Factors associated with overall survival in 1706 patients with nasopharyngeal carcinoma: Significance of intensive neoadjuvant chemotherapy and radiation break

Radiotherapy and Oncology 96 (2010) 94–99

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NPC radiotherapy

Factors associated with overall survival in 1706 patients with nasopharyngeal carcinoma: Significance of intensive neoadjuvant chemotherapy and radiation break Luying Xu a,c, Jianji Pan a,*, Junxin Wu a, Caizhu Pan a, Yu Zhang a, Shaojun Lin a, Ling Yang a, Chuanben Chen a, Chun Zhang a, Wei Zheng a, Senan Lin a, Xiaolei Ni a, Feng-Ming (Spring) Kong b,c a

Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University, Fuzhou, China; b Department of Radiation Oncology, University of Michigan Hospitals, Ann Arbor, MI, USA; c Sino-American Network for Therapeutic Radiology and Oncology, Ann Arbor, MI, USA

a r t i c l e

i n f o

Article history: Received 11 December 2009 Received in revised form 18 March 2010 Accepted 5 April 2010

Keywords: Neoadjuvant chemotherapy Radiation break Nasopharyngeal cancer

a b s t r a c t Background and purpose: To exam factors associated with overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Materials and methods: This study is a retrospective study of a total of 1706 consecutive NPC patients from a single institution between January 1995 and December 1998. One thousand eighty-one patients were treated with radiotherapy (RT) alone and 625 with an intensive course of neoadjuvant chemotherapy followed by RT. Patient, tumor and treatment factors were analyzed for their significance on 5-year overall survival (OS). Results: Younger age, female gender, absence of anemia pre-RT, early tumor stage, interruption of RT, and neoadjuvant chemotherapy were significantly associated with survival under multivariate analysis (all P < 0.05). The 5-year OS rates were 100%, 75.9% (95%CI 71.6–80.2%), 66.5% (95%CI 62.8–70.2%), and 49.3% (95%CI 45.0–53.6%) for stage I, II, III, and IV (P < 0.05); 68.9% (95%CI 66.2–71.5%) and 63.7% (95%CI 61.5–65.8%), for patients treated with or without neoadjuvant chemotherapy (P = 0.0051), and 51.7% (95%CI 45.0–58.4%) and 69.5% (95%CI 67.2–71.7%) for patients with or without treatment break (P < 0.0001), respectively. Conclusion: Intensive neoadjuvant chemotherapy and absence of radiation break seem to be favorable factors associated with long-term survival in patients with NPC. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 96 (2010) 94–99

Nasopharyngeal carcinoma (NPC) has a distinct epidemiology, etiology, and clinical course compared with other head and neck squamous cell carcinomas. The highest incidence rates of NPC are found in Southern China and Southeast Asia, while it is an uncommon tumor in the Western countries, with an annual incidence of less than 1 per 105 in whites [1–4]. The incidence rate of NPC is up to 25–50 cases per 105 person-years in the Southern regions, where it is considered endemic [3]. Fujian is one of the most affected endemic areas. There are 500–700 new cases of NPC treated annually in the Department of Radiation Oncology of Fujian Medical University, Fujian Cancer hospital. The standard treatment for NPC is radiotherapy (RT) alone for early stage and combined RT and chemotherapy for more advanced diseases [3–6]. Aggressive radiation therapy was the traditional standard of care, with only a 30–45% 5-year survival rate in patients with advanced disease [5] in the Western world and 34–59% in China [9a]. Recent results from combined chemotherapy

with RT [6–9] reported superior results, with 5-year survival rates ranging 60–67%. Many factors are associated with the treatment results of NPC. It is generally agreed that gender, age, anemia, T-stage, N-stage, M-stage, histopathology, RT dose, RT field, and a combination of chemotherapy affect results [2,10,11]. Regarding chemoradiation, optimal doses and sequencing (i.e., neoadjuvant, concurrent, and adjuvant approaches) remain controversial. During the study period in China, sequential chemotherapy was an acceptable modality for advanced disease, and the use of an intensive course of neoadjuvant chemotherapy and tolerance to treatment breaks were largely based on preferences of the treating physicians. This study aimed to (1) report the survival results in 1706 patients and study the impact of various patient and tumor factors, (2) investigate the effect of neoadjuvant chemotherapy and RT break on long-term survival in patients treated in a large-volume tertiary referral center in an endemic area for NPC. Materials and methods

