged <50 years, with WHO type II or III histology, and rT1N0M0 or rT0N1M0 had better OS rates (P = 0.008, 0.046 and 0.015). Patients <50 years and with WHO type II or III histology had better PFS rates (P = 0.032, 0.047).
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The multivariate analysis results dealing with the prognostic factors are shown in Table 4. Patients <50 years and rT1N0M0 or rT0N1M0 showed a significantly better OS rate (P = 0.011, 0.006). Patients <50 years and with rT1N0M0 or rT0N1M0 also had a significantly better PFS rate (P = 0.022, 0.017).
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Treatment Toxicities
The hematologic toxicities that were above Grade 3 were leukopenia in eight patients (22.2%), neutropenia in eight patients (22.2%), anemia in two patients (5.5%) and thrombocytopenia in four patients (11.1%).
The late toxicities related to re-treatment are shown in Table 5. Two patients died of late toxicities. For Patient 1, 120 Gy of prior external radiotherapy was too much prescribed dose. The first irradiation dose was 70 Gy, and 6 months later 50 Gy was added because residual tumor was recognized, these were done in another hospital. Afterwards, the patient consulted our hospital. The patient had aggressive pain caused by recurrent tumor at that time and hoped strongly more treatment instead of explanation about possibilities of severe complication, so we decided palliative re-irradiation for relief of pain. The patient died of infection from necrosis of the nasopharynx and the cervical vertebrae. Patient 2 died as a result of bleeding from an ascending pharyngeal artery; this patient’s total EBRT dose was 104.7 Gy, with a brachytherapy dose of 12.4 Gy.
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Grade 2 dermatitis occurred in one patient whose total EBRT dose was 111.9 Gy.
Central nervous system (CNS) necrosis, especially of the temporal lobe, occurred in three patients, all of whom had Grade 3 involvement. The patients’ total doses were 112 Gy of EBRT, 113.2 Gy of EBRT and 127.2 Gy of EBRT with 30 Gy of gamma knife treatment. Two of these three patients also developed Grade 3 middle ear otitis. Dysphagia, trismus, diplopia and visual dysfunction of greater than Grade 2 were not seen. Over Grade 3, late toxicities were often seen more than 110 Gy at total dose of external beam radiation (P = 0.003).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Patients with NPC are good candidates for radiation therapy due to the difficulty of surgery and the tumor’s high sensitivity for radiotherapy. Chemoradiotherapy was thought to be the standard therapy for advanced NPC given the survival advantage reported by the Intergroup Study 0099 (19–21). Despite improvements in outcome related to the use of combined modalities and the improved PFS associated with advances in radiation treatment techniques, local recurrence is still an important issue in patient care. Local recurrence has been reported to be 15–58% (at 5 years), and it still remains a serious issue in the management of patients with NPC (1–8). The prognosis following local relapse is very poor without re-treatment (1,22). Salvage additional radiotherapy with or without chemotherapy is reported to be advantageous for local control and survival (4,22–26). Surgery for recurrent NPC has been attempted with some success, but the best candidates for salvage surgery have not been defined and the technique is complicated (27,28).
In the literature, the 5-year survival after re-irradiation, with or without neck dissection, ranges from 5.8 to 41%, and local control ranges from 14 to 61% (1,2,22–26,29–34). In the present study, the 3-year local OS was 58.3%, and the PFS was 25.0%.
The incidence of severe late toxicities after re-irradiation has been reported to the range from 6 to 45% (1,22,24–26,31). Fatal toxicity, mainly the incidence of fatal nasopharyngeal hemorrhage, has been reported to be 2–3.7% (25,31). Teo et al. (32) reported that the incidence of temporal lobe brain necrosis was 20.4%. In the present study, the rate of fatal toxicity was 5.6% and that of CNS damage was 8%. These results appear to be reasonable compared with those reported by other studies. Thus, the use of chemoradiotherapy, involving a combination of high-dose platinum-based chemotherapy and EBRT, which primarily involved dynamic rotational conformal techniques in the present study, could become one of the treatments of choice in patients with locally recurrent NPC.
The histological type is an independent prognostic factor for the local PFS rate, as well as survival. Hwang et al. (30) showed that patients with undifferentiated carcinoma (WHO III) had a significantly better 5-year PFS rate and better survival than those with squamous cell or keratinizing carcinoma (WHO I) and nonkeratinizing carcinoma (WHO II). Pryzant et al. (25) also reported that patients with lymphoepithelioma had a significantly better survival than those with squamous cell carcinoma, though histology was not predictive of local control. The result of the present study, in that WHO type II or III is not associated with a better OS on multivariate analysis than WHO type I, is not clear.
Several researchers have reported that advanced clinical stage is correlated with poorer local control. Most studies have shown better local control and survival for patients with disease stage T1–T2 than stage T3–T4. Lee et al. (1,4,26,29,31–34) reported that patients with rT1–T2 disease had a significantly higher salvage rate. In the present study, the clinical stage proved to be an independent prognostic factor for local control, in accordance with previous reports.
In re-recurrence pattern, distant metastasis is not often seen, and later lymph node metastasis should be careful even if local lesion is under control after re-treatment.
Using the IMRT, dose escalation could be achieved without increasing the dose to organs at risk, such as the temporal lobe, the internal ear, the optic pathway and the brain stem. Thus, for re-irradiation for NPC, especially for recurrent primary lesions, IMRT is better than conventional 3-dimensional planning (14). In our institute, helical tomotherapy was installed in June 2006. Thus, treatment planning for patients with recurrent NPC now involves 45–50 Gy using IMRT.
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CONCLUSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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In the present study, chemoradiotherapy was found to be an effective treatment for locally recurrent NPC based on clinical outcome and feasibility. Although the cohort of patients was small, and the follow-up period was short, the clinical results were comparable to those previously reported. Severe late toxicity is seen with total radiation doses (sum of initial and re-treatment radiation doses) of more than 110 Gy; it may be the upper limit dose that can be given, and it is thought to be the optimal dose for recurrent tumor.
Conflict of interest statement
None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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