1991, The British Journal of Radiology, 64, 901-908

A retrospective comparison between different stage classifications for nasopharyngeal carcinoma By P. Teo, M B , BS, FRCR, DMRT, S. F. Leung, M B , BS, FRCR, P. Yu, MSc, W. Y. Lee, BSc and W. Shiu, M D , FRCP Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong {Received August 1990 and in revised form May 1991) Keywords: Stage classifications, NPC, Comparison

Abstract. From 1984 to 1987, 659 patients with untreated nasopharyngeal carcinoma (NPC) were investigated by computed tomography of the nasopharynx and skull base, and fibreoptic nasopharyngoscopy. Thirty-one patients presenting with distant metastasis were treated palliatively; 628 were treated with intent to cure. Prospective staging was performed for the Ho's classification but since all T- and N-stage data required for staging according to the Huang's, the Changsha and the UICC classifications were recorded and stored in a computer database, retrospective staging according to these classifications could be accurately performed. Ho's classification was concluded to be the best in view of highly significant differences between the overall stages in survival and between N-stages in distant metastasis. The number of prognostically distinct overall stages and N-stages was greatest for Ho's classification. Huang's T-stage classification was superior, however, because it emphasized the significant adverse effect on local tumour control of cranial nerve(s) palsy (Tn) and intracranial tumour extension (Tc). Changsha and UICC classifications were demonstrably less powerful in predicting NPC prognosis. Multiple sites of involvement within the nasopharynx by NPC had no adverse influence on local tumour control. The grouping together of both soft-tissue and skull-base lesions into Changsha's T3 has been shown to be unjustified because of significant differences in local failure.

Different stage classifications for nasopharyngeal carcinoma (NPC) (de-The & Ito, 1978; Fu, 1980) are used in different locations, such as the Ho's in Hong Kong (Ho, 1978), the Huang's in Taiwan (Huang & Lui, 1985), the Changsha in mainland China (Li et al, 1983) and the UICC in Western countries (World Health Organization (WHO), 1987) (Table I). Each has employed a different set of tumour characteristics thought to be of prognostic significance for staging. Even though retrospective multivariate analysis has been performed to compare the relative prognostic significance of different tumour characteristics (Sham & Choy, 1990), a consensus has not been reached on the superiority of one stage classification in preference to the others. A consistent finding, though, is the significant impact on survival and distant metastasis rates by low-lying (de-The & Ito, 1978; Ho, 1978; Fu, 1980; Ho, 1982; Teo et al, 1989b; Sham & Choy, 1990) or large (Huang & Lui, 1985; Sham & Choy, 1990) cervical nodal metastasis and the worsening of local tumour control by an advanced primary with skull base or cranial nerve infiltration (Meyer & Wang, 1971; Wang & Meyer, 1971; Hoppe et al, 1976; Ho, 1978; Li et al, 1983; Huang & Lui, 1985; Neel et al, 1985; Teo et al, 1989b; Sham & Choy, 1990). The effects of distant metastases from bilateral, contralateral and fixed cervical nodal metastasis and of advanced primaries has, however, been controversial. On the other hand, the success of a stage classification lies not only in its embodiment of significant prognostic factors but also in its ability to group together patients of comparable prognosis into the same overall stage. Very few studies Vol. 64, No. 766

have tried to study this issue. Also important is the power of the overall stage in predicting survival, the T-stage in predicting local failure and the N-stage in predicting distant metastasis. Hitherto, there has been no study comparing the different stage classifications for NPC in these respects. The present study has been performed for this purpose. Material and methods