* Corresponding author. Address: Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China. E-mail addresses: [email protected] (J. Pan), [email protected] (F.-M. (Spring) Kong). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.04.006

Patient characteristics This is an institutional review board approved retrospective study. A total of 1706 consecutive patients with a newly diagnosed

L. Xu et al. / Radiotherapy and Oncology 96 (2010) 94–99

histology-proven nasopharyngeal carcinoma underwent definitive treatment in Fujian Cancer Hospital, between 1/1/1995 and 12/31/ 1998. There were 1267 males and 439 females (male:female = 2.9:1). The median age was 48 (range 10–84). The disease was staged according to Fuzhou classification [3], a system approved and recommended by the Chinese Association of Radiation Oncology in Fuzhou, and widely used in mainland China since 1992. A comparison of this staging system and the Sixth edition of the AJCC staging system [12] is summarized in Table 1. All of the patients had contrast-enhanced computed tomography for staging work-up. Treatment regimen and consideration of chemotherapy At the time of study, chemotherapy was left to the treating physician of their preference, and ability of each individual patient’s to afford the treatment financially. When chemotherapy was chosen, RT normally started within 2–5 days of completion of the last dose of chemotherapy (Fig. 1). The chemotherapy regimen consisted of cisplatin 80 mg/m2 by rapid IV infusion over 15–20 min given for three consecutive days (days 1–3) and 5-FU 750 mg/m2/day by IV infusion for more than 12 h/day on days 1 through 5. Patients were admitted to hospital for all treatments and all of them were given an antiemetic prophylaxis consisting of 5-hydroxytryptamine-3 receptor antagonists. The patients were assessed weekly for chemotherapy side effects. Patients who tolerated treatment without severe side effects and with leukocyte counts >3000/ mm3 or platelet counts >100,000/mm3 were given the next cycle of chemotherapy. The decision of the 3rd cycle of chemotherapy was based on the tolerance and blood counts of each individual pa-

tient at that time. Chemotherapy was either given in full dose or none for each cycle based on the counts and the patient’s tolerance.

Radiotherapy All patients received definitive RT using two-dimensional planning, starting from day 21 (after two cycles of chemotherapy) or 35 (after three cycles of chemotherapy). The patients were treated by 2 Gy daily fractions, five times a week. The prescription dose to the primary tumors was 70 Gy with external beam radiotherapy (EBRT) except some patients discontinued treatment earlier due to medical intolerance or financial burdens. Patients with a residual tumor in the primary site after 70 Gy received a boost RT of 10 Gy. The prescription doses for nodes were 66 and 50 Gy to the involved and uninvolved areas, respectively. Any palpable residual neck nodes after 66 Gy of EBRT were boosted to 70–74 Gy with an electron field (9–12 MeV). A detailed description of each of the above techniques had been published previously [14,15]. RT break was applied in patients with severe mucositis supportive care, analgesics and nutritional supplement per discretion of the treating physician.

Follow up and statistical consideration Patients were followed up every 3–6 months from the end of treatment through 5 years and annually thereafter. At each visit, a physical examination, including a direct flexible fiberoptic endoscopy examination and palpation of the neck were performed. A contrast-CT scan of the nasopharynx and neck was obtained within

Table 1 Staging systems for nasopharyngeal carcinoma. The sixth edition of the AJCC staging system

Fuzhou ’92 staging of China

Tumor in nasopharynx (T) T1 Tumor confined to the nasopharynx T2 Tumor extends to soft tissues of oropharynx and/or nasal fossa

Primary tumor (T) T1 Tumor confined to the nasopharynx T2 Involvement of nasal fossa, oropharynx, soft palate prevertebral soft tissue, and parapharyngeal space extension before SO line T3 Extension over SO line, involvement of anterior or posterior cranial nerves alone, skull base, pterygoprocess zone, and pterygopalatine fossa T4 Involvement of both anterior and posterior cranial nerves, paranasal sinus, cavernous sinus, orbit, infratemoral fossa, and direct invasion of first or second cervical vertebra

T2a Without parapharyngeal extension T2b With parapharyngeal extension T3 Tumor invades bony structures and/or paranasal sinuses T4 Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space Regional lymph nodes (N) N0 No regional lymph node metastasis N1 Unilateral metastasis in lymph node(s), 66 cm in greatest dimension, above the supraclavicular fossa N2 Bilateral metastasis in lymph node(s), 66 cm in greatest dimension, above the supraclavicular fossa N3 Metastasis in lymph node(s) N3a >6 cm in greatest dimension N3b extension to the supraclavicular fossa

N2 Lower neck lymph node or the diameter between 4 and 7 cm

Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis

Distant metastasis (M) M0 Absence of distant metastasis M1 Presence distant metastasis

Stage grouping Stage I T1 N0 M0 Stage IIA T2a N0 M0 Stage IIB T1–2 N1 M0 T2b N0 M0 Stage III T1–3 N2 M0 T3 N0–1 M0 Stage IVA T4 N0–2 M0

Stage grouping Stage I T1 N0 M0 Stage II T2 N0–1 M0 T1–2 N1 M0

Stage IVB Any T N3 M0

Stage IVC Any T Any N M1

95

Regional lymph nodes(N) N0 No enlarged lymph node N1 The diameter of upper neck lymph node <4 cm, movable

N3 Supraclavicular lymph node or the diameter >7 cm or fixed or skin infiltration

Stage III T3 N0–2 M0 T1–3 N2M0 Stage IVA T4 Any N, M0 Any T N3, M0 Stage IVB AnyT, Any N, M1 SO line: The line connected from the styloid process to the midpoint on posterior edge of the great occipital foramen. The boraer between upper and lower neck is the lower margin of the cricoid cartilage

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Neoadjuvant chemotherapy and treatment break in nasopharyngeal cancer

1 2 3 4 5 First cycle chemo

15 16 17 18 19 Second cycle chemo

21 22 23 24 Radiotherapy

Fig. 1. Timing of neoadjuvant chemotherapy and radiotherapy.

2–6 months after completion of radiotherapy as the post treatment baseline and then yearly or when clinically indicated. The primary endpoint was overall survival (OS). Survival status was confirmed from population registration office (similar to Social Security System in United States). Local tumor and failure pattern were not tested due to concerns of data reliability of a retrospective study. SPSS 11.5 statistical software was used for data analysis. The Kaplan–Meier product-limit method was used for OS estimation. Time was measured from the date of the treatment start (either radiation or chemotherapy) until the time of the death, or the most recent follow-up if the patients were alive. The statistical significances of differences were analyzed using the Logrank test; a P value of 0.05 or less was considered to be statistically significant. Cox regression models were used for multivariate analysis. Data presented in parenthesis are 96% confident intervals unless otherwise specified. Results Patient characteristics The patient characteristic and stage distribution is shown in Table 2: stage I in 19, stage II in 403, stage III in 680, stage IVa in 548, and stage IVb in 56. Based on the 2003 WHO NPC classification [13], 1700 were non-keratinizing carcinoma. The median follow-up was 75 months (range 6–120 months). The follow up rate was 90.5% with 162 of 1706 patients lost follow up. At the completion of RT, 30 patients (2%) had residual diseases in the primary site, 379 (25%) had residual diseases in the neck, and 23 (1%) patients had residual disease in both the primary site and the neck nodal regions. Neoadjuvant chemotherapy was given in 625 of the 1284 advanced patients with stage III and IV. The other 659 patients did not receive chemotherapy. A total of 177 (10%) patients had a RT break of more than one week. No patients required a permanent feeding tube. Factors associated with overall survival – univariate analysis The 5-year overall survival rates of stage I, II, III, and IV were 100%, 75.9% (95% CI 71.6–80.2%), 66.5% (95% CI 62.8–70.2%), and 49.3% (95% CI 45.0–53.6%), respectively (Fig. 2). Table 2 shows the results of univariate analysis of patient, tumor, and treatment factors tested. Age, gender, anemia pre-RT, hypertension, TNM classification, T-stage, N-stage, M-stage, planned brachytherapy, neoadjuvant chemotherapy, a treatment break of more than 7 days and residual disease in the primary site or neck nodal regions at the end of treatment were significantly associated with overall survival. History of diabetes was borderline significant. Radiation dose was not a significant factor in this group of patients.

