Radiotherapy and Oncology, 23 (1992) 79-93 @ 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/92/$05.00 79 RADION 00940 Prognostic factors in nasopharyngeal carcinoma investigated by computer tomography an analysis of 659 patients P. Ten, W. Shiu, S. F. Leung and W. Y. Lee Department of Clinical Oncology, Prince of Wales Hospital, Shatin, N.T., Hong Kong (Received 18 April 1991, revision received 17 September 1991, accepted 29 October 1991) Key words: Computed tomography; Prognostic factors; NPC Summary A total of 659 freshly diagnosed nasopharyngeal carcinoma (NPC) (1984-1987), were investigated by computed tomography (CT), treated with locoregional radiotherapy to radical dose, and given neoa~uvant chemotherapy (CHEMO) with 2-3 courses of cisplatinum and 5-ftuorouracil for bulky (>~4 cm) cervical nodal metastasis and booster radiotherapy (PPB) for para- pharyngeal disease. All except 15 patients were fully evaluable with complete data entry till death or to the last follow-up (minimum 2 years). The data have been analysed extensively to identify variables of potential prognostic significance. The assessed factors include patients' sex and age, nasal involvement (NAS), oropharyngeal involvement (ORO), parapharyngeal involvement (PAR), muscle involvement (MU), skull base involvement (BS), cranial nerves (II-VIII) palsy (CN1), cranial nerves (IX-XII) palsy (CN2), intracranial extension (IC), laryngopharyngeal extension (HYP), confinement to nasopharynx (NP), Ho's N-stage (Nho), maximal nodal size (Nmax), nodal mobility (Nf- fixed, Npf- doubt in mobility, Nm- mobile), nodal laterality (unilateral, contralateral, bilateral), nodal multiplicity (single, multiole), and presentation with distant metast~sis (M l). These factors have been assessed as to their interdependence and correlation with the clinical course (study endpoints) using both mooovariate analyses and Cox's Regression model. Significant association among Ho's T 2 and T 3 features was identified. Advanced Ho's N-stage correlated significantly with bulky nodes, multiple nodes, fixed nodes, and, comralateral and bilateral nodes. Poor prognostic factors found to be significant by both monovariate analyses and Cox's Regression model included the MI, Nho (advanced), CN1, BS, and CN2 for the actuarial survival (ASR) for all patients (659), the Nho (advanced), CN1, CN2, and BS for the ASR for the non-metastatic patients (628), the abscence of NP and the male sex for the local failure rate (628), the Nho (advanced), CN2, and BS for the distant metastasis rate (628), and the Nho (advanced), CN1, and BS for the disease-free survival (DFS) (628). In addition, old age, male sex, and the presence of parapharyngeal disease were probably significant in predicting poor survival (ASR); CN1 was probably significant in predicting more local failures, aod, the para- pharyngeal disease and the intracranial extension for more distant metastases. The Ho's N-staging is superior to the other N-stage classifications, because once the Ho's N-stage has been determined, other nodal characteristics including nodal size, multiplicity, laterality, and fixity, are prognostically insignificant. lntrocluctJon In the pre-computer tomography (CT) era, there were many studies for prognostic factors in nasopharyngeal carcinoma (NPC) [4-6,8,14-16,18,20,21,23,24,34, 35,37,38,40-a2,57]. Most of these used survival as the only study endpoint; few analysed the rates of distant metastases and local failures by both monovariate and multivariate analyses. Certain variables such as the presence of the cervical node metastasis [4,6,12- 16,18,20,23-25,33,34,36-38,41,42,48,50-52,57 ], the level [14-18,42,47,48] of cervical nodal metastasis (if any), the extension of the primary beyond nasopharynx [4,6,14,20,23,33-38,41,42,48,50-52,57 ], and the pres- Address for correspondence: Dr. P. Ten, Department of Clinical Ontology, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
Transcript
Radiotherapy and Oncology, 23 (1992) 79-93 @ 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/92/$05.00 79
RADION 00940
Prognostic factors in nasopharyngeal carcinoma investigated by computer tomography an analysis of 659 patients
P. Ten, W. Shiu, S. F. Leung and W. Y. Lee
Department of Clinical Oncology, Prince of Wales Hospital, Shatin, N.T., Hong Kong
(Received 18 April 1991, revision received 17 September 1991, accepted 29 October 1991)
A total of 659 freshly diagnosed nasopharyngeal carcinoma (NPC) (1984-1987), were investigated by computed tomography (CT), treated with locoregional radiotherapy to radical dose, and given neoa~uvant chemotherapy (CHEMO) with 2-3 courses of cisplatinum and 5-ftuorouracil for bulky (>~4 cm) cervical nodal metastasis and booster radiotherapy (PPB) for para- pharyngeal disease. All except 15 patients were fully evaluable with complete data entry till death or to the last follow-up (minimum 2 years). The data have been analysed extensively to identify variables of potential prognostic significance. The assessed factors include patients' sex and age, nasal involvement (NAS), oropharyngeal involvement (ORO), parapharyngeal involvement (PAR), muscle involvement (MU), skull base involvement (BS), cranial nerves (II-VIII) palsy (CN1), cranial nerves (IX-XII) palsy (CN2), intracranial extension (IC), laryngopharyngeal extension (HYP), confinement to nasopharynx (NP), Ho's N-stage (Nho), maximal nodal size (Nmax), nodal mobility (Nf- fixed, Npf- doubt in mobility, Nm- mobile), nodal laterality (unilateral, contralateral, bilateral), nodal multiplicity (single, multiole), and presentation with distant metast~sis (M l). These factors have been assessed as to their interdependence and correlation with the clinical course (study endpoints) using both mooovariate analyses and Cox's Regression model. Significant association among Ho's T 2 and T 3 features was identified. Advanced Ho's N-stage correlated significantly with bulky nodes, multiple nodes, fixed nodes, and, comralateral and bilateral nodes. Poor prognostic factors found to be significant by both monovariate analyses and Cox's Regression model included the MI, Nho (advanced), CN1, BS, and CN2 for the actuarial survival (ASR) for all patients (659), the Nho (advanced), CN1, CN2, and BS for the ASR for the non-metastatic patients (628), the abscence of NP and the male sex for the local failure rate (628), the Nho (advanced), CN2, and BS for the distant metastasis rate (628), and the Nho (advanced), CN1, and BS for the disease-free survival (DFS) (628). In addition, old age, male sex, and the presence of parapharyngeal disease were probably significant in predicting poor survival (ASR); CN1 was probably significant in predicting more local failures, aod, the para- pharyngeal disease and the intracranial extension for more distant metastases. The Ho's N-staging is superior to the other N-stage classifications, because once the Ho's N-stage has been determined, other nodal characteristics including nodal size, multiplicity, laterality, and fixity, are prognostically insignificant.
