Volumetric staging (VS) is superior to TNM and AJCC staging in predicting outcome of head and neck cancer treated with IMRT

Abstract

The UICC classification (TNM) represents the validated standard tool to describe tumor extent and includes prognostic information on the probability of disease control. The American Joint Committee on Cancer (AJCC) stage grouping is based on the evaluation of treatment and outcome. Gross tumor volume (GTV) might be more relevant than pure description (TNM) or stage grouping as prognostic factor for local control in head and neck cancer (HNC). Based on the observation of GTV-correlated outcome in our initial HNC patient cohort treated with IMRT, we tested the hypothesis that the GTV is the most reliable predictive tool in HNC outcome. A GTV based volumetric staging system (VS) was introduced, using two volumetric cut-off values (15 and 70 cm³). VS, TNM, and AJCC stages were assessed and correlated with outcome following primary radiation in 172 HNC patients. Analyses were based on Kaplan-Meier survival curves. VS proved to be superior to the TNM/AJCC in predicting outcome. In addition, VS enabled to stratify high- and low-risk patients in advanced TN stages. GTV represented the most important prognostic indicator in HNC treated with IMRT and is recommended to be considered for therapeutic decisions and estimation of outcome.

Tumor volume extension is the prognostic key factor for local control by radiation therapy in head and neck cancer (HNC). This fact is known for a long time, and already described by Fletcher et al. for tumors of the uterine cervix ([1]: ‘Stage to be ignored’).

The UICC tumor-node-metastasis (TNM) classification includes prognostic information on the probability of disease control and represents the validated standard tool to describe disease extent, based on metric and anatomic criteria. This offers the advantage of a detailed descriptive assessment of the individual tumor extent in a precise, short code.

The American Joint Committee on Cancer (AJCC) is based on the evaluation of the T, N, and M components and the assignment of a stage grouping (I–IV).

Gross tumor volume (GTV) is an important prognostic factor in HNC, however it is not a direct part of the TNM classification and the AJCC stages in HNC, but only indirectly incorporated in the diametric measurement used in the TNM definition of tumor sites.

Together with other factors like treatment, age, gender, tumor grading, tumor site, GTV has been analysed as a prognostic factor by several authors [2–13]. A number of authors found a significant association between the HNC tumor volume and disease control [2–20].

Based on the observation of GTV-correlated outcome in our initial HNC patient cohort treated with IMRT between January 2002 and December 2004, we hypothesized that GTV is underestimated in its impact on disease control by the TNM. Consecutive patients treated between January and November 2005 were prospectively assessed, in order to confirm this observation.

This study aimed at quantifying the effect of tumor volume on disease outcome in IMRT treated HNC patients.

Patients

Hundred and seventy two head and neck carcinoma (HNC) patients were included in this volumetric analysis. All were treated with definitive curative IMRT at our institution between January 2002 and November 2005. Patients with glottic, thyroid, and parotid gland tumors were excluded. Patient characteristics are listed in Table I. 127/172 patients (74%) of the assessed cohort presented with locally advanced (T3/4 any N, T1-2N2c-N3, or recurrent) disease.

Table I.  Patient characteristics in the assessed IMRT cohort (n = 172).SIB-IMRT = Intensity modulated radiation therapy using simultaneously integrated boost, NPC = nasopharyngeal cancer, PNS = paranasal sinus cancer, GTV = Gross Tumor Volume, FU = Follow-Up.

Characteristics	n patients	%
N patients	172	100
Sex (M:F)	139:33
Mean age (years)	59
WHO PS
0	133	77
1	35	20
2	4	2
SIB-IMRT	172	100
Chemotherapy	129	75
T stage
T1	12	7
T2	57	33
T3	35	20
T4	53	31
Recurrence	15	7
Nstage
N0	42	24
N1	24	14
N2a	8	5
N2b	47	27
N2c	47	27
N3	4	2
AJCC Stages
I	2	1
II	15	7
III	25	14
IVA	110	64
IVB	5	3
Recurrence	15	7
HNC entity
Oropharynx	69	40
Oral Cavity	19	11
Hypopharynx	38	22
NPC	23	13
PNS	8	5
Supraglottic	15	7
GTV mean, cc
Primary GTV	38
Nodal GTV	15
Total GTV	58
FU mean, months	17

Weekly concomitant cisplatin based chemotherapy (40mg/m², once a week, 1–7 cycles) was given to 129 patients (75%): 94/129 patients (73%) received 5–7 cycles (depending on the fractionation regime); 16 (12%) underwent 4 cycles, 19 (15%) tolerated only between 1 and 3 cycles.