Table 2 Univariate analysis for overall survival. Factor Gender Male Female Age (years) 630 30–50 >50 TNM stage I II III IV T-stage T1 T2 T3 T4 N-stage N0 N1 N2 N3 M-stage M0 M1 Brachytherapy No Yes Treatment break (P7d) No Yes Residual in primary site No Yes Residual in neck No Yes Chemotherapy No Yes Anemia pre-RT No Yes Hypertension No Yes Diabetes Yes No Radiation dose <68 Gy 68–72 Gy >72 Gy

Number of cases

5-year OS (%)

1267 439

65.62 73.34

133 894 679

78.37 71.35 60.48

19 403 680 604

100.00 75.93 66.47 49.34

149 774 324 459

76.80 74.56 63.51 55.18

360 566 616 164

78.11 68.69 65.80 46.18

1650 56

68.41 29.68

1544 162

66.27 78.49

1529 177

69.45 51.69

1653 53

68.02 54.88

1304 402

69.54 61.16

1081 625

63.67 68.87

1086 622

70.32 63.35

1596 110

67.83 58.50

50 1656

64.28 67.99

106 874 726

72.1 68.5 68.7

v2

P

12.60

0.000

43.65

0.000

124.28

0.000

74.73

0.000

81.20

0.000

61.38

0.000

10.69

0.001

22.58

0.000

6.68

0.010

11.92

0.001

7.84

0.005

8.31

0.004

8.61

0.003

3.09

0.079

1.25

0.534

early tumor stage, no treatment break of radiation therapy, and a combination of neoadjuvant chemotherapy were significant predictors for favorable survival.

Multivariate analysis Cox regression multivariate analysis showed that gender, age, and anemia pre-RT, the TNM classification, T-stage, N-stage, Mstage, treatment break, combination of neoadjuvant chemotherapy, were significant factors (P < 0.05), while residual disease at the end of treatment, RT dose, RT field arrangement, planned brachytherapy, history of hypertension or diabetes were not (Table 3). Younger age, female gender, absence of anemia pre-RT,

Significance of chemotherapy and RT break The 5-year overall survival of patients treated with or without neoadjuvant chemotherapy were 68.9% (95% CI 66.2–71.5%) and 63.7% (95% CI 61.5–65.8%) respectively (P = 0.0051) (Fig. 3). The 5-year overall survival rates of patients with or without RT break were 51.7% (95% CI 45.0–58.4%) and 69.5% (95% CI 67.2–71.7%), respectively (P < 0.0001) (Fig. 4).

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L. Xu et al. / Radiotherapy and Oncology 96 (2010) 94–99

1.0

1.0

stage

0.8

Neoadjuvant Chemotherapy

stage

0.6

Overall Survival

Overall Survival

0.8

stage

stage

0.4 0.2

0.0

0.6

2

=7.84 p=0.0051

No Chemotherapy

0.4

0.2 0

20

40

60

80

100

120

Time (months) 0.0

NO. of Patents stage

0

20

40

60

80

100

120

Time (months) stage

NO. of Patents Neoadjuvant Chemotherapy

stage

No Chemotherapy stage

Fig. 3. Neoadjuvant chemotherapy on overall survival. Fig. 2. Stage and overall survival.

1.0

Table 3 Multivariate analysis for overall survival.

v2

P

Gender Age Anemia T-stage N-stage M-stage TNM-stage Treatment break Chemotherapy

5.87 36.54 3.20 7.28 16.25 25.38 8.04 15.82 21.01

0.015 0.000 0.021 0.007 0.000 0.000 0.005 0.000 0.000

Discussion This study reports overall survival results of 1706 patients treated with radiation with and without chemotherapy at a single institution, showing that many factors are significantly associated with the survival outcome in patients with NPC in endemic regions. This is one of the largest studies on survival outcome in patients with NPC. In addition, to confirm the effect of some common prognostic factors such as age, gender, tumor stage and anemia, this study further demonstrated the significant positive effect of an aggressive neoadjuvant chemotherapy and radiation break in NPC patients. The survival outcome and the stage distribution of the patients of our study are comparable to other series [1,16–19]. The 5-year overall survival rates of 67.6% versus 64.4–67.9% of He et al. [17] and Gao et al. [19] treated with 2D technique. There are 75.3% staging III–IV in this series versus 70–75% stage III–IV disease from Geare et al. [1] and Teo et al. [18]. The survival results from our study is slightly better than some earlier series of 56–60% from Southeast Asian and Southern China [20,21], most probably due to the updated CT/MRI imaging technology for staging, and the improvement of quality control of radiotherapy. As expected, gender, age, and stage are significant factor on survival in NPC. The effect of anemia is less clear in NPC, although it is a well known prognostic factor for non-NPC head and neck cancers

0.8

Treatment break 0.6

Overall Survival

Factor

χ2=22.58 p<0.0001

0.4

Treatment break

0.2

0.0

0

20

40

60

80

100

120

Time (months) NO. of Patents Treatment break Treatment break Fig. 4. Radiation break on overall survival.

[22,23]. Glaser et al. [24] results showed a lower survival and local control rate in patients with uncompensated anemia, while there was no difference between the compensated anemia with erythropoietin (EPO) and no-anemia groups. Chua et al. reported that mid radiation hemoglobin (Hb) level was an important prognostic factor with respect to local control and survival in patients with NPC and anemia after chemotherapy has a negative impact on treatment outcome in patients treated induction chemotherapy [11]. The poor survival in anemia patients may be because of the reduced capability of oxygen delivery, inducing hypoxia status in tumor cells which decreases radiation sensitivity, as previously reported by Peter Vaupel et al. [25]. The negative effect of anemia

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Neoadjuvant chemotherapy and treatment break in nasopharyngeal cancer

indicates the need of close monitoring the Hb level prior or during the course of treatment. In general, addition of chemotherapy is associated with improved overall survival in patients with advanced NPC. Results from selected important trials for combined chemoradiation are summarized in Table 4 [1,6,7,9,26,27,30–32]. The significance of neoadjuvant chemotherapy remains controversial [1,7,9,26,27]. Theoretical advantages of neoadjuvant chemotherapy include better distribution through an intact vascular bed, cytoreduction, and eradication of micrometastases [28]. Complete response rates after neoadjuvant chemotherapy were 10–66%, with objective responses rates ranging 75–98% in NPC [29]. The past results with neoadjuvant chemotherapy (mostly given one cycle every 3–4 weeks) have been uncertain for evidence of long-term benefits. Our study has demonstrated that neoadjuvant chemotherapy, used in a relative intensive fashion, is a major factor influencing the overall survival in our patient population. The use of neoadjuvant chemotherapy was significantly associated with OS improvement (from 63.7% to 68.9%) in this study, while it was not significantly different in series of Ma et al. [9a] and Chua et al. [26]. The positive results of our study may be contributing to the large sample size. It may also be due to aggressiveness of our chemotherapy regimen. Indeed, the cycle duration of our regimen is remarkably shorter (14 days) than 21–28 days in the other studies [1,9,26]. We started radiotherapy within 2–5 days from the last cycle (Fig. 1), while the regimen from Ma et al. of Guangzhou China [9a] initiated radiotherapy within 2 weeks of the completion of chemotherapy while Hong Kong [26] and US institutions [1] normally initiate radiotherapy at the 4th week from the last cycle of chemotherapy. The role of intensive neoadjuvant chemotherapy needs to be tested in a prospective study. Currently, concomitant chemotherapy is usually integrated into the RT approach for patients with advanced-stage NPC (Table 4) [6,27,30–32], largely based on favorable results of the meta-analysis results from Baujat et al. [27] and the intergroup study [6]. The intergroup trial randomized patients to receive three cycles of concurrent cisplatin followed by three cycles of adjuvant cisplatin and fluorouracil compared with the same RT schedule without chemotherapy. The 5-year results showed a statistically significant difference in overall survival: 37% in the RT-alone arm, compared with 67% in the chemo-RT arm. There was also an improvement in dis-