lntrocluctJon
In the pre-computer tomography (CT) era, there were many studies for prognostic factors in nasopharyngeal carcinoma (NPC) [4-6,8,14-16,18,20,21,23,24,34, 35,37,38,40-a2,57]. Most of these used survival as the only study endpoint; few analysed the rates of distant
metastases and local failures by both monovariate and multivariate analyses. Certain variables such as the presence of the cervical node metastasis [4,6,12- 16,18,20,23-25,33,34,36-38,41,42,48,50-52,57 ], the level [14-18,42,47,48] of cervical nodal metastasis (if any), the extension of the primary beyond nasopharynx [4,6,14,20,23,33-38,41,42,48,50-52,57 ], and the pres-
Address for correspondence: Dr. P. Ten, Department of Clinical Ontology, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
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entation with distant metastasis [ 14,17,23,47,48] have been generally agreed as prognostically significant in predicting survival. Nodal factors such as size [6,20,23,24,34,35,42] fixity, and laterality have also been considered important and the N-stagings of the UICC [27] and AJC [2] classifications are based on the nodal size, multiplicity, contralaterality, and bilaterality. However, the importance of patient's sex and age, the relative significance of the Hb's N-stage [ 14,17] versus the other nodal characteristics, and the survival impact ofneoadjuvant chemotherapy have been controversial. The issue is further compounded by the advance in imaging technology and improvement in tumor locali- zation. With routine use of CT and magnetic resonance (MR) imaging, more accurate delineation of tumor extent is possible [43,48,54,56], resulting in better treat- ment and outcome. This renders conclusions in NPC prognosis of the studies prior to such investigations rather irrelevant in the modern imaging era. Therefore, in our present study, we analysed the prognostic var- iables for NPC after routine CT by both monovariate and multivariate methods. The findings should have a
significant bearing in formulating a modern stage- classification for NPC.
M a t e r i a l s and methods
In the Clinical Oncology Department of the Prince of Wales Hospital, Hong Kong, from July 1984 to Decem- ber 1987, 659 previously untreated NPC were investi- gated by CT of the nasopharynx and skull base and fibreoptic nasopharyngoscopy. Prospective staging was done for the Ho's classification [14,17] (Table I). The investigative and treatment protocol is shown in Fig. 1. The external radiotherapy techniques (ERT) were those described by Ho [14-19]. The nasopharynx and the adjacent muscles and bones were treated to 60 Gy/24 fractions per 6 weeks by a 3-field technique [ 15 ] (one anterior and two lateral facial 6 MeV* photon fields) or to 62.5 Gy/29 fractions per 6 weeks by a
Tumor confined to the nasopharynx (space behind the choanal orifices and nasal septum and above the posterior margin of the soft palate in the resting position)
Extension to the nasal fossa, oropharynx, or adjacent muscles or nerves below the base of the skull. In the text:
T2n nasal fossa extension only T2o oropharyngeal extension only T2p parapharyngeal extension only T2( ..... p) combinations of the above
Beyond T 2 limits T3a bone involvement below the base of the skull. This includes floor of the sphenoid sinus T3b Involvement of the base of the skull T3c Involvement of the cranial nerve(s) T30 Involvement of the orbits, laryngopharynx, or infratemporal fossa
No cervical lymph nodes palpable Node(s) wholly in the upper cervical level bounded below by the skin crease extending laterally and
backward from or just below the thyroid notch (laryngeal eminence) Node(s) palpable between the crease and the supraclavicular fossa, the upper limit being a line joining
the upper margin of the sternal end of the clavicle and the apex of an angle formed by the lateral surface of the neck and the superior margin of the trapezins
Node(s) palpable in the supra-clavicular fossa and/or skin involvement in the form of carcinoma 6n cuirasse or satellite nodules above the clavicles
No hematogenous metastases Hematogenous metastases present, and/or lymph nodal metastases below the clavicle
Fig. 1. Investigative and treatment protocol at the Prince of Wales Hospital in H o n g K o n g , 1 9 8 4 - 1 9 8 7 ( a - c ) .