From 1984 to 1987 inclusive, a total of 659 patients with untreated NPC presented to the Prince of Wales Hospital Clinical Oncology Department. All had primary tumour biopsy via fibreoptic nasopharyngoscopy and computed tomographic (CT) scans of the skull base and soft tissues around the nasopharynx (Teo et al, 1989b). Over 95% had undifferentiated carcinoma. Thirty-one patients presented with distant metastasis. All except 15 patients were followed-up till death or for a minimum of 2 years. The 15 patients who defaulted follow-up intervals between 3 and 46 months after treatment were also evaluated to the date of last follow-up. For the whole group of 659 patients, the mean and median follow-up were 36.4 months and 36.6 months, respectively, by May 1990. At the time of the patients' presentation, a computer database was formed recording the size, laterality, fixity, multiplicity and Ho's N-level of the cervical nodal metastasis (if any) and the CT evidence of parapharyngeal, skull base, intracranial, orbital and other bony or softtissue infiltration by the primary tumour. Fibreoptic scope evidence of nasal or oropharyngeal infiltration and the number of tumorous sites within the naso901

Stage grouping

M-stage

N-stage

T2p

Supraclavicular node(s)

T2

T3

N3

II

III

IV

Ml

T1N0

(any T)

and/or N2

and/or Nl

Distant metastases

I

Ml

MO No distant metastases

N3

Direct invasion to the adjacent brain evident on CT scan (newly added item)

Primary soft-tissue tumour only Basal skull destruction evident on radiographs Cranial nerve(s) involvement

TsNOMO (primary soft-tissue tumour only) TsNIMO or T0N0-1N0 (any condition with Nl and/or Tb) TsN2M0 or TbN2M0 or TnN0-2M0 or TcN0-2M0 or TbnN0-2M0 or TbcN0-2M0 or TbncN0-2M0 (any condition involving N2 or Tn or Tc or more combinations) M1 (any of the above conditions with distant metastasis evident clinically) I

IV

III

II

Distant metastasis evident clinically MO No distant metastasis Ml Clinically evident distant metastasis beyond the cervical lymph node involvement

Unilateral (ipsilateral) small lymph nodes with total diameter < 5 cm Bilateral (contralateral) larger lymph nodes with total diameter > 5 cm

M

N2

Nl

Cervical lymph node NO No palpable cervical nodes

Tc

Tn

Tb

Ts

Huang's (1985)

Bone involvemment below the base of the skull including floor of the sphenoid sinus T3b Base of the skull T3c Cranial nerve palsy T3d Orbits, laryngopharynx (hypopharynx) or infratemporal fossa NO No nodes N Nl Node(s) above skin crease at laryngeal carcinoma N2 Node(s) below skin crease but above supraclavicular fossa

Parapharyngeal region

T20

T3a

Oropharynx

T2n

T2

T3

Nasal fossa

NP

Tl

T-stage

only

Ho's (1978)

Stage

Table I. NPC stage classifications

T1N0 T2N0 T3N0; T1-3N1

I II III

T1N0 T2N0; T0-2N1 T3N0-1; T0-3N2

T4N0-2; T0-4N3; Ml

I II III

IV

T4N0-1 N2-3 (any T) M1 (any T, any N)

Distant metastases

Ml Distant metastases

Ml

IV

MO No metastases

> 6 cm node(s)

MO No metastases

Supraclavicular and/or > 8 cm

N3

Nasal cavity, oropharynx (including parapharyngeal region) Skull base and/or cranial nerve

5J two walls NP

N3

T4

T3

T2

NO No node Nl Single homolateral node ^ 3 cm N2 N2a single homolateral node > 3 - ^ 6 cm

Nasal fossa, oropharynx (including parapharyngeal region) Bone of skull base ^ two features of T3

One wall or corner between two walls > two walls

NO No nodes Nl Mobile and/or < 3 cm above supraclavicular fossa N2 Fixed and/or (3-8) cm above supraclavicular fossa

T4

T3

T2

Tl

One wall NP

Tl

TO

Subclinical

UICC (1978)

Changsha (1983)

Stage classifications for NPC

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(d)

Figure 1. ASR of the overall stages in (a) Ho's, (b) Huang's, (c) Changsha, and (d) UICC stage classifications. The number of patients followed-up is plotted against time. pharynx were also entered into the database. Cranial nerve palsy was assessed clinically. Systemic investigation included bone scan, chest radiograph, liver ultrasonogram and complete blood picture with renal and liver function tests. The methods of radiotherapy were standardized and have been reported previously (Ho, 1978, 1982; Teo et al, 1989a, b). The computer database was considered complete in recording all tumour characteristics used for staging in the Ho's (Ho, 1978), the Huang's (Huang & Lui, 1985), the Changsha (Li et al, 1983) and the UICC (WHO, 1987) classifications. Therefore, even though prospective staging was performed only acccording to Ho's classification, retrospective staging according to the other classifications could be performed accurately, enabling retrospective comparison of the four stage classifications. Vol. 64, No. 766