ease-free survival: 29% (control arm) vs. 58% (chemo-RT). However, concurrent chemoradiation with either lower weekly ‘‘sensitizing” drug therapy or every 3-week systemic dose of chemotherapy seemed to have a modest effect on distant metastases. The role of neoadjuvant or adjuvant chemotherapy is not clear in patients treated concomitant chemoradiation. Brockstein et al. [33] have reported pattern of failure results from multicenter experiences in patients treated with concomitant chemoradiotherapy for advanced head and neck cancer. Five-year locoregional failure fell from 31% to 17% with more aggressive concomitant chemoradiation, whereas distant failure rates increased to 22%, suggesting a need of neoadjuvant chemotherapy. Hui et al. reported favorable outcome with neoadjuvant chemotherapy followed by concomitant chemoradiation [34]. Additionally, adjuvant chemotherapy after concurrent chemoradiation is often associated with disappointing compliance in Asia [35,36]. The role of neoadjuvant chemotherapy on this respect deserves further study. Future randomized studies are needed to determine if such a regimen with concurrent chemoradiation is equivalent or superior to concurrent chemotherapy alone. Although the overall treatment time (OTT) is a well known significant factor for non-NPC head and neck patients [22,37]. Under conventional fractionation, a break of about 1 week is associated with an absolute reduction in local control rates of 10–12%. A break of even 1 day could reduce the local control rate by about 1.4%, regardless of the fractionation schedule and primary tumor site. However, such evidence is limited in NPC patients. Researchers from Hong Kong Queen Mary Hospital first reported [38] an adverse effect of treatment break for NPC on locoregional control and disease-free survival. Patients with prolonged OTT fared worse in terms of locoregional control, distant metastases-free and disease-free survival. The negative effect of a treatment break was not offset by the use of an additional boost [38]. The rate of locoregional failure increases by 3.3% for each day of interruption, its impact on overall survival was not reported. Our study suggests that treatment break is an independent prognostic factor associated with long-term survival in patients with NPC. In this study, 177 cases of 1706 (10.4%) had a treatment interruption of more than one week. Radiation interruption more than 7 days is associated with an 18% reduction of 5 year survival rates. Our current study is one of the largest series in NPC reporting the negative effect of

Table 4 Results of randomized prospective studies on application of chemotherapy and radiotherapy in the management of nasopharyngeal carcinoma. Trial [reference]

Type

Arm

N

OS (%)

P

DFS (%)

M.D. Anderson [1]

Neo Neo Neo

AOCOA+ Guangzhou [9b] AOCOA [26]

Neo Neo

Int-0099 [6]

Conc/Adj

Taiwan [30]

Coc

Meta-analysis [27]

Mixed (focused on Conc)

QMH [31]

Factorial

48 ± 7(5y) 69 ± 6(5y) 60(5y) 48(5y) 56(5y) 63(5y) 58.1(5y) 61.9(5y) 72(3y) 80(3y) 37(5y) 67(5y) 52.4(5y) 72.3(5y) 56(5y) 62(5y) 83(3y) 84(3y) 71(3y) 89(3y) 78(3y) 78(3y)

42 ± 7(5y) 64 ± 6(5y) 55(5y) 43(5y)

Guangzhou [9a]

61 61 40 40 228 228 392 392 152 134 69 78 143 141 1753 (8 trials) 55 53 54 57 176 178

0.012

Japan [7]

RT C + RT RT C + RT RT C + RT RT C + RT RT C+RT RT C + RT RT C + RT RT C + RT (Conc) RT Conc Adj Conc/Adj RT C + RT

Conc/Adj NPC_9901 [32]

Conc/Adj

NS 0.11

0.21

0.002

29(5y) 58(5y) 53(5y) 71.6(5y)

P 0.015 NS

49(5y) 59(5y) 42.7(5y) 50.9(5y) 46(3y) 58(3y)

0.092

0.001

RFS (%)

0.05 0.014 0.053 <0.001 0.053

0.003

NS NS NS 0.97

61(3y) 69(3y) 54(3y) 70(3y) 61(3y) 70(3y)

NS NS NS 0.1

Abbreviations: OS, overall survival; DFS, disease-free survival; RFS, relapse-free survival; C, chemotherapy; RT, radiation therapy; Neo, neoadjuvant; Conc, concurrent; Adj, adjuvant; NS, not significant; AOCOA, Asian Oceana Clinical Oncology Association; QMH, Queen Mary Hospital.