shrinking-field technique [15] (two lateral faciocervical 6 MeV photon fields to 40 Gy/20 fractions per 4 weeks and then followed by a 3-field treatment to 22.5 Gy/9 fractions per 2 weeks). The shrinking-field technique was used in the presence of oropharyngeal involvement and/or upper cervical lymph nodal metas- tases near the angle of the mandible. In cases of nasal involvement, an anterior facial electron field [ 15] was added to the 3-field technique with modification of the weightings of the photon fields [ 15 ]. CT scan at the base of the skull was performed in all patients from the level of the anterior clinoids down to the C3 vertebra at 2.5-10 mm intervals parallel to the orbito-meatal line. Coronal scans were performed for doubtful involve- ment of the sphenoid floor, nasal cavity, or maxillary
antrum. Parapharyngeal disease was defined as the presence of soft tissue swelling, deforming the para- pharyngeal fibrofatty tissue plane between the pharyn- geal constrictors and the pterygoids [43 ] in two or more axial sections at the level of the C1 vertebra. In the presence of parapharyngeal disease, the anterior and lateral facial fields of the 3-field technique or the lateral faciocervical fields of the shrinking-field technique were enlarged to cover the posterolateral and the inferior tumor extensions. In addition, a boost (PPB) was given at 2 weeks after the ERT. The boosting field (6 x 8 cm) was below the level of the eyes and temporal lobes and extended down to include the C3 vertebra. A dose of 20 Gy/10 fractions per 2 weeks was delivered at the 90~o isodose level. The patient's head was rotated
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towards the contralateral side so that the ipsilateral temporo-mandibular joint was spared the high dose. The spinal cord was also spared. To increase reproduci- bility and accuracy of the treatment, patients were immobilized in cobex casts; simulator check films and regular treatment portal verification films were routinely performed. Any palpably residual nodes after ERT were boosted to 7.5 Gy/2 fractions per 1 week at the 90~o isodose level with an electron field (8-10 MeV). For No, 38 Gy/10 fractions per 5 weeks was given for elective cervical irradiation. Intracavitary afterloading treatment with 192Ir (ICT)* was performed for local persistences proven by fibreoptic scope examination and biopsy at 2 weeks after completion of the ERT. During ICT, 192Ir-sources were afterloaded into pre- placed nylon tubes with terminal spacers immobilized by a self-invented helmet-like devise, delivering a dose of 18-24 Gy/3 fractions per 15 days to 1 cm above and below the midpoint of the plane of the sources [47,48]. For bulky N1-N3 (/> 4 cm lymphadenopathy, Table II), neoadjuvant chemotherapy with cis-diamminedichloro- platinum(II) (75-100mg/m 2 D1) and 5-fluorouracil ( l g / m 2 D1-D3 or D1-D5) [1,11] was given for 2 to 3 courses, 3 weeks apart prior to radiation therapy. All patients had pre- and post-hydration with 3 1 of normal saline over 24 h for cis-diamminedichloroplatinum(II). Patients were followed-up monthly for the first year and once every 2 months for the second year after com- pletion of treatment. After the second year, the follow- up intervals lengthened 3 to 4 months. All local recur- rences were diagnosed by fibreoptic nasopharyngo- scopy and biopsy and/or CT scan of the nasopharynx and the base of skull showing progressive bone erosion and/or soft tissue swelling. Regional recurrences were diagnosed by clinical examination of the neck and in doubtful cases, by find needle aspiration. Distant metastases, mostly to the axial skeleton, the lung, and the liver, were diagnosed by the history, physical exami- nation, and suitable imaging methods including plane radiographs, bone scintigram, and liver ultrasonogram. Over 95% of the 659 had undifferentiated NPC [26]. Thirty-one patients presented with distant metastases. All except 15 were followed up till death or for a mini- mum of 2 years. The mean and median follow-up were 36.4 months and 36.6 months, respectively. The actu- arial (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 with the Kaplan-Meier method [30] and comparison done by the log-rank test. Multivariate analysis by the Cox Regression model [10] was performed for identifying
* Buchler GmbH, Postfach, Braunschweig, F.R.G.
the independent prognostic variables governing each of the four study endpoints (ASR, DFS, FDM, and FLF). Factors included in the analyses included patients' sex and age (both as a continuous variable, and also sepa- rately as < 40 years versus >~ 40 years old), NAS (nasal involvement), ORO (oropharyngeal involvement), PAR (parapharyngeal involvement), MU (muscle involve- ment), BS (base of skull involvement), CN1 (cranial nerves II-VIII palsy), CN2 (cranial nerves IX-XII palsy), IC (intracranial extension), HYP (laryngo- pharyngeal extension), NP (confined to NP), Nho (Ho's N-stage), Nmax (maximal cervical nodal size, both as a continuous variable, and also separately cate- gorized as <3 cm, 3-6 cm, and >6 cm), Nf (fixed node), Npf (doubt in node mobility), Nm (mobile node), Nuni (unilateral node), Ncontral (contralateral node), Nbil (bilateral node), Nmulti (multiple nodes), and, histological types (undifferentiated vs non-keratinizing squamous vs well to moderately differentiated squamous). The neoadjuvant chemotherapy, the para- pharyngeal boost radiotherapy and the intracavitary treatment (ICT) with 192Ir w a s not included in the multivariate analyses because of obvious patient selec- tion and their strong association with certain other prognostic factors as a consequence. Statistical signifi- cance was taken conventionally at p < 0.05.
Results
Monovariate analysis
For the non-metastatic (Mo) NPC (628), there were significant differences in ASR among the Ho's N-stages [14,17] (Table I) (Fig. 2a), between the two sexes (Fig. 2b), between those older than 40 years and those younger than 40 (Fig. 2c), and, between those with skull base involvement (T3-BS), those with cranial nerve palsies with or without skull base involvement (T3-CN), and those without either features (Fig. 2d). Small nodal metastasis had better survival than large nodal metas- tasis (Fig. 3a), but the survival difference between dif- ferent nodal sizes was insignificant when stratified according to the Ho's N-stages (Fig. 3b). There was no significant difference in survival after the use of the neoadjuvant chemotherapy for nodes of similar size (Fig. 4a), and for nodes stratified by the Ho's N-stage (Fig. 4b). However, apparently there was worse sur- vival after chemotherapy when all patients (169) with nodal metastases (42 < 4 cm, 127 >f 4 cm) were con- sidered together, p = 0.0424 (Fig. 4c). Forty-two with non-bulky ( < 4 cm) nodes and seven without nodes (No) were given the neoadjuvant chemotherapy for advanced primaries, with most or all of the Ho's T 3
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Pretreatment staging
(1) Nasophary~lgeal tumor biopsy
(2) Chest radiograph (3) Plane radiographs
at skull and nasopharynx
(4) CT scan of nasopharynx
(5) Fibreoptic scope [ i examination I
(6) Clinical assessment for level and size L
of cervical lymph ] nodal metastases (if any)
(7) giver ultrasound (8) Bone ')~"Tc-
scintigram (9) Fine needle
aspiration of doubtful cervical lymph nodes
~ Bulky cervical nodes Nj-N 3 I ( > 4 cm in maximal I diameter) 1
Ot distant ] - - f astases ( M o ) Non-bulky cervical nodes N~-N 3 (<4cm in maximal diameter)
[
N e g a t i v e cervical nodes No
k
Neoadjuvant chemotherapy
tra ~ Pret~eatment 1 bulky ] Parapharyngeal ~ - ~
(dTS2~aaSed T3p ) I [
Para- pharyngeal boost
Local residual disease for _ lntracavitary
therapy T~ or T2~
O 1 metastasis ( M ~ ) treatment
Fig. 2(a) ASR of the Ho's N-stages; (b) ASR of the two sexes; (c) ASR of patients divided by 40 years (years) old; (d) ASR comparison among Ho's T-stages with subclassification of Y 3 into those with skull base invoivement only (T3-BS) and those with cranial nerve palsies with or
15 . . o - = o - , 9 , - - ' = - N 3 > 6 c m , - - = - - 4 , - = - - ° = = = - - = - - - - - - - , 0
Fig. 3(a) ASR of different nodal sizes ( <3 cm; 3-6 cm; >6 cm); (b) ASR of different nodal sizes (<3 cm; 3-6 cm; >6 cm) when stratified according to the Ho's N-stages.
[ 14,17] features; their survival was similar to that typi- cal of their T-stage and N-stage.
Fixity, bilaterality, and contraiaterality of cervical nodal metastasis did not adversely influence survival or
FDM. There was a significant difference in FLF between the two sexes (Fig. 5), and among the Ho's T-stages [14,17] (Table I)(Fig. 6). There was a signifi- cant difference in F D M among the Ho's N-stages
(Fig. 7). Advanced primaries with parapharyngeal dis- ease (Tp), and skull base and/or cranial nerve involve- ment (Ho's T 3 excluding two patients with laryngo- pharyngeal disease but without other T 3 features) had significantly more distant metastases than primaries confined to the nasopharynx (Ho's T]) or primaries with nasal and/or oropharyngeal extension (Ho's T2 excluding parapharyngeal disease, i.e. T2n + T2o )
Fig. 4(a) ASR comparison between NPC given and those not given neoadjuvant chemotherapy (PF), with stratification according to nodal sizes ( < 3 cm; 3-6 cm; > 6 cm). (b) ASR comparison between NPC given and those not given neoadjuvant chemotherapy (PF), with stratification according to the Ho's N-stages (N; N2; N3). (c) ASR comparison between all NPC (excluding No) given and not
(Fig. 8). The six patients with intracranial extension (Tc) had the greatest distant metastasis rate (Fig. 8). Histological types [26,44,45] (undifferentiated vs non- keratinizing squamous vs well to moderately well dif- ferentiated squamous) of the NPC were not significant in determining any of the four study endpoints.
Multivariate analysis
The significant prognostic factors governing ASR, DFS, FDM, and FLF are listed in Table II. The patients' age and the maximal cervical nodal size were either analysed as a continuous variable or as a cate-
Fig. 8. FDM of Ho's T-stages, modified by classifying tumors with parapharyngeal disease (Tp) together with T3, and separately
classifying tumors with intracranial extension (Tc).
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gorized variable (age ~< 40 years and >~ 40 years; nodal size ~< 3 cm, 3-6 cm, > 6 cm). There were only minor differences in the list of significant prognostic factors when the patients' age and the nodal size were repre- sented in these different manners. When all 659 patients were studied, the presentation with distant metastasis (M]) and the Ho's N-stage (Nho) were the most signifi- cant predictors for survival (ASR). After excluding the 31 NPC with distant metastasis (M 1 ), the Ho's N-stage, the presence of skull base involvement (B S) and cranial nerve palsies (CN1 and CN2) were significant predic- tors for survival. The patient's age and sex and the presence of parapharyngeal (PAR) and oropharyngeal (ORO) tumor were borderline in significance (0.05 < p < 0.1, Table [I).
The FLF was mainly governed by factors concerning the primary tumor - confinement to the nasopharynx (NP) predicted a good local tumor control whereas cranial nerves (II-VIII) palsy (CNI) predisposed to more local failures, in addition to the male gender of the patient (Table II). Meanwhile, none of the nodal char- acteristics had a significant impact on local tumor con- trol.
The FDM were governed by both T- and N-factors. The Ho's N-stage [14,17] remained the most powerful predictor for distant metastasis, followed by the lower- four cranial nerve palsy (CN2) and skull base involve- ment (BS) (Table II). Intracranial extension (IC) and parapharyngeal disease (PAR) were marginally signifi- cant in predicting distant metastasis (0.0636< p < 0.0801) (Table II). Maximal nodal size (Nmax) was not found to be significant in predicting survival (DFS, ASR) or distant metastasis (FDM), whether it was analysed as a continuous or as a categorized varia- ble (Table II). While oropharyngeal involvement (ORO) might predict less distant metastases and better survival (ASR), with borderline p-values (Table II), laryngopharyngeal extension (HYP) [ 14,17] and histo- logical types [26,44,45] were insignificant in predicting any of the four study endpoints.
Interrelationships of parameters
Association between the significant prognostic varia- bles was explored by the zLtest and the significant p-values are listed in Table III. Some of the more important associations (p < 0.05) between the signifi- cant prognostic variables are:
(1) the male sex with skull base involvement (BS) and cranial nerves (II-VIII) palsy (CN1);
(2) age ~>40-year-old with cranial nerves (II-VIII) palsy (CN1);
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TABLE II
p-Values of prognostic variables: Methods of analysis, a
I Ageb/Nmax c II Age (40)d/Nmax (3, 6) e III Age (40)a/Nmax c IV Ageb/Nmax (3, 6) e
ASR (659) f Ml 0.0001 Mi 0.0001 Ml 0.0001 M t 0.0001 NHO 0.0002 NHO 0.0001 NHO 0.0003 NHO 0.0001 CN 1 0.0028 CN 1 0.0030 CN 1 0.0031 CN 1 0.0042 Age 0.0050 BS 0.0142 BS 0.0117 Age 0.0063 BS 0.0182 CN2 0.0400 CN2 0.0380 BS 0.0201 CN2 0.0338 PAR 0.0499 CN2 0.0342 Male 0.0400 Male 0.0373 PAR 0.0450 PAR 0.0486
NHO 0.0001 NHO 0.0001 NHO 0.0001 NHO 0.0001 CN2 0.0360 CN2 0.0390 CN2 0.0375 CN2 0.0376 B S 0.0496 B S 0.0442 B S 0.0430 B S 0.0511
PAR 0.0636 PAR 0.0720 PAR 0.0647 PAR 0.0716 IC 0.0801 IC 0.0746 1C 0.0772 IC 0.0776 O RO -0.0857 O RO -0.0878 ORO -0.0899 O RO -0.0834
NP - 0.0180 NP - 0.0174 NP - 0.0182 NP - 0.0172 Sex 0.0291 Male 0.0332 Male 0.0325 Sex 0.0296 CNI 0.0384 CN1 0.0479 CN1 0.0362 CN1 0.0465
Negative p-values predict good prognosis. b Age: patients' age analysed as a continuous variable. c Nmax: Nmax analysed as a continuous variable. d Age (40): patients' age analysed as a categorized variable (<40 yrs > 40 yrs). e Nmax (3, 6): Nmax analysed as a categorized variable (< 3 cm, 3-6 cm, > 6 cm). r 659 include 31 NPC with distant metastasis (M1). g 628 exclude 31 NPC with distant metastasis (M~).
(3) p a r a p h a r y n g e a l d i sease ( P A R ) wi th skull base in-
v o l v e m e n t (BS) , m o r e a d v a n c e d H o ' s N-s t age ,
mul t ip le n o d e s (Nmul t i ) , and, f ixed n o d e s ( N O ;
(4) skull b a s e i n v o l v e m e n t (BS) wi th any c ran ia l ne rve
i n v o l v e m e n t ( C N I and C N 2 ) , and, in t rac ran ia l
ex t ens ion ( IC) ;
(5) l ower - fou r c ran ia l ne rve pa lsy ( C N 2 ) wi th c ran ia l
In addition, bulkier nodes (greater Nmax) were asso- ciated with fixed nodes (Nf), and, multiple (Nmulti) and fixed (Nf) nodes were associated with contralateral (Ncontral) and bilateral (Nbil) metastases (Table III).
The features characterizing the Ho's Trstage [14,17] (NAS, ORO, PAR, M U ) w e r e significantly associated with one another; the same can be said about the features characterizing the Ho's T 3 stage (B S, CN1, CN2). There was also significant correlation between Ho's T 2- and T3-features. On the other hand, the advanced Ho's N-stage [14,17] contained signifi- cantly more nodal features characterizing the advanced N-stage in the UICC [27], the AJC [2], the Huang's [23], and the Changsha's [57] classifications (large nodal size, nodal fixity, and, nodal bilaterality and con- tralaterality).
Discussion
The prognostic variables shown to be significant by both monovariate and multivariate analysis are proven important in predicting the treatment outcome of NPC. These include the Ho's N-stage [ 14,17 ], the presence of cranial nerve palsies, and the skull base involvement for survival (ASR) in the non-metastatic cases (628) (Table II, Fig. 2a,d). For all NPC (659), the presen- tation with distant metastasis influences survival in addition to the above factors (Table II). This is in good agreement with previous studies in the pre-CT era [4,6,8,12,14,16,18,20,23,24,34,37,38,41,42,57]. The variables found significant in the monovariate analysis and significant or marginally significant (0.05 < p < 0.1) in some or all of the multivariate analyses (depending on how patients' age and maximal nodal size were analysed) are considered as probable prognostic factors; these are listed in Table IV for each of the study endpoints (ASR, DFS, FDM, FLF).
Age and sex The older age and the male sex probably predict a poorer survival (ASR) (Table II, Fig. 2b,c). Ho [17], Huang [23], Meyer and Wang [34], and Qin [38] reported better 5-year-survival rates in NPC younger than 40 years old, and, Ingersoll et al. [25] reported a trend towards better survival for patients younger than 15 years old among 57 NPC (age 4-21 years). Arbitrary division of NPC patients by the age of 40 might not be
TABLE IV
Significant prognostic variables.
Definite Probable
ASR (659) ~ M 1 Age NHO Male CN 1 PAR BS CN2
ASR(628)
FLF (628)
FDM(628)
NHO Age CN 1 M ale CN2 PAR BS
Np b
Male CN1
NHO PAR CN2 IC BS
DFS (628) NHO Male CN1 BS
a 659 patients included 31 presenting with distant metastasis (M1). b NP was negatively associated with more local failures. ASR = actuarial survival; DFS = disease-free survival; FDM = free from distant rate; FLF = free from local failure rate.
the most appropriate, because the tendency towards worse survival (ASR) in advancing age is likely a phenomenon that affects most age groups, even though its importance is predictably more pronounced in the peak incidence age groups. On the contrary, worsened survival for NPC younger than 20 years old was report- ed by Scalon [41] and Bohorquez [6], but very few of our patients belonged to this age group, rendering monovariate analysis not possible by dividing patients into two groups by this age. Therefore, care should be taken in generalizing the detrimental impact on NPC of advancing age to children and teenagers. Further studies are required to delineate the prognostic factors in the very young NPC.
Previously, there has been controversy concerning the prognostic significance of the patients' sex, with Ho [14-16,18] contradicting others [23,25,34,36,38,42]. Our present study has proven, by both monovariate and multivariate analyses, that males have more local failures than females (Table II, Fig. 5). At the same time, it is also highly suggestive that males have worse survival (both ASR and DFS) (Table II, Fig. 2b). The reason why males should have more local failures and probably worse survival than females is, however, not
clear, other than its strong association with BS and CN1 (Table III).
Nodal status (N-factors) The Ho's N-stage [14,17] remains the most powerful factor in determining the distant metastasis rate (p = 0.0001, Cox Regression) and hence the survival rates (ASR and DFS) (Table II). After defining the level of the cervical nodal metastasis (if any) and the corresponding Ho's N-stage, all other nodal charac- teristics (maximal size, fixity, bilaterality, contra- laterality, and multiplicity) lose independent prognostic significance (Table II and Fig. 3b). Especially notable is the lack of independent prognostic significance of nodal size and nodal laterality, because the N-stagings of the UICC [27], the AJC [2], the Huang's [23,24], and the Changsha's [57] classifications for NPC have been based on the use of one or both of these nodal charac- teristics. It is now legitimate to question the advisability of continuing to use these classification systems [47] for NPC. In fact, earlier monovariate analysis of 568 NPC [47] from 1984 to mid 1987 from our center had already shown the superiority of the Ho's stage-classification [ 14,17 ] over the others. The present multivariate analy- sis has given further evidence to support this con- clusion. Sham et al. [42] indicated that it might be important to classify NPC nodal metastasis by virtue of nodal size together with nodal fixity by classifying nodes into three types ( < 4 cm and mobile; 4-6 cm or par- tially fixed; > 6 cm or fixed). However, Sham's study [42] did not analyse separately the prognostic signifi- cance of nodal size and that of nodal fixity and gave no reason for grouping together the two in the manner proposed. In our present study, we were unable to demonstrate any independent prognostic significance of the three types of cervical nodal metastases as pro- posed by Sham et al. [42] or of their basic constituting nodal characteristics, namely, maximal size and fixity. Meanwhile, it has been found that the advanced Ho's N-stages contained significantly more bulky nodes (greater Nmax), multiple nodes, fixed nodes, and, con- tralateral and bilateral nodes, which are features char- acterizing the more advanced N-stages in the UICC [27], the AJC [2] the Huang's [23], and the Changsha's [57] classifications. Reports [20,23,25,34,35] that proclaimed prognostic significance for these nodal features without analysing the Ho's N-stage [14,17], might have merely reflected the prognostic significance of the Ho's N-stage (Table I), [14,17].
We thus conclude that the Ho's N-stage is of para- mount importance in governing distant metastasis and survival, overriding all the other nodal characteristics, that classifying the nodal metastasis in NPC is sufficient
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solely by its level in the neck [14,17], and that other nodal characteristics being prognostically unimportant should not be used for the N-stage classification.
Primary tumor status (T-factors) While distant metastasis rate is governed by both T- and N-factors (Tables II and IV, Figs. 7 and 8), the local failure rate is governed by T-factors only, in addi- tion to the patients' sex (Tables II and IV, Figs. 5 and 6). Huang [23] believed that base of skull destruction had a minor effect on the treatment results but cranial nerve palsies represented a life-threatening situation in NPC. On the contrary, our multivariate analysis showed that both skull base involvement and cranial nerve palsies were significant in governing survival (ASR) and rate of distant metastasis. It thus seems appropriate, for the sake of depicting their poor progno- sis overall, to group the two together within the Ho's T3 [14,17] (Table I). However, monovariate analysis showed a worse survival of NPC with cranial nerve palsies with or without skull base involvement (T3-CN) than those with skull base involvement but no cranial nerve palsies (T3-BS) (Fig. 2d). Also, the Cox Regres- sion has demonstrated independent prognostic signifi- cance of the two features (Tables II and IV). Therefore, substaging the Ho's T 3 by these features is also recom- mended.
Significance of intracranial extension (IC) and para- pharyngeal disease (PAR) Meanwhile, the advanced primaries with CT-evidenced intracranial extension with or without other T 2 and T 3 features (Tc), and those with parapharyngeal and/or skull base and/cranial nerve involvements (Ho's T 3 + Tp, excluding two patients with laryngopharyn- geal disease only) had a significantly higher distant metastasis rate than less advanced lesions (Fig. 8), and multivariate analysis also indicated that both para- pharyngeal involvement per se (PAR) and intracranial extension per se (IC) were marginally significant in predicting more distant metastases (Table II). From the pathological point of view, it could be envisaged that tumors involving the skull base (BS) gain ready access to the Batson's plexus for hematogenous spread. Intra- cranial extension (IC) appears frequently as a contrast- enhancing lesion juxtaposed to the cavernous sinus, which may explain its propensity to blood-borne dis- semination. On the other hand, it is difficult to differen- tiate by CT between retropharyngeal nodal metastasis from direct extension of the primary tumor to the retro- pharyngeal compartment of the parapharyngeal space, with both sharing a common radiological abnormality of the distortion of the fatty tissue plane sandwiched
90
between the lateral pterygoid muscle and the lateral pharyngeal wall [43,56]. This explains why we loosely classify the too together into the same category as "parapharyngeal involvement". In our experience, it is exceptional rather than the rule that the rim-contrast- enhancement of a parapharyngeal tumor, distinct from the primary tumor in the nasopharynx, belies the nodal nature of the disease. Thus, when we talk about para- pharyngeal disease (PAR), we are referring to a hetero- geneous group of tumors, composed of both situa- tions. The retropharyngeal nodal metastasis, though indistinguishable from the direct primary tumor exten- sion by CT, may well have accounted for the significant predictive value of the parapharyngeal disease as a whole for distant metastasis. In fact, Neel et al. [36] regarded the retropharyngeal nodes as the first station nodes in NPC rather than those clinically palpable in the neck. Improvement of tumor imaging by MR may help to differentiate between the two situations and so contribute to refinement in the stage-classification. Until then, we recommend grouping together Tp with Ho's T 3 [ 14,17] (Table I), both sharing the same F D M (Fig. 8), and, classifying tumors with intracranial exten- sion (Tc) separately, in view of their outstanding pro- pensity to develop distant metastases (Fig. 8).
Ho [ 14-18] reported worse survival for tumors with oropharyngeal extension than tumors limited to the nasopharynx and classified the former into T 2 (Table I). However, 10 year follow-up of 1302 NPC in China [57] showed no difference in survival between the two. In our study, oropharyngeal involvement (ORO) was found to be marginally significantly associated with fewer distant metastases and better survival in the multi- variate analysis (Table II), but this was not substan- tiated by the monovariate analysis, thus leaving doubt as to its real prognostic significance. At present, we recommend that the more advanced lesions with para- pharyngeal disease, intracranial extension, skull base involvement, and cranial nerve palsy be distinguished from the less advanced lesions (confinement to naso- pharynx; nasal and/or oropharyngeal extension/s) with separate classification in the T-staging. In this sense, our recommendation is more in line with the Huang's T-staging [23,24], which classifies separately skull base involvement (Tb), cranial nerve palsy (Tn), and, intra- cranial extension (Tc). However, the parapharyngeal disease should be separated from the other soft tissue leisons (Huang's Ts) [23,24] in the T-staging.
Concurring with others [ 14,23,36,42], tumors con- fined to the nasopharynx (Ho's T 1 = NP) had the least local failures (Table II and Fig. 6). However, sub- division of these into one and more than one sites involvement within the nasopharynx as in the T-stag-
ings of the UICC [27] and the AJC [2] classifications, is not justified, because a significant difference in local tumor control is not demonstrable between the two. Ho [ 14-18] and Fu [ 13] also opined that it was unrealistic to separate the primary tumor into different T-stages based on the number of sites of nasopharynx involved.
Our monovariate analysis showed significant differ- ence in FLF among the Ho's T-stages (Fig. 6), but multivariate analysis only showed cranial nerves (II-VIII) palsy (CN1) to be significant (Table II and IV). Firstly, it is possible that with longer patient follow- up time and more local failures, the adverse influence on local tumor control of skull base involvement, para- pharyngeal disease, intracranial extension, and the last- four cranial nerve palsies may become evident by the Cox Regression in the future. This point is especially relevant since a significant number of local failures in NPC occur late [14,18,20,23,38,41,57]. Secondly, it is possible that CT-evidenced skull base erosion carries less prognostic impact when compared to the historical plane-radiograph-evidenced skull base erosion. Thirdly, it is alsopossible that routine CT, by improving tumor localization and presumably radiotherapy, has improv- ed local tumor control and minimized the impact of these sinister features to a degree not discernible by the Cox Regression. In our preliminary report of 407 NPC [48], monovariate analysis showed enhancement in local tumor control of the bulky parapharyngeal disease by booster radiotherapy (PPB) after the ERT described by Ho [14,15,18,19]. Since 1986, we have been giving booster radiotherapy liberally to all NPC with para- pharyngeal disease. Thus, CT tumor localization has led to a change in radiation technique which can possi- bly result in enhanced local tumor control.
Indeed, for the non-metastatic NPC (628), the 5-year FLF of 78 .1~ is significantly better than the Ho's historical results in Hong Kong [ 14-16,18]. However, longer patient follow-up time is necessary before definite conclusions can be drawn on the T-factors significant in governing the ultimate local tumor control, and before the apparent reduction in local failures of the skull base involvement and the parapharyngeal disease can be substantiated.
A difference in prognosis between the undifferen- tiated and the more differentiated squamous types of NPC had been suggested [5,8,21,25,33,34,41,44], but others [23,35,37,40,55,57] did not concur; Ho sug- gested a poorer survival for laryngopharyngeal exten- sion and classified it as T3d [ 17] (Table I), but Huang classified all soft tissue lesions as Ts [23]. Here, we have found no prognostic significance in either the dif- ferent histological types or the laryngopharyngeal exten- sion, by both monovariate and multivariate analyses.
91
Chemotherapy Historical use of a combination with low tumor response rate has produced detrimental effects in NPC [46]. More recent use of neoadjuvant chemotherapy in various head and neck cancers including NPC has accomplished significant tumor response prior to defini- tive surgery or radiotherapy [ 1,3,11,45,48]. However, as reviewed by Clark and Frei [9], randomized studies for neoadjuvant chemotherapy for head and neck can- cers have produced no evidence of improved survival [7,31,32,54]. During the present study interval from 1984 to 1987, we gave neoadjuvant chemotherapy with the cisplatinum-5-fluorouracil combination [ 1,11,45] liberally to NPC with bulky nodes (/>4 cm) (Fig. 1), because of the historical experience of poor regional control and survival with radiotherapy alone for very large cervical lymphadenopathy [48]; and, initial high tumor response rates have been reported [48]. How- ever, in spite of the early promising results, there was no difference in survival for nodal metastases of similar size or Ho's N-stage after using the combination in 169 NPC (Fig. 4a,b). Even though for all node-positive patients, those given neoadjuvant chemotherapy had a worse survival than those not given neoadjuvant chemotherapy (Fig. 4c). This can be explained by the significant association of the chemotherapy with poor prognostic factors such as advanced Ho's N-stage and skull base involvement. Also, in view of such an asso- ciation governed mainly by the protocol (Fig. 1), multi- variate analysis was not performed for the neoadjuvant chemotherapy, leaving its prognostic impact an uncon- cluded issue. This issue has to be addressed by a prospective randomized study with stratification according to significant prognostic factors. In other
advanced head and neck cancers, non-randomized studies [22,28,29,53] suggested a benefit in regional control and/or survival after adjuvant chemotherapy following the surgery and/or radiotherapy. However, Rossi et al. [39] found no survival benefit with the use ofvincristine, doxorubicin, and cyclophosphamide after definitive radiotherapy for NPC in a randomized study. An open question thus remains, concerning the role and efficacy of both neoadjuvant and adjuvant chemo- therapy for NPC. On the other hand, chemotherapy may have a greater therapeutic role in the young (less than 21 years old) [25] than in the adult NPC. As a radiosensitizer, synchronous use of chemotherapy [24] with radiotherapy is another method that may worth further study.
Conclusion
In conclusion, significant prognostic variables have been identified governing each of the four study endpoints in NPC in the present CT-era, and, the uncertain role of the neoadjuvant chemotherapy with cisplatinum and 5-fluorouracil has been discussed.
Acknowledgements
The authors would like to acknowledge the contribu- tions by Drs. W. T. Leung, V. Tsang, C. L. Ting and C. Martin, in the treatment of some of the patients. We would like to thank Mr. Peter Yu for checking the statistical analyses, Ms. Eva Li for typing the manu- script, and Mr. K. H. Kwok for preparing the glossy prints of the figures.
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