The actuarial (ASR) and disease-free (DFS) survival, the free-from-distant-metastasis rate (FDM), and the free-from-local-failure rate (FLF) were plotted against time using the Kaplan-Meier method and comparisons were performed by the log rank test, with p values less than 0.05 considered as significant.

Results Irrespective of the stage classification, the survival correlated best with the overall stage, the local failure best with the T-stage, and the distant metastasis best with the N-stage. Therefore, to facilitate comparison, the relevant curves were plotted for the ASR (Fig. 1), the FDM (Fig. 2) and the FLF (Fig. 3). The curves for DFS corresponded closely to those for ASR. 903

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101

— - 67

Time (x100 days)

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(c)

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Figure 2. FDM of the N-stages in (a) Ho's, (b) Huang's, (c) Changsha, and (d) UICC stage classifications. The number of patients followed-up is plotted against time.

Survival (ASR and DFS) Both Ho's and Huang's classifications showed highly significant differences between the overall stages for both ASR [Fig. l(a),(b)] and DFS. The UICC classification was inferior in this respect with no significant difference between Stage I and the other stages [Fig. Table II. Patient number distribution Overall stage

I

II

III

IV

V

Ho

48 119 21 11

166 192 103 37

313 317 165 125

101 31 370 486

31 — — —

Huang Changsha UICC

904

l(d)]; Changsha's Stage I also did not differ significantly from Stages II and III [Fig. l(c)]. Ho's classification was considered more detailed than Huang's because there were five stages for the former and only four stages for the latter. The small number of patients in Stage I could account for its lack of difference in survival from the other stages in both the Changsha and UICC classifications (Table II). Distant metastasis Ho's and Huang's N-stages showed significant differences in FDM with comparable p values [Fig. 2(a), (b)]. The Changsha and UICC were inferior since there was no difference between Nl and N2 [Fig. 2(c), (d)]. With four N-stages rather than three, Ho's classification The British Journal of Radiology, October 1991

Stage classifications for NPC

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Tb Tn Tc Tn Tc Tc

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provides the largest number of N-stage categories. The lack of difference between Nl and N2 in both the Changsha and the UICC cast doubt on the prognostic significance of lymph nodal mobility, multiplicity and laterality. In the Ho's, Huang's and UICC, advanced primaries involving the skull base (Ho's T3, Huang's Tb and UICC's T4) had significantly more distant metastases than primaries confined to soft tissue (Ho's Tl and T2, Huang's Ts and UICC's T1-T3). In addition, Huang's classification identified a particularly poor prognostic T-stage (Tc) with intracranial extension, which had significantly more distant metastases than the other T-stages. The present findings indicated that advanced primaries increased significantly the risk of distant metastasis. Vol. 64, No. 766

Local failure

Ho's and Huang's T-stages showed significant correlation with local failure (Fig. 3(a), (b)]. Huang's Ts was equivalent to Ho's Tl +T2. However, since there was a significant difference between Ho's Tl and T2 in FLF [Fig. 3(a)], Huang's Ts could be further subclassified into two different T-stages. On the other hand, Huang's T-classification had highlighted the adverse impact on local tumour control by tumours with cranial nerve palsy (Tn) and tumours with intracranial extension (Tc). These had more local failures than tumours with skull base involvement only (Tb) [Fig. 3(b)]. Although Ho's classification also made a distinction between tumours with cranial nerve palsy (T3c) and those with skull base involvement only (T3ab), they were grouped together under the same T-stage (T3) and the same overall stage 905

P. Teo, S. F. Leung, P. Yu, W. Y. Lee and W. Shiu

60 50 40 30 20 -

T4N01 vs T4N23 T4N01 VST1-3N23 T4N01 vs Ml T4N23 VST1-3N23 T4N23 vs Ml T1-3N23VS Ml

P 0.0215 0.8929 0.0002 0.0044 0.0002 0.0002

10 -

8 12 Time (x100 days) 216 110 125 31

194 --102 • - - • 106 3

(Stage III or above). Therefore, Huang's T-classification was considered superior to Ho's in emphasizing more clearly the effect on survival and local control of the very advanced primaries by separately staging Tn and Tc into the overall Stage III and Tb into the overall Stage II (Table I). Changsha and UICC T-stages were considered inferior in predicting local failure when compared with Ho's and Huang's because some of their T-stages did not differ in FLF [Fig. 3(c), (d)]. Both classifications failed to demonstrate a difference between Tl and T2, supporting the hypothesis that primaries confined to the nasopharynx had similar local failure rates irrespective of the number of sites or walls involved. Patient number distribution This is summarized in Table II. For the Ho's, the Huang's and the Changsha, there were over 300 patients in Stages III, III and IV, respectively. For the UICC, over 400 patients were grouped into Stage IV. The excess in UICC Stage IV was accounted for by the fact that it included patients of different tumour characteristics and with different prognosis (Fig. 4). On the other hand, the most numerous stage in the other three classifications (Ho's Stage III, Huang's Stage III and Changsha's Stage IV) showed much less heterogeneity in patient composition and prognosis. Noteworthy also was the small number of patients in the Changsha's and UICC Stage I, which indicated that very few NPC involved only one site within the nasopharynx after adequate examination by CT, nasopharyngoscopy and multiple biopsies. The discrepancy in numbers of patients between Changsha's Stage I and UICC Stage I was due to the inclusion of tumours cornered between two walls in the former. The "corner between two 906

Figure 4. ASR of the sub-groups constituting Stage IV in the UICC stage classification. The number of patients followed-up is plotted against time.

nasopharyngeal walls" is an anatomical situation that is difficult to define precisely in practice by CT and nasopharyngoscopy, with relatively great interobserver variation in interpretation. Discussion In the present study, Ho's classification (1978) was able to divide the patients into the greatest number of distinct prognostic groups with five overall stages and four N-stages. The distribution of patients was also relatively more even among Ho's overall stages (Table II). Together with the strong correlation between survival and the overall stage [Fig. l(a)], distant metastasis and the N-stage [Fig. 2(a)] and local failure and the T-stage [Fig. 3(a)], this made Ho's classification more powerful and useful than the others in staging NPC. Huang's classification (Huang & Lui, 1985) was also effective in predicting prognosis [Figs l(b), 2(b), 3(b)], yielding comparable p values and levels of statistical significance comparable to those of Ho's stages. Thirty-one patients presenting with distant metastasis were classified as Ho's Stage V and Huang's Stage IV, and the two were identical. However, for patients without distant metastases (628), Ho's classification was able to divide them into four prognostically distinct overall stages, whereas Huang's could only divide them into three. Similarly, Ho's had a finer N-stage classification than Huang's in terms of number. It remains to assess by multivariate analysis the relative prognostic significance of the different factors used in the N-stagings — Ho's cervical nodal levels (Ho, 1978) against Huang's nodal size (5 cm) and laterality (Huang & Lui, 1985). Huang's T-stages were very similar to Ho's with its Ts equivalent to Ho's T1+T2, its Tb equivalent to Ho's T3a + T3b, and its Tn equivalent to The British Journal of Radiology, October 1991

