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Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large volume head neck cancer

Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large... Background: Former prospective analyses revealed gross tumor volume (GTV) as the most reliable parameter to statistically significantly predict disease control in head neck cancer (HNC) patients treated with definitive intensity modulated radiation therapy (IMRT) +/-concomitant systemic therapy. The most ‘unfavourable’ subgroup was characterized by total GTV (tGTV) of > 70 cc, translating in ~50 and 65% 3-year disease free (DFS) and overall survival (OAS, vs 68% and 88% in tGTV < 70 cc, p = 0.001 and 0.0001), and ~25% distant spread (vs 6% for tGTV < 70 cc, p < 0.0001). The aim of this report was to analyze whether there is a subgroup out of patients with tGTV > 70 cc, which only marginally benefits from intensive curative treatment. Results: Between 03/2002-03/2011, 112 HNC patients with tGTV > 70 cc were definitively irradiated with curative intention. Mean tGTV was 104 cc (71-251). 98/112 (88%) patients underwent systemic therapy. Parameters with potential impact on disease outcome were retrospectively tested. The 3-year local-regional control (LRC), DFS and OAS rates were 61%, 50%, and 58%. The used cut-off value of 130 cc revealed an inverse association between tGTV and outcome. Patients able to undergo any systemic therapy (n = 98, mean tGTV0 103 cc, mean age 60 years) showed a satisfying and significantly superior outcome compared to the subgroup with radiation alone (n = 14, mean tGTV 99 cc, mean age 73 years), with 53% vs 17% 3-year DFS (p = 0.01). Radiation alone for tGTV > 130 cc failed to aim its curative goal in 3/3 patients. Conclusion: Patients with tGTV > 70 cc unable to undergo any systemic therapy represented a subgroup in which disease control was achievable in < 20% following curatively intended IMRT. Prospective testing of a larger sample size is needed to evaluate, if radiation alone for tGTV >~130 cc fails to meet its curative aim. Keywords: loco-regionally advanced HNC, tumour volume as prognostic factor, systemic therapy in advanced HNC, IMRT in advanced HNC Background and 65% 3-year disease free (DFS) and overall survival Former analyses revealed gross tumor volume (GTV) as (OAS, vs 68% and 88% for tGTV < 70 cc, p = 0.001/ the most reliable prognostic parameter for outcome in 0.0001), with distant spread in ~25% (vs 6% if tGTV < head and neck cancer (HNC) patients treated with 70 cc, p < 0.0001) [2]. This ‘unfavourable’ subgroup represents one quarter of simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) +/- concomitant systemic all squamous cell carcinoma (SCC) HNC patients therapy [1]: the ‘unfavourable’ subgroup was character- referred to our institution for definitively IMRT in cura- ized by total GTV (tGTV) of > 70 cc, translating in ~50 tive intention (112/458 (23%), 03/2011). Many patients presenting with such advanced tumours are suffering form alcohol abuse with related co-morbidities and fre- * Correspondence: gabriela.studer@usz.ch quently limited compliance. For this cohort with consid- Department of Radiation Oncology, University Hospital Zurich, Raemistrasse erable risk for treatment failure and tolerance problems, 100, 8091 Zurich, Switzerland Full list of author information is available at the end of the article © 2011 Studer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Studer et al. Radiation Oncology 2011, 6:120 Page 2 of 6 http://www.ro-journal.com/content/6/1/120 the risk-benefit ratio of intensive treatment approaches Table 1 Characteristics of the analyzed cohort with curative intention remains difficult to estimate in Parameters Patients advance. Our philosophy is to try to prevent patients N patients included 112 (100%) from usually quickly developing severe loco-regional definitive SIB-IMRT 112 (100%) symptoms due to large tumor volumes. conc. syst Tx, IC, no syst Tx 75 (70%), 24 (21%), 14 (12%) The aim of this report was to analyze whether there is time interval 3/2002 - 03/2011 a subgroup identifiable which only marginally benefits male/female (%) 96/16 (86/14) from intensive curative treatment. age, mean/median (range) 62/61 years (33-87) Between March 2002 and March 2011, 112 HNC WHO performance status 0/1/2 78 (70%)/33 (29%)/1 (1%) patients with tGTV > 70 cc were treated using a pro- Diagnosis (%) spectively defined curative