Non-metastatic stage IV nasopharyngeal carcinoma patients: analysis of the pattern of relapse and survival

Radiotherapy and Oncology 72 (2004) 71–77 www.elsevier.com/locate/radonline

Non-metastatic stage IV nasopharyngeal carcinoma patients: analysis of the pattern of relapse and survival ¨ zyar*, Murat Gurkaynak, Ferah Yildiz, I. Lale Atahan Enis O Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey Received 7 April 2003; received in revised form 13 February 2004; accepted 25 February 2004 Available online 10 April 2004

Abstract Background and purpose: The objective of this study is to analyze the mode of recurrence patterns and survival of our 96 non-metastatic stage IVA and IVB nasopharyngeal carcinoma (NPC) patients. Patients and methods: A total of 234 previously untreated, histologically confirmed non-metastatic NPC patients were treated in our department between 1993 and 2001. Among them 96 patients (41%) were staged as IVA or B disease. All patients were uniformly staged using the fifth edition of AJCC/UICC staging system. There were 76 male and 20 female patients. Their ages ranged from 9 to 72 years (median age: 43.5). Histopathological diagnosis was WHO 2 and 3 in 89 (93%) patients. All patients were treated with external radiotherapy and 77 out of 96 patients (80%) with stage IV disease received either concomitant or neoadjuvant cisplatin based combined chemotherapy regimens. Median follow-up time was 30 months (range: 4 – 101 months). Results: At the time of this analysis, 60 (62%) patients were alive and 48 of them were free of disease. Local recurrence rate was found to be significantly higher in stage IVA patients (28 vs. 11%, P ¼ 0:02) and distant metastasis rate was significantly higher in stage IVB patients (40 vs. %8, P ¼ 0:0001). The 3 year overall (OS), disease free (DFS), loco regional relapse free (LRRFS) and distant metastasis free survival (DMFS) rates were 71, 74, 77 and 94% for stage IVA and 60, 46, 77 and 58% for stage IVB patients, respectively. Three year LRFS rates for stage IVA and IVB were 77 and 89%, respectively ðP ¼ 0:1Þ: Age older than 40 years was found to be statistically significant adverse prognostic factor both for OS ðP ¼ 0:01Þ and LRRFS ðP ¼ 0:005Þ in univariate analysis. Advanced N status was an unfavorable prognostic factor both for OS ðP ¼ 0:03Þ; DFS ðP ¼ 0:0004Þ and DMFS ðP ¼ 0:0003Þ: DMFS was adversely affected by the presence of cranial nerve palsy at diagnosis ðP ¼ 0:01Þ; advanced T status ðP ¼ 0:03Þ and advanced N status ðP ¼ 0:0003Þ: In univariate analysis treatment with chemotherapy was found to be an unfavorable prognostic factor for DMFS ðP ¼ 0:02Þ: According to the multivariate analysis, older age (.40 year of age) was a significant independent prognostic factor for OS ðP ¼ 0:02Þ; DFS ðP ¼ 0:05Þ and LRRFS ðP ¼ 0:01Þ: Patients with advanced N status had worse OS ðP ¼ 0:03Þ; DFS ðP , 0:0001Þ and DMFS ðP ¼ 0:07Þ: Patients treated with chemotherapy as an adjuvant to radiotherapy had tended to have a better DFS ðP ¼ 0:04Þ: Conclusions: The local relapse was the major cause of failure in patients with stage IVA disease, and distant metastasis was the predominant treatment failure in stage IVB patients. While stage IVA patients may benefit more intensive local treatment strategies, stage IVB patients definitely need more systemic treatment. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Nasopharyngeal carcinoma; Stage IV; Recurrence patterns

1. Introduction The TNM staging system of International Union against Cancer (UICC) and American Joint Committee on Cancer (AJCC) for nasopharyngeal cancer (NPC) patients has been revised extensively in 1997 due to the drawbacks of the 4th edition [14]. An important drawback was the uneven patient number distribution among the stages. Especially, patients * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.02.012

with N2, N3, T4 and M1 disease accumulated in stage IV in most of the series and it was shown that these patients had very different prognosis in the literature [30]. The 5th edition of the TNM system provided a more even distribution of patients and several reports—including ours—validating the new staging system have been published in the literature [8,10,12,24]. Moreover, the 6th edition of the UICC staging system was very recently published with a minor revision in NPC staging system [27].