Stage classifications for NPC

Ho's T3c. However, there was no Ho's counterpart for Huang's Tc, which had significantly more distant metastases and local failures [Fig. 3(b]. Also, in accordance with Huang and Lui (1985) and Neel et al (1985), the significance of cranial nerve palsy in NPC has been substantiated in the present study [Fig. 3(b)]. Ho's T3d, on the other hand, was not prognostically distinct. In our previous study (Teo et al, 1989b), tumours involving the parapharyngeal region had a local failure rate similar to those involving the skull base, and a suggestion was made to distinguish between parapharyngeal lesions and the other soft-tissue lesions beyond the boundaries of the nasopharynx (Ho's T2). It appeared that to predict distant metastasis, classifying the primary simply into early (Ho's Tl +T2n + T20) and advanced (Ho's T2p + T3) (Teo et al, 1989b) would be sufficient. However, concerning local failure, the primary tumours fell into five prognostically distinct groups: Ho's Tl (included in Huang's Ts); Ho's T2n + T20 (included in Huang's Ts); Ho's T2p + T3ab (part of Huang's Ts + Huang's Tb); Ho's T3c (identical to Huang's Tn); and Huang's Tc (without Ho's counterpart). It appeared that Ho's T-staging could be improved by (1) excluding parapharyngeal involvement from T2 and grouping it into T3; (2) sub-dividing T3 into (a) relatively early lesions with parapharyngeal or skull base involvement and (b) relatively advanced lesions with cranial nerve palsy; (3) omitting T3d altogether; and (4) designating ultra-advanced tumours with intracranial extension (CT evidence) as the new T4. The new Ho's T4 (corresponding to Huang's Tc) had a very poor prognosis, which justified its classification (with N3) as the overall Stage IV. The Changsha (Li et al, 1983) and the UICC (WHO 1987), like Huang's classification (Huang & Lui 1985), divided the patients into four overall stages. Like Ho's classification (Ho, 1978), they had four N-stages. However, they were considered inferior to both Ho's and Huang's classifications in predicting NPC prognosis. Their overall stages correlated less well with survival, with no significant difference in ASR between Stage I and the other stages, other than that between Changsha's Stage I and Stage IV [Fig. l(c), (d)]. Also, there was no difference in FDM between Nl and N2 [Fig. 2(c), (d)]. This cast doubt on the significance of some of the cervical nodal characteristics used by the two classifications for defining Nl and N2 — single versus multiple, mobile versus fixed, homolateral versus contralateral and bilateral, and small size ( < 3 cm) versus medium size (Changsha's 3-8 cm, UICC's 3-6 cm). In a recent retrospective multivariate analysis of 759 NPC, Sham and Choy (1990) included Ho's Nand T-stages, and the size and the degree of fixation of neck nodes as important tumour factors affecting survival; the number and the laterality of the cervical nodal metastasis were not prognostically significant. Since the survival impact of cervical nodal metastasis is mediated mainly by causing distant metastasis rather than local failure (Ho, 1978, 1982; Teo et al, 1989b), Sham and Choy's finding (1990) can be further interpreted as that Vol. 64, No. 766

the main cervical nodal factors predictive of distant metastasis are Ho's N-stage, the size and the degree of fixation. In concordance with this, the present lack of difference in FDM between UICC's Nl and N2 further emphasized that the cervical nodal characteristics (single versus multiple; homolateral versus contralateral and bilateral) used in defining UICC's Nl and N2 were not prognostically significant. Changsha and UICC's T-stagings were considered inferior in predicting local failure [Fig. 3(c), (d)] — for the former, there was no difference between Tl and T2, and between T3 and T4; for the latter, there was no difference between Tl and T2, and between Tl and T3. The lack of difference between Tl and T2 in both classifications indicated that multiple site involvement within the nasopharynx had no adverse effect on local tumour control, a finding shared by Ho (1978), Neel et al (1985) and Sham and Choy (1990). Also, a significant difference in FLF existed between soft-tissue tumours (except parapharyngeal involvement; Teo et al, 1989b) and tumours involving the skull base, making it inappropriate to group the two together in Changsha's T3. Moreover, other than Qin et al (1988), there was no other report showing a poorer local control for tumours involving more than one organ beyond the nasopharynx. Classifying these as Changsha's T4 was not based on very sound scientific grounds. In fact, in both our series and Sham and Choy's series (1990), many NPC extending beyond the nasopharynx had involved more than one organ {e.g. parapharynx together with oropharynx), but the number of extra-nasopharyngeal organs involved was not shown to be of prognostic significance in either series. In conclusion, Ho's (1978) and Huang's (Huang & Lui, 1985) classifications for NPC were better than Changsha's (Li et al, 1983) and the UICC (WHO, 1987). While Ho's produced the finest overall stage and N-stage classifications with highly significant differences among the stages for survival and distant metastasis, respectively, Huang's T-stage classifications were superior to Ho's in showing the significance of cranial nerve palsy and intracranial tumour extension. With better investigative tools, such as CT scans, it still remains an important task to weigh by multivariate analysis the relative prognostic significance of the various tumour characteristics used by the different classifications in defining their T- and N-stages. Acknowledgments The authors would like to acknowledge Dr Tsao S. Y., Dr O S. K. and Dr Foo W. for planning radiotherapy, and Dr Leung W. T. and Dr Tao M. for giving chemotherapy to some of the patients. We would like to thank Ms Eva Li for preparing the manuscript, and Mr Kwok Kwei-him for preparing the glossy prints of the figures. References DE-THE, G. & ITO, Y., (Eds), 1978. Clinical Staging Recommendation. Nasopharyngeal Carcinoma: Etiology and Control, Scientific Publications No. 20 (International Agency for Research on Cancer, Lyon), pp. 594-595.