No treatment interruption was related to radiation induced toxicity. The mean total treatment time was 46 days (33–60).

Methods

GTV delineation of all 172 patients was based on physical examination and endoscopy as well as on diagnostic preoperative Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Positron Emission Tomography (PET), which was performed in all patients. In the majority of the patients, fused ‘PET-Planning CTs’ were performed. GTV was contoured on all relevant axial computerised images without interpolation. Volumetric three-dimensional measurements (cm³) of contoured structures were calculated by the Varian Treatment Planning System (Eclipse®, Version 7.3.10) volume algorithm.

Outcome (loco-regional and distant tumor control rates, disease free survival) was assessed using (1) the UICC TNM classification (6^th edition, 2002), (2) the AJCC staging, and (3) a volumetric staging system (VS) based on primary and nodal GTV in cubic centimetres (cm³). Separation of three prognostic VS groups (low-risk, intermediate-risk, and high-risk stratum) was achieved by choosing two volumetric cut-off values, based on the retrospectively analysed cohort of 88 HNC patients treated with definitive IMRT between January 2002 and December 2004. Those same cut-off values were then prospectively tested in 84 patients who were treated between January 2005 and November 2005. The prospective and retrospective subgroups were well balanced with respect to mean total GTV (51 vs 49 cm³), age (60 vs 58 years), gender (male to female = 4: 1 each), body weight loss during radiation course (7 vs 8%) and performance status before the start of treatment (80% PS 0, and ∼ 20% PS 1 each). The two subgroups differed in the amount of advanced stages (62 vs 71%), and in the duration of the follow up period (mean 8 vs 22 months).

Both subgroups were also analysed as pooled cohort (n = 172).

In addition, the volumetric staging was separately tested in the same manner in oropharyngeal tumor patients as the largest HNC subsite (n = 85/172) in our study population.

Assessment of volumetric cut-off values

All tumor volumes of the retrospective subgroup (n = 88) have been ranked, and locally failed cases were marked. Two cut-off values were then visually chosen, based on the frequency of local failure in the ranked tumor volumes. A favourable group with primary GTV (PGTV) of 1–15 cm³, an intermediate group with PGTV between >15 and 70 cm³, and an unfavourable group with PGTV > 70 cm³ were defined (Table IIa). The same cut-off values were employed using the total gross tumor volume (TGTV = PGTV plus nodal GTV (NGTV)), Table IIb.

Table IIa.  Three prognostic groups were defined for the volumetric staging (VS), the TN classification, and the AJCC (number of patients in parenteses). The cut-off values are the same when used for the primary gross tumor volumes (PGTV) as for the total gross tumor volumes (TGTV).

	Staging Systems
	VS (n PGTV, n TGTV)	T(n)	N(n)	AJCC(n)
Favourable	1–15 cc (54, 30)	T1/2 (69)	No (42)	I–III (42)
Intermediate	>15–70 cc (89, 100)	T3 (35)	N1-2b (79)	IVA (110)
Unfavourable	>70 cc (29, 42)	T4, rec (68)	N2c, 3 (51)	IVB, rec (20)

Table IIb.  Primary gross tumor volume (PGTV) and total gross tumor volume (TGTV) employed to predict local, nodal, distant disease free survival, and disease free survival, respectively. For both PGTV and TGTV the same two cut-off values (15 and 70 cm³) were used to define three prognostic groups.

Volumes	Outcome
PGTV (cut-off values 15 and 70 cc)	→ local control
TGTV (cut-off values 15 and 70 cc)	→ nodal and distant control, disease free survival

Comparison of the staging systems (TNM vs AJCC vs VS)

The TN as well as the AJCC staging were first tested in their original version. In order to obtain comparable systems and to avoid small sample sizes in the stage arms, the TNM as well as the AJCC stages were reduced to three arm systems each, like the VS is: the few T1 cases (n = 12/172) were included into the T2 group, recurred patients (n = 15/172) were included into the T4 group after recurred patients have been shown to develop similar Kaplan Meier survival curves as T4.

Similarly, AJCC stages l–lll were comprised to one favourable group (n = 42/172). The intermediate risk group was represented by the large stage lVA patient subgroup (n = 110/172). lVB (n = 5) and recurrences (n = 15) build the unfavourable group (n = 20). The AJCC staging system was cumbersome to compare to the two other staging systems due to its numerically imbalanced arms. Table IIa shows the final arm sample sizes of all three staging systems when broken down to three arm systems each; Table III shows the distribution of T stages in the three groups of the VS. This reduction of the TNM and AJCC staging to three arm systems is certainly debatable, however it was a way to ease comparison, and to create larger samples per arm.

Table III.  Distribution of the T stages in the volumetric staging system (VS) based on primary gross tumor volume (PGTV).

T distribution	Volumetric staging system (PGTV based)
	favourable (54)	intermediate (89)	unfavourable (29)
T1	9	3	0
T2	33	23	1
T3	1	31	3
T4	5	24	24
Recurrence	6	8	1

In order to additionally test the staging systems for nodal outcome, the UICC ‘N’-stages were tested separately and then similarly broken down to a three arm system, comparable to the volumetric system: N0 stages (n = 42) represent the favourable group, N1-2b (n = 79) the intermediate, and N2c/3 (n = 51) the unfavourable group, respectively.

IMRT treatment

Schedules

IMRT using simultaneously integrated boost (SIB-IMRT) technique was performed in all patients using the following schedules (5 fractions/week each):66 Gy (PTV1) and 54 Gy (PTV2) in 30 fractions (n = 35), 69.6 Gy (PTV1) and 54 Gy (PTV2) in 33 fractions (n = 111), 66–70 Gy (PTV1) and 54–56 Gy (PTV2) in 33–35 (n = 26).

Planning Computerized Tomography (Planning CT)

Planning CT (Somatom Plus 4, Siemens) was acquired with 2–3 mm slice thickness and with no interslice gap throughout the whole sequentially acquired region of interest. Patients were immobilized with an individually customised bite block, and a commercially available thermoplastic mask (Sinmed, Reenwijk, NL), that covered the head and neck down to the shoulders.

Planning systems

Contouring and plan optimisation was performed on a Varian Treatment Planning System (Eclipse®, Version 7.3.10, Varian Medical Systems, Hansen Way, Palo Alto CA, 94304-1129).

Radiation

Irradiation was delivered by 6 MV photon beams on a Varian linear accelerator with sliding window technique. For most patients (n = 154), five field arrangements (‘class solution’) were used; six fields were applied in six patients, seven fields in 12 patients.

Patient alignment was checked before radiation by portal imaging; deviations of > 2 mm in nasopharyngeal cancers and paranasal sinus tumors, and > 3 mm in all other tumors were corrected before treatment.

Statistics

All our statistical analyses consisted of comparing three groups according to a time-to-event’ endpoint (survival analysis). This was done using Kaplan-Meier curves and log-rank tests implemented in StatView® (Version 4.5). P-values smaller than 0.05 were considered as significant.

Results

Tumor response and survival

Actuarial two year local, nodal and distant control rates in the entire group (n = 172) was 76, 87 and 90%, respectively. For the oropharyngeal subgroup (n = 85) this was 77, 90, and 92%. All but one local failure occured ‘in-field’ (inside the 95% isodose of the high dose area); 50% (16/36) presented as tumor persistence.

Thirty six (21%) local, 20 (12%) nodal and 15 (9%) distant events were observed.

At the time of data analysis (February 2006), 129/172 patients were alive with no evidence of disease (ANED, 75%), 27 patients were alive with loco-regional and/or distant disease (AD, 16%). Fourteen patients died of disease (DOD, 8%), two patients died of intercurrent disease.

Tumor volumes

PGTV measured mean 38 cm³ (range 1–206 cm³), TGTV mean 52 cm³ (range 1–217 cm³). PGTV and TGTV were mean 33 and 50 cm³ in oropharyngeal tumors, 32 and 50 cm³ in hypopharyngeal tumors, 32 and 37 cm³ in oral cavity tumors, 56 and 60 cm³ in paranasal, and 58 and 80 cm³ in nasopharyngeal tumors. PGTV in patients who failed locally measured mean/median 59/57 cm³ (range 6–140 cm³), vs 37/28 cm³ (range 3–142 cm³) in locally controlled individuals.

Disease free survival (DFS) and local disease free survival, assessed using the three staging systems

T classification and AJCC staging system

The T classification and AJCC staging system failed to significantly predict outcome in the tested subgroups (retrospective, prospective, pooled, and oropharyngeal tumors only). This was the case when tests were performed using the original 5-tiered AJCC system (stages l, ll, lll, lVA, lVB) and 4-arm T system (T1-4, recurrences separately analysed), respectively, as well as when broken down to the three arm systems (l-lll vs lVA vs lVB, and T1/2 vs T3 vs T4/recurrences, see ‘methods’).

Table IV shows significance levels (p-values, using the log-rank test) of the compared three staging systems (VS TNM, AJCC staging,) in predicting outcome in the tested samples.

Table IV.  Logrank (Mantel-Cox) p-values of Kaplan-Meier survival curves for local control (LC), disease free survival (DFS), distant control (DC), and nodal control (NC) in the tested subgroups, using the TNM classification, the AJCC staging, and the volumetric staging (VS) system.

	LC		DFS		DC		NC
Sub groups (n)	VS	T/AJCC	VS	T/AJCC	VS	T/AJCC	VS	N/AJCC
Retrospective (88/172)	0.016	NS	0.018	NS	–	–	–	–
Prospective (84/172)	0.006	NS	0.002	NS	–	–	–	–
Pooled (172)	0.0001	NS	0.007	NS	<0.0001	NS	0.04	0.027/NS
Oropharynx 85/172	0.0003	NS	0.01	NS	–	–	0.02	–
Loc advanced* (127/172)	0.002	–	0.04	–	0.007	NS	–	–

*subgroup with locally advanced tumors, including T3-4, and any T N2c-3 stages as well as patients with recurrent tumors.

Volumetric staging (VS) system

Only 5.5% (3/54) of all tumors measuring 1–15 cm³ failed locally. A local failure rate of 20% was found for tumor volumes between >15–70 cm³ (18/89), of 48% (14/29) for tumors ≥ 70 cm³, respectively.

The primary GTV (PGTV) has shown to most accurately predict local control; for the assessment of nodal control, the total GTV (TGTV = PGTV plus nodal GTV, NGTV) was found superior to NGTV or PGTV. Distant control and disease free survival (DSF) were similarly well predicted either by the PGTV or the TGTV.

As a consequence, PGTV was used for assessments of the local control, TGTV for nodal control, distant failure, and for DFS, respectively, employing the same cut-off values (15 cm³ and 70 cm³, Table IIb).

Lowest and highest tumor volumes consistently mirrored favourable and unfavourable survival strata in all tested groups. PGTV and TGTV showed a highly significant impact on local control and disease-free survival, respectively (Figures 1–3,Table IV).

Figure 1.  Actuarial disease free survival curves, based on the volumetric staging (VS; n = 172, 44 events, p = 0.007), using the total gross tumor volume (TGTV, volume of the primary and the nodes).

Figure 2.  Actuarial local disease free survival curves, based on the volumetric staging (VS; n = 172, 36 events, p = 0.0001), using the primary gross tumor volume (PGTV).

Figure 3.  Actuarial local disease free survival curves in oropharyngeal tumors, based on the volumetric staging (VS; n = 85, 11 events, p = 0.0003), using the primary gross tumor volume (PGTV).

The diagnosis (tumor site) and the volumetric staging were the only significant factors in predicting disease-free survival and local control in our series (p = 0.001 and 0.02, respectively); T staging, AJCC staging, WHO performance status, age and gender were not significantly correlated with outcome.

Table V shows approximate disease control rates in our patients with favourable, intermediate and unfavourable tumor volumes.

Table V.  Approximative actuarial 2 year disease control rates for patients with favourable, intermediate and unfavourable tumor volumes. LC = local control, NC = nodal control, DC = distant control, DFS = disease free survival, OAS = overall survival.

	Total Gross Tumor Volume (TGTV)
Actuarial	1–15cc	>15–70 cc	>70 cc
2-y LC*	95%*	70%*	50%*
2-y NC	95%	90%	75%
2-y DC	99%	99%	60%
2-y DFS	90%	70%	50%
2-y OAS	95%	90%	70%

Prediction of nodal and distant control

Nodal and distant control was assessed for the pooled sample (n = 172, Table IV). The smaller other subgroups were not tested for nodal and distant outcome because of the low number of events.

• Nodal outcome was similarly well predicted by both the VS (Figure 4, based on TGTV) and the N classification. The AJCC staging, T stages, and the VS based on PGTV, were not of significant influence on nodal outcome.

• Distant spread (15 events in 172) was highly significantly predicted by the VS (using the TGTV, p < 0.0001, Figure 5), while non-significantly stratified by the T-classification and by the AJCC staging. Twelve of 15 events occurred in patients with a total tumor volume of > 70 cm³; distant outcome in the favourable and the intermediate group did not differ.

Figure 4.  Actuarial nodal disease free survival curves, based on the volumetric staging (VS; n = 172, 20 events, p = 0.04), using the total gross tumor volume (TGTV).

Figure 5.  Actuarial distant disease free survival curves, based on the volumetric staging (VS; n = 172, 15 events, p < 0.0001), using the total gross tumor volume (TGTV).

Stratification of advanced TN stages using the VS system

In addition, the VS system was also evaluated in locally advanced TN stages (T3-4 any N, and T1-2N2c-3, and recurrent cases, n = 127) in an attempt to extract patients at highest and lowest risk in this TN-defined ‘high risk’ group. There was again obvious capacity of the VS system in significantly distinguishing different risk strata for local and distant outcome, and disease free survival (Table IV, Figure 6).

Figure 6.  Actuarial local disease free survival in T3-4, or any T N2c-3, and recurrent patients, stratified according to the volumetric staging (VS, n = 127, 33 events, p = 0.002), using the primary gross tumor volume (PGTV).

Discussion

Gross tumor volume was classified according to its prognostic value in IMRT-treated HNC patients. The strong impact of tumor volume on local outcome is known for decades. With this work we tried to quantify this impact on our IMRT series.

The results confirm our hypothesis that tumor volume may be the most reliable prognostic indicator for outcome in HNC patients treated with IMRT. Three subgroups with different prognosis could be defined using the volumetric cut-off values of 15 and 70 cm³ (Table IIa, b). The primary tumor volume was most accurate in predicting local outcome, the total tumor volume revealed the highest power in predicting nodal and distant outcome, and disease free survival.

The strength of the volumetric system lies in its ability to reliably distinguish low and high patients in basically all tested samples. This allows pre-therapeutic identification of patient subgroups that may benefit from intensified treatment strategies, e.g. dose escalation.

The AJCC staging and the T-classification were not significantly predicting outcome in the tested series, likely due to too small sample sizes, and to the fact that wide tumor volume ranges are included in each stage. The significant prognostic stratification of advanced TN stages into favourable and unfavourable patients by the volumetric staging confirms that even in loco-regionally extended disease, the volumetric factor is a strong and reliable predictor.

Nodal outcome was anticipated equally accurate by the UICC ‘N’-classification as by the volumetric system. This is probably due to the fact that the N-classification is based on numeric and metric assessment of spheroid structures, which approximates the volumetric approach.

Volumetric studies in HNC have previously been reported for selected sites as well as for mixed cohorts (Table IV). There is a large reported cut-off value range from 3.5 cm³ in laryngeal tumors [6–8], up to 112 cm³ in a mixed series [19]. Several authors used the mean GTV as cut-off point. Similarly to our study, two cut-off values were used in two other reports [9], [10]. Two values offer the advantage of distinguishing an intermediate-risk stratum. However, this approach requires larger patient samples for sufficient statistical power.

Considering the substantial differences in tumor volumes in ‘advanced’ disease of the different HNC sites, we excluded laryngeal tumors from our analysis, because this entity is anticipated to require lower cut-off values, as employed by Gilbert et al. [6], Lee et al. [7], and Pameijer et al. [8], respectively.

In the majority of published analyses there was a statistically significant correlation between GTV and local or survival control (Table VI) (2–11, 13–16, 19–21). In three analyses on oropharyngeal tumors [2], [22], [23], there was no significant correlation. In contrast, volumetric staging in our oropharyngeal subgroup showed the same strong capacity for stratifying prognostic subgroups as in the pooled cohort.

Table VI.  On literature on head and neck cancer (HNC) outcome prediction based on volumetric classifications. N is the number of analysed HNC patients (soft pal = soft palate, ant/post tons pil = anterior/posterior tonsillar pillar, hypo = hypopharyngeal tumor, OC = oral cavity tumor, oro: oropharyngeal tumor, NPC = nasopharyngeal tumor, RT = radiotherapy, CT = chemotherapy, 3DCRT = three-dimensional conventional radiotherapy, IMRT = intensity modulated radiation therapy, PGTV = primary gross tumor volumes, NI: not indicated, “–“ = no value, TGTV = total gross tumor volume, LC = local control,OS = overall survival.

Author [ref]	year	HNC entity	N	Stages	Treatment	RT technique	mean PGTV (cc)	cut-off value	p-value LC	p-value OS
Mendenhall et al. [2]	2003	soft pal/ supragl/ glottic/ant tons pil	12/114/55/37	T1-4	RT(-CT)	3DCRT	5/12/8/3/12	6	<0.05
Mendenhall ∣2]	2003	hypo/BoT/tonsil + post tons pil	45/72/69	T1-4	RT(-CT)	3DCRT	6/24/18	6	NS
Pameijer et al. [3]	1998	pyrifrom sinus	23	T1/2	RT	3DCRT	N1	6.5	0.021
Keberle et al. [4]	2004	Hypo	45	pT1-4	S(-RT)	3DCRT	8.1	8.1	0.004
Plataniotis et al. [13]	2004	OC/Oro/Hypo/ Larynx	101	lll-IV	RT(-CT)	3DCRT	17/13/22.6/14.8 median TGTV	22.8		0.01
Grabenbauer et al. [14]	1998	OC/Oro/Hypo/ Larynx	87	lll-IV	RT(-CT	3DCRT	median 110ml	110		0.0001
Rudat et al. [19]	1999	OC/Oro/Hypo/ Larynx	68	T2-4	RT-CT	3DCRT	median 112 TGTV	112	0.0008
Mukherji et al. [5]	2000	supraglottic	37	pT1-4	S(-RT)	3DCRT	9.3	16	0.04
Freeman et al. [21]	1990	supraglottic	31	T1-4	RT	3DCRT	Nl	6	0.038
Gilbert et al. [6]	1987	Larynx	37	T2-4	RT	3DCRT	21.8* vs 8.9*	–		0.02
Lee et al. [7]	1993	glottic	29	T3	RT	3DCRT	Nl	3.5	0.02
Pameijer et al. [8]	1997	glottic	42	T3	RT	3DCRT	Nl	3.5	0.0002
Chua et al. [9]	1997	NPC	290	T1-3	RT(-CT)	3DCRT	6.9/18.8/52.4 in T1,2,3	20 / >60	<0.05
Nathu et al. [22]	2000	oro	114	T2-4	RT(-CT)	3DCRT	6.8/14.8/42.6 in T2,3,4	N1	NS
Keberle et al. [23]	2003	oro	80	PT1-4	S(-RT)	3DCRT	median 4.7	Nl	NS
Hermans et al. [10]	2001	oro	112	T1-4	RT	3DCRT	3.1/10.6/14.5/44.9 in T1-4	6/14.5/31	0.047	NS
Chao et al. [11]	2004	oro	31	l-IV	RT(-CT)	IMRT	30.5	Nl	0.05
Present study	2006	oro	85	T1-4	RT(-CT)	IMRT	34	15/70	<0.001
Present study	2006	all except larynx	172	T1-4	RT(-CT)	IMRT	37.7	15/70	<0.02
Doweck et al. [20]	2002	all	64	lll-IV	RT-CT	3DCRT	35.4	19.6		0.0018
Johnson et al. [15]	1995	all	51	advanced	RT	3DCRT	median 35 TGTV	35	0.0001
Kurek et al. [16]	2003	all	107	T1-4	RT(-CT)	3DCRT	median 32.5 and 44.4	Nl		0.02

Assessments of nodal and distant outcome related to GTV have not been reported in the listed articles.

To our knowledge, there is one previous article reported on the volumetric impact of GTV on outcome in HNC patients treated with IMRT. The unfavourable impact of the tumor volume on outcome in our series confirms results of a multivariate analysis by Chao et al. [11]. These authors showed GTV (primary volume with a mean value of 30.5 cm³) to be the only significant independent parameter predicting local and distant control in oropharyngeal tumor patients treated with definitive IMRT.

In patients with an intermediate GTV, careful dose escalation confined to the GTV may be of potential benefit and also tolerable with respect to the excellent normal tissue tolerance reported from all IMRT centres. Another issue to consider is hyperfractionation or moderate acceleration in this patient selection.

Conclusion

Tumor volume (GTV) was shown to represent the most important prognostic indicator in HNC patients treated with IMRT. GTV offers a useful tool in stratifying prognostic subgroups. In addition to the TNM classification, tumor volume is recommended to be considered for therapeutic decisions and estimation of outcome.

Further prospective analyses are in evaluation, in order to assess the value of volumetric staging in different HNC entities.

This work is in part sponsored by a credit of the Zurich Cancer League. There are no issues of conflict of interest.