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The 5th edition of staging system divided stage IV patients into three groups as IVA, IVB and IVC. While stage IVA included T4 patients, stage IVB patients included N3 and stage IVC included M1 patients [14]. Despite all these patients were grouped as stage IV, their mode of recurrence and survival may differ substantially and this may necessitate further tailoring their treatment. However, pattern of recurrence and survival data for stage IVA and IVB subgroups is very scarce with new staging system and to the best of our knowledge, there are only few studies in the literature which gave survival rates for stage IVA and IVB patients, separately [15,16]. Thus, more data on recurrence pattern and survival was needed for these poor prognostic subgroups to generate new treatment strategies. The objective of this study was to analyze the mode of recurrence patterns and survival of our 96 non-metastatic stage IVA and IVB NPC patients treated at our department between 1993 and 2001.

2. Materials and methods A total of 234 previously untreated histologically confirmed non-metastatic NPC patients were treated with definitive radiotherapy and with or without chemotherapy in our department between 1993 and 2001. While there were 138 (59%) patients with stage I– III disease, 96 (41%) of these patients were either stage IVA or B. All patients were uniformly staged using the fifth edition of AJCC/UICC staging system with physical examination, nasopharyngeal endoscopies and tumor biopsy, chest radiograph, complete blood count, blood chemistry, CT and/or MRI scan of the nasopharynx and neck, abdominal ultrasonography and bone scan. There were 76 male and 20 female patients. Their ages ranged from 9 to 72 years (median age: 43.5). Histopathological diagnosis was WHO 2 and 3 in 89 (93%) patients. All patients were treated with external radiotherapy using 6 MV photons generated from linear accelerators. Conventional treatment planning was used in all patients. Patients were treated with opposing lateral fields including nasopharynx and upper neck. An anterior field was used to treat lower neck with a laryngeal block. Palpable neck nodes were boosted with electron beams of appropriate energy (8 –15 MeV). Daily fractionation was between 1.8 and 2 Gy, five fractions per week. External radiotherapy doses to the nasopharynx were between 53 and 71.6 Gy (median: 69 Gy) and doses to the nodal disease varied between 49 and 72 Gy (median: 66 Gy). Total doses to the nasopharynx were reduced by 10% in patients less than 12 years of age. Intracavitary high dose rate (HDR) Ir-192 brachytherapy (BRT) was applied in 76 (79%) patients. BRT was not applied in 20 patients due to the following reasons; (i) unavailability of the unit, (ii) patients below 18 years, (iii) patients receiving accelerated hyperfractionated ERT, and (iv) refusal of BRT. The prescribed BRT dose was

12 Gy in three fractions over 3 –5 days to 1 cm above the midpoint of the Ir-192 source [25]. The distance between BRT prescription point and nasopharyngeal mucosa was 0.5 cm at the center of the balloon. Cisplatin based either concomitant or neoadjuvant combined chemotherapy regimens were administered in 77 (80%) patients. Details of chemotherapy, agents used and dose intensity were given in Table 1. Median follow-up time was 30 months (range: 4 – 101 months). None of the patients were lost to follow-up. 2.1. Clinical end points Patients were evaluated clinically and radiologically every 3 months in the first 2 years, every 4 months in the third year and every 6 months thereafter. A thorough physical examination in addition to routine complete blood counts, serum biochemical analyses, chest X-Ray, MRI scans of nasopharynx and neck was performed in every follow-up visit. In case of suspected local recurrence, nasopharyngeal endoscopies with random and suspected lesion biopsies were also performed. When there was a suspicion of distant metastases in abdomen, abdominal ultrasonography or CT scans were routinely performed and in case of bone metastases, bone scintigraphy was the study of choice. Toxicity was assessed according to Radiation Therapy Oncology (RTOG) criteria. At the time of follow-up, patients were classified as no evident disease (NED) if they were without any suspicion of tumor recurrence or persistence, alive with disease (AWD) if any signs of local or distant recurrence were detected, dead of disease (DOD) if nasopharyngeal cancer related death occurred and dead of other causes (DOC) if death occurred due to other causes. Loco regional recurrence free survival (LRRFS) and distant metastases free survival (DMFS) was defined as time of the occurrence of the event after treatment as loco regional recurrence for LRRFS or distant metastases for DMFS. Beside LRRFS, local relapse free survival (LRFS) was defined as the time from the occurrence of the local recurrence alone after treatment. Overall survival (OS) was defined as time of death due to nasopharyngeal cancer or other causes after the treatment. Table 1 Details of chemotherapy in stage IV patients Mode of treatment

Number of patients

%

RT alone CCRT NAC þ RT NAC þ CCRT NAC þ CCRT þ ADC

19 28 21 27 1

20 29 22 28 1

CCRT, concomitant chemo-radiotherapy (cisplatinum, 80 mg/m2— d1,22,43 or 40 mg/m2—weekly, or 6 mg/m2—daily or carboplatinum, 25 mg/m2 —daily); NAC, neoadjuvant chemotherapy (cisplatinum, 100 mg/m2—d1, 5-flourouracil, 800 mg/m2—d1-5); RT, radiotherapy; ADC, adjuvant chemotherapy (cisplatinum, 100 mg/m2—d1, 5-flourouracil, 800 mg/m2—d1-5).

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Disease free survival (DFS) was defined as the time of any event either as loco regional or distant after treatment.

Table 2 Failure sites for stage IVA and IVB patients Failure site

2.2. Statistical analysis Statistical analyses were performed using SPSS for Windows (Release 10.0.1, SPSS inc., Chicago, IL, USA). DFS, OS, DMFS, LRRFS rates were calculated using the Kaplan – Meier method and possible prognostic factors were evaluated by log-rank test. Various prognostic factors analyzed included patient’s gender, age, stage, T status, N status, external radiation dose, administration of BRT, administration of chemotherapy, and cranial nerve involvement at diagnosis. The comparison of groups according to patients’ and tumor characteristics was made using Fisher’s Chi-square test. Mann Whitney U test was used for the comparison of median follow-up times, age and dose to the nasopharynx. Cox regression multivariate analysis was performed for each of the clinical end points (OS, DFS, LRRFS and DMFS) in order to evaluate the potentially significant prognostic factors [13].

3. Results 3.1. Patient distribution between stage IVA and IVB patients Patient, tumor and treatment characteristics were compared between stage IVA and IVB patients. The median age, male/female ratio, histopathological subtype, T status, application of adjuvant brachytherapy boost and median follow-up time were equally distributed in both groups. All patients were T4 in stage IVA and N3 in stage IVB patients due to the definition by the staging system. There were significantly more patients with cranial nerve palsy at diagnosis in stage IVA patients as expected (85 vs. 7%, P ¼ 0001). Median external radiotherapy dose to nasopharynx was significantly higher in stage IVA patients (68.1 Gy (range: 58.8– 71.6 Gy) vs. 65.4 Gy (53 –70.7 Gy), P ¼ 0:001) and chemotherapy was more frequently administered to stage IVB patients (56 vs. 97%, P ¼ 0:0001). 3.2. Failure pattern Failure sites for stage IVA and IVB patients were summarized in Table 2. It is noteworthy to mention that the local recurrence was significantly higher in stage IVA patients (28 vs. 11%, P ¼ 0:02) and distant metastasis rate was significantly higher in stage IVB patients (40 vs. 8%, P ¼ 0:0001). For a better comparison, we analyzed the proportion of local failure as a result of failure, too. We observed that local failures constitutes 23 and 13% of all failures in stage IVA and IVB patients, respectively ðP ¼ 0:03Þ: At the time of this analysis, 60 (62%) patients were alive and 48 of these were free of disease. Twelve patients (six patients with distant metastasis and six with local

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Local ^ regional

IVA ðn ¼ 39Þ IVB ðn ¼ 57Þ P value

Regional alone

Distant metastasis

No.

%

No.

%

No.

%

11 6

28 11 0.02

– 4

– 7 NS

3 23

8 40 0.0001

NS, not significant.

recurrence alone) were alive with disease at their last control. Of 36 (38%) patients who have died, 29 died due to the progression of disease, three died due to the complications of chemotherapy and four due to the intercurrent disease. 3.3. Survival analysis Three year OS, DFS, LRRFS and DMFS rates were 71, 74, 77 and 94% for stage IVA patients, respectively. Same figures were 60, 46, 77 and 58% for stage IVB patients. Three year LRFS rates for stage IVA and IVB were 77 and 89%, respectively ðP ¼ 0:1Þ: LRFS and DMFS rates for stage IVA and IVB are shown in Figs. 1 and 2. 3.4. Analysis of prognostic factors Univariate analysis of stage IVA and IVB patients revealed older age (. 40 years of age) as an unfavorable prognostic factor for OS ðP ¼ 0:01Þ and LRRFS ðP ¼ 0:005Þ; advanced N status as an unfavorable prognostic factor for OS ðP ¼ 0:03Þ; DFS (0.0004) and DMFS ðP ¼ 0:0003Þ and presence of cranial nerve palsy at diagnosis ðP ¼ 0:01Þ; advanced T status ðP ¼ 0:03Þ; advanced N status ðP ¼ 0:0003Þ and treatment with chemotherapy ðP ¼ 0:02Þ as unfavorable prognostic factors for DMFS. By Cox multivariate analysis, older age (. 40 year of age), advanced N status were unfavorable prognostic factors for both OS and DFS (Table 3). Patients treated with chemotherapy beside radiotherapy had tended to have a better DFS. Only older age was found to be an unfavorable factor for LRRFS. None of the possible prognostic factors were found to be significant in determining DMFS. But there was a trend for advanced N status for being an adverse prognostic factor for DMFS ðP ¼ 0:07Þ:

4. Discussion Radical radiotherapy has remained as the primary modality of choice for the treatment of non-metastatic NPC for many years. However, patients with loco regionally

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¨ zyar et al. / Radiotherapy and Oncology 72 (2004) 71–77 E. O

Fig. 1. Local recurrence free survival for stage IVA and IVB patients.

advanced disease have a high loco regional and distant metastasis rate and this caused unsatisfactory survival rates with radiotherapy alone [15]. As NPC is a chemo sensitive disease, several efforts have been made to clarify the role of the chemotherapy in the management of NPC [26,31]. A number of randomized studies were published and these studies mainly compared addition of chemotherapy to radiotherapy with radiotherapy alone [1–3,7,11,17,20,23,26].

All but one of these randomized trials failed to improve overall survival. The only trial showing an improved overall survival advantage was Intergroup 0099 trial [1]. The results of this study were significantly better for combined treatment arm and revealed both progression-free and overall survival advantage. However, several issues precluded this trial to become a universally standard treatment and it is postulated that the favorable outcome may be the

Fig. 2. Distant metastases free survival for stage IVA and IVB patients.

¨ zyar et al. / Radiotherapy and Oncology 72 (2004) 71–77 E. O Table 3 Multivariate Cox proportional hazards analysis of overall (OS), disease free (DFS), loco regional relapse free (LRRFS) survivals for stage IVA and B patients RR

95% CI

P value

OS Age #40 year .40 year

1 2.6

1.1–5.7

0.02

N status N0 N1 N2 N3a N3b

1 0.6 3.5 1.2 3.1

0.1–2.7 0.9–14.2 0.5–2.9 1.2–8.3

0.04

DFS Age #40 year .40 year

1 2.03

1–4.1

0.05

N status N0 N1 N2 N3a N3b

1 2.1 6.6 4.5 17.9

0.4–10.0 0.9–48.4 1.1–17.7 0.08–0.9

,0.0001

Chemotherapy Yes No

0.3 1

0.08–0.9

0.05

LRRFS #40 year .40 year

1 4.6

1.3–15.8

0.01

result of factors other than addition of chemotherapy [9]. Hopefully, the results of recently completed two similar randomized trials in Singapore and Hong Kong will clarify this issue in the near future [10]. In most of these randomized trials, advanced nonmetastatic stage III and IV (AJCC/UICC, 4th edition, 1992) NPC patients were enrolled [1,17]. However, these patients are classified as stage II – IV in the 5th edition of staging system and constitute a heterogeneous group with respect to their failure patterns. It is postulated that any benefit associated with the use of chemotherapy may be masked as these patients have different failure patterns [10]. Chua et al. proposed selecting patients for randomized studies according to the failure patterns defined by prognostic categories rather than stage groups [10]. Thus, more data on the recurrence pattern using 5th edition will help generating new treatment strategies in NPC. Ongoing randomized studies focused on testing the role of concurrent chemotherapy, adjuvant chemotherapy, and radiotherapy using accelerated fractionation and IMRT in various combinations [10,21,28,29]. Hopefully, two of these protocols were designed to select patients according to failure

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patterns defined by prognostic categories instead of stage groups alone [10,19,23,29]. Since the publication of the 5th edition of AJCC/UICC staging system, limited number of reports has been published for stage IV patients (Table 4) [5,8,10,12,15,16,24]. In the literature, 3 and 5 year OS rates for stage IV patients ranged between 55 – 71% and 28 –73%, respectively [5,8,10,12,15,18,24]. While these figures were worse for the patients treated with radiotherapy alone, it is higher for patients treated with combined treatment modalities [15,16]. Only in two reports, survival rates were given separately for stage IVA and IVB patients in the literature [15,16]. In one of these reports, Hong et al. analyzed 111 NPC patients treated with chemo radiotherapy and reported 5 year OS rates of 56 and 73% for patients with stage IVA and IVB, respectively [16]. In the second report, Heng et al., analyzed 677 patients treated in Singapore with radiotherapy alone and reported 5-year OS rates of 35 and 28%, for stage IVA and IVB patients, respectively [15]. In our current analysis, we found 3-year OS rates of 71 and 60% and DFS rates of 74 and 46% for stage IVA and IVB patients, respectively. As seen from these results, it is evident that new treatment strategies should be urgently developed for these high risk patients. The local failure was the major cause of failure in patients with stage IVA disease and distant metastasis was the major cause of treatment failure in stage IVB patients [10,28,29]. While patients with stage IVA disease may benefit from various strategies improving local control, stage IVB patients may benefit from intensive chemotherapy regimens. Hong et al. analyzed their 111 patients treated with three cycles intensive neoadjuvant chemotherapy before radiotherapy. As stated before, they reported 5 year overall survival rates of 56 and 73% for patients with stage IVA and IVB, respectively [16]. These results were superior than the results reported by Heng at al., probably due to the addition of chemotherapy to radiotherapy [15]. While no recurrence pattern analysis was made by Heng et al., in their manuscript, Hong et al., made a detailed analysis of failure sites. They reported loco regional failure rate of 38% and distant metastasis rate of 13% for stage IVA patients, same figures were 20 and 24% for stage IVB patients. It is noteworthy to mention that authors reported that primary tumor at intracranial portion received only 46 Gy!! in 22 fractions to avoid excessive irradiation of the neural structures and that might explain the lower survival and higher local recurrence rate of their stage IVA patients compared to our results. Cheng et al. reported treatment results of 149 patients, all treated with concomitant chemo radiotherapy and adjuvant chemotherapy [6]. They reported loco regional failure rate of 15% and distant metastasis rate of 31% for stage IVA patients, same figures were 11% and 39% for stage IVB patients. Our analysis revealed that local recurrence rate was almost three times higher in stage IVA patients compared to stage IVB patients (28 vs. 11%, P ¼ 0:02) and distant

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Table 4 Survival results for non-metastatic stage IV patients in the literature using 5th edition of AJCC/UICC staging system Author

No. of patients

No. of stage IV patients

Treatment modality

5-Year DFS (%)

5-Year OS (%)

Cooper Chua Chien Hong Heng ¨ zyar O Cheng Current

107 324 117 111 677 90 149 234

32 82 39 92 (IVA: 25, IVB: 67) 254 (IVA: 160, IVB: 94) 35 64 96 (IVA: 39, IVB: 57)

RT RT, CRT RT, CRT CRT RT RT, CRT CRT RT, CRT

40 41 – – – – 60a 74a (IVA) 46a (IVB)

30 61 48 56 (IVA) 73 (IVB) 35 (IVA) 28 (IVB) 55a 66a 71a (IVA) 60a (IVB)

a

RT, radiotherapy alone; CRT, combined chemoradiotherapy. 3-Year survival rates.

metastasis rate was six times higher in stage IVB patients compared to the stage IVA patients (40 vs. 8%, P ¼ 0:0001). When we compare our data with other two studies, it seems that recurrence pattern of our stage IVA patients were more similar to the Hong et al.’s results and our stage IVB patients data was more close to the Cheng et al.’s results [5,16]. This may be related to the heterogeneous (20% treated with radiotherapy alone, 30% treated with concomitant chemo radiotherapy and 50% treated with neoadjuvant chemotherapy) treatment characteristics of our patients. It is also important to mention that failure to use CT—guided treatment techniques with eye beam view planning in our patients may have resulted in a number of geographic misses in stage IVA patients. Significant limitations of 2D planning in achieving adequate gross tumor volume and the role of high-dose, highprecision radiation therapy for boosting in NPC is shown very recently by various authors in the literature [4,22,32]. This issue can be clarified by the studies comparing standard and image-guided treatment techniques like ongoing RTOG study. We strongly recommend 3D planning using either conformal techniques of dose delivery or intensity modulated radiation therapy when available. As a conclusion, in this manuscript we documented recurrence patterns and made a survival analysis of our stage IVA and IVB patients, and compared it with the data in the literature. It is evident from our results and the data from the literature that these patients need more effective treatment. While stage IVA patients may benefit from more intensive local treatment strategies like IMRT or stereotactic boost to improve local control, stage IVB patients definitely need more systemic treatment by increasing number of cycles of chemotherapy, inserting new drugs like taxanes, gemcitabine or tripazamine and even with high dose chemotherapy with stem cell support. References [1] Al-Sarraf M, LeBlanc M, Giri SPG, et al. Chemo radiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol 1998;16:1310– 7.

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