L. Xu et al. / Radiotherapy and Oncology 96 (2010) 94–99

treatment break on overall survival reported. While further validation study is needed, every effort should be made to keep treatment on schedule and interruptions for whatever reason should be minimized. Since mucositis is the major cause of these unplanned treatment breaks, efforts must be rigorous in oral and dental hygiene, and oropharyngeal normal tissue low-thawing lead shield or intensity-modulated radiotherapy treatment and placement of enteric feeding tubes should be implemented when it is necessary. To summarize, early stage, younger females with no anemia pre-RT, treated by combined neoadjuvant chemotherapy, and with no treatment break for radiation therapy are the major beneficiaries for long-term survival of nasopharyngeal carcinoma in this study. The favorable survival effects of aggressive neoadjuvant chemotherapy and absence of treatment breaks is consistent with the tumor biology of nasopharyngeal cancer. Prospective randomized trial is needed to study if such a regimen with concurrent chemoradiation is equivalent or superior to concurrent chemotherapy especially with the use of high conformal radiation therapy. Acknowledgements We are grateful to our patients and staff who involved in the patient care to make this work possible. We are in debt to Drs. Avahram Eisbruch and Angel Blanco for their critical review, valuable comments and edits of the manuscript. References [1] Geara FB, Glisson BS, Sanguineti G, et al. Induction chemotherapy followed by radiotherapy versus radiotherapy alone in patients with advanced nasopharyngeal carcinoma: results of a matched cohort study. Cancer 1997;79:1279–86. [2] Wei W, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;365:2041–54. [3] Hong MH, Mai HQ, Min HQ, Ma J, Zhang EP, Cui NJ. A comparison of the Chinese 1992 and fifth-edition International Union against cancer staging systems for staging nasopharyngeal carcinoma. Cancer 2000;89:242–7. [4] Lee N, Xia P, Jeanne M, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53:1–3. [5] Cooper JS, Lee H, Torrey M, Hochster H. Improved outcome secondary to concurrent chemoradiotherapy for advanced carcinoma of the nasopharynx: preliminary corroboration of the intergroup experience. Int J Radiat Oncol Biol Phys 2000;47:861–6. [6] (a) Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310–7; (b) Al-Sarraf M, LeBlanc M, Giri PG, et al. Superiority of 5-year survival with chemoradiotherapy vs radiotherapy in patients with locally advanced nasopharyngeal cancer. Intergroup 0099 Phase III study: final report [Abstract]. Proc Am Soc Clin Oncol 2001;20:227a. [7] Hareyama M, Sakata K, Shirato H, et al. Prospective, randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in patients with advanced nasopharyngeal carcinoma. Cancer 2002;94:2217–23. [8] Chi KH, Chang Y, Guo W, et al. A phase III study of adjuvant chemotherapy in advanced stage nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2002;52:1238–44. [9] (a) Ma J, Mai HQ, Hong MH, et al. Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 2001;19:1350–7; (b) Chua DT, Ma J, Sham JS, et al. Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol 2005;23:1118–24. [10] Liu MT, Hsieh CY, Chang TH, Lin JP, Huang CC, Wang AY. Prognostic factors affecting the outcome of nasopharyngeal carcinoma. Jpn J Clin Oncol 2003;33:501–8. [11] Chua DT, Sham JST, Choy D. Prognostic impact of hemoglobin levels on treatment outcome in patients with nasopharyngeal carcinoma treated with sequential chemoradiotherapy or radiotherapy alone. Cancer 2004;101:307–16. [12] Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging handbook from the AJCC cancer staging manual. 6th ed. New York: Springer; 2002. [13] Shanmugaratnam K, Sobin LH. World Health Organization. International histological classification: histological typing of tumors of the upper respiratory tract and ear. 2nd ed. Berlin: Springer-Verlag; 1991. p. 32–3.

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