907

P. Teo, S. F. Leung, P. Yu, W. Y. Lee and W. Shiu Fu, K. K., 1980. Prognostic factors of carcinoma of the nasopharynx. International Journal of Radiation Oncology, Biology, Physics, 6, 523-526. Ho, J. H. C , 1978. Stage Classification of Nasopharyngeal Carcinoma: A Review in Nasopharyngeal Carcinoma, Etiology and Control, I ARC Scientific Publications No. 20 (IARC, Lyon), pp. 99-113. Ho, J. H. C , 1982. Nasopharynx For Treatment of Cancer, ed. by K. E. Hallnan, J. L. Boak, D. Crowther, C. F. vonEssen, J. S. Orr and M. J. Peckham (Iqaku-shoin, New York), pp.249-267. HOPPE, R. T., GOFFINET, D. R. & BAGSHAW, M. A., 1976.

Carcinoma of the nasopharynx, eighteen years' experience with megavoltage radiation therapy. Cancer, 37, 2605-2612. HUANG, S. C. & Lui, L. T., 1985. Nasopharyngeal cancer: Study III. A review of 1206 patients treated with combined modality. International Journal of Radiation Oncology, Biology, Physics, 11, 1789-1793. Li, C. C , PAN, Q. C. & CHEN J. J.,

1983. Clinical and

experimental research on carcinoma of the nasopharynx in science technology (Guangdong Prov.), pp. 199-252 (in Chinese). MEYER,

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C. C ,

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the

NEEL,

H. B.,

TAYLOR,

W. F.

&

PEARSON,

G. R.,

1985.

Prognostic determinants and a new view of staging for patients with nasopharyngeal carcinoma. Annals of Otology, Rhinology, Laryngology, 94, 529-537. QIN, D., Hu, Y., YAN, J., X U , G., LAI, W., W U , X., CAO, D. & Gu, X., 1988. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer, 61, 1117-1124. SHAM, J. S. T. & CHOY, D., 1990. Prognostic factors of

nasopharyngeal carcinoma: a review of 759 patients. British Journal of Radiology, 63, 51-58. TEO, P., TSAO, S. Y. & LEUNG, S. F., 1989a. Afterloading

intracavitary radiation treatment of carcinoma. Acta Oncologica, 28, 525-527.

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TEO, P., TSAO, S. Y., SHIU, W., LEUNG, W. T., TSANG, V., Yu,

P. & Lui, C , 1989b. A clinical study of 407 cases of nasopharyngeal carcinoma in Hong Kong. International Journal of Radiation Oncology, Biology, Physics, 17, 515-530. WANG,

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management of carcinoma of the nasopharynx: an analysis of 170 patients. Cancer, 28, 566-570. WHO, 1987. Handbook for Reporting Results of Cancer Treatment, (World Health Organization, Geneva).

of therapy.

The British Journal of Radiology, October 1991