radiation therapy schedule. oropharynx 62 (55%) Patients diagnosed with other than squamous cell carci- hypopharynx 22 (20%) noma or with nasopharyngeal cancer were excluded (n oral cavity 10 (9%) = 24). In 98/112 patients (88%), systemic therapy was larynx 5 (4%) administered. Table 1 shows patient and tumour charac- others 9 (8%) teristic. A second (n = 24), third (n = 2) or even fourth CUP 4 (4%) (n = 1) malignancy was diagnosed prior or after comple- T (number),% recurrence 5, 4% (101 cc, 10-206) tion of treatment of the HNC in 27 patients of the (mean volume, range) cohort (24%). Twelve patients (10%) were initially diag- CUP 4, 4% (0 cc) nosed with or suspicious for small distant metastases T1 6, 5% (7 cc, 4-13) (lung in most cases). This was not considered a contra- T2 15, 13% (34 cc, 5-63) indication for a curative loco-regional IMRT approach. T3 23, 20% (60 cc, 10-122) Patients with small or questionable M1 lesions were T4 59, 53% (77 cc, 12-206) included into this analysis, as for those patients the N (number),% recurrence 1, 1% (5 cc) same difficult question (loco-regionally curative treat- (mean volume, range) ment or not?) has to be answered in the clinical routine, N0 10, 6% (0 cc) and as suspicion for/limited initial M+ status did not N1a-2b 39, 13% (34 cc, 1-125) turn out as an inverse parameter allowing to exclude N2c 37, 64% (30 cc, 1-119) patients from loco-regionally curative treatment (see N3 25, 23% (83 cc, 28-160) results). Gross Tumor Volumes (GTV) The selection of patients considered as ‘still potentially mean primary GTV (range) 62 cc (0-206) loco-regionally radio-curable’ remains somewhat arbi- mean nodal GTV (range) 41 cc (0-160) trary and influenced by personal experience, however, mean total GTV (range) 104 cc (71-251) was consistent over the analyzed time period, as all Follow up, mean/median (range) months patients were evaluated by the same radiation oncolo- all patients 26/21 (3-91) gists (CG and GS). Main criteria for the decision to sup- alive patients (n = 58) 30/24 (5-85) port a curative treatment approach were 1) the anatomic dead patients (n = 39) 18/13 (4-60) tumor extent, including the GTV relation to surround- SIB-IMRT: simultaneously integrated boost intensity-modulated radiation ing critical structures, with respect to the boost dose therapy volume, 2) oral cavity tumors (as definitive radiation of Conc. CT: concomitant chemotherapy oral cavity tumors resulting in low disease control [3]), IC: induction chemotherapy CUP: carcinoma of unknown primary and 3) taking patients’ compliance and interest in undergoing a time consuming therapy with risk for tol- between 01/2002-12/2004 and 01-11/2005; n = total erance problems into account. In patients who pre- 172), the volumetric staging system (VSS) was found to sented with very advanced loco-regional disease with represent the most important predictor for local-regio- doubtful curative radio-therapeutic options, induction nal outcome [1]. This VSS bases on two cut-offs (15 cc chemotherapy (IC) was provided if possible (n = 24). and 70 cc), resulting in three volumetric subgroups: pri- The aim of the IC was to ease the decision to initiate a mary GTV or total GTV (tGTV) of 1-15 cc (favourable) potentially curative versus palliative loco-regional treat- vs 16–70 cc (intermediate) vs > 70 cc (unfavourable). ment approach, based on the response to IC [4]. While the primary GTV was used to predict local con- trol rates, tGTV was shown to best predict nodal con- - Volumetric staging trol, distant metastasis free, disease free and overall In a former evaluation based on 88 retrospectively and survival, respectively. The volumetric criterion has since 84 prospectively analysed IMRT patients (treated Studer et al. Radiation Oncology 2011, 6:120 Page 3 of 6 http://www.ro-journal.com/content/6/1/120 2.00 been applied prospectively on our definitive IMRT � SIB : daily dose 2.00 Gy (PTV1)/1.70 Gy (PTV2)/ patients to estimate disease outcome. 1.54 Gy (PTV3); total dose: 68-70.00 Gy (n = 20); 2.11 In thecurrent work, wefocus on theabovedescribed � SIB : daily dose 2.11 Gy (PTV1)/1.80 Gy (PTV2)/ unfavourable subgroup with tGTV > 70 cc. Additional 1.64 Gy (PTV3); total dose: 69.60 -71.7 Gy (n = 76); 2.20 volumetric sub-grouping (cut-off 130 cc) and the impact � SIB : daily dose 2.20 Gy (PTV1)/2.00 Gy (PTV2)/ of systemic therapy were retrospectively tested, aiming 1.80 Gy (PTV3); total dose: 66.00 -72.6 Gy (n = 16). to try to identify a palliative subgroup out of the ‘unfa- The dose was normalized to the mean dose in PTV1. vourable’ cohort with tGTV > 70 cc (outcome data were For intensity optimization 95% of the prescribed dose first analyzed by retrospectively testing two cut-offs, 100 should encompass at least 95% of the PTV and 100% of cc and 130 cc, resulting in nearly identical outcome the prescribed dose encompassed the GTV. No more results for patients with tGTV 71-100 cc and 101-130 than 20% of any PTV would receive > 110% of its pre- cc, while patients with tGTV > 130 cc did worse; this scribed dose, while no more than 1% of any PTV would finding lead to the retrospective use of one single cut- receive < 93% of the desired dose. off value of 130 cc). If the normal tissue volume or the exposed mucosal Volumetric three-dimensional measurements (cc) of tissue volume was felt to be too large to receive 70 Gy contoured GTVs were calculated by the Varian Treat- by using the above described standard PTV1 (GTV plus ment Planning System (TPS, Eclipse V8.5, Varian Med- 1-1.5 cm), the dose to PTV1 was reduced to 66-68 Gy, ical Systems, Palo Alto, CA) volume algorithm. with no change to the prescription dose delivered to the GTV (’GTV-PTV’). Methods - IMRT planning - Chemotherapy Patients were immobilized from head to shoulders with a) Cisplatin commercially available thermoplastic masks and an indi- Systemic standard concomitant cisplatin based therapy vidually customized bite block. CT images (2 mm slice was given to eligible patients (n = 76, 68%); our pre- thickness) were acquired from the upper aspect of the ferred cisplatin regimen of 40 mg/m2 i. v. per radiation orbita to the level of the carina. Contrast agent enhance- week was used in all cases. ment was used whenever possible. b) Cetuximab The target volumes were drawn on each axial planning Since April 2006, cetuximab has been used for patients CT slice, based on diagnostic CT images, supplemented who were not eligible to undergo cisplatin chemother- with fused diagnostic MRI and/or PET-CT scans. The apy. Most frequent reasons for initial cetuximab therapy GTV included the gross extent of the primary disease or switch from standard cisplatin based chemotherapy and involved lymph nodes. PTV1 (planning target to cetuximab were decreased hearing, tinnitus, or volume) was defined by adding a 1 - 15 mm margin to impaired renal function (n=26, 23%).Anintravenous the GTV, dependent on the proximity of the lesion to loading dose of 400 mg/m cetuximab was administered critical structures. PTV2 covered areas at high risk for in the week prior to the commencement of radiation, potential microscopic disease. PTV3 included the clini- followed by 250 mg/m2 per radiation week. cally negative cervical lymphatic nodes down to the c) Induction Chemotherapy (IC) supra-clavicular fossa (elective PTV). Organs at risk were In 24 (21%) compliant patients with no serious medical outlined in three dimensions with an estimated planning contra-indications for IC, who presented with very organ-at-risk volume (PRV) margin of 2-10 mm. We advanced loco-regional disease (mean 120 cc, range 73- used an extended-field IMRT (EF-IMRT) technique, 177) with poor curability, IC was offered. The aim of IC where the primary was treated in one phase along with was to ease the decision to initiate potentially curative the regional lymph nodes. Irradiation was delivered with radiation therapy, based on the response to IC. Most five or seven coplanar beam angles by a 6-MV dynamic frequently used IC drug combination was taxotere/cis- multi-leaf collimator (MLC) system (sliding-window platin/5-fluoro-uracil. technique; Varian Medical Systems, Palo Alto, CA, USA). In some patients, volumetric modulated arc therapy Statistics (VMAT) technique on a Truebeam Varian linear accel- Theinfluenceof thetumourvolume(tGTV)and sys- erator was applied. All patients signed an informed con- temic therapy was retrospectively tested. In addition, sent as approved by our local ethical board. univariate analysis of the impact of TN stages, age, diag- nosis, distant metastasis at initial diagnosis, and pre- - Prescription Dose therapeutic performance status were performed. Statisti- As previously described [5], SIB-IMRT was performed cal calculations were performed using the statistics pro- using the following schedules (five fractions/week each): gram implemented in StatView (version 4.5; SAS Studer et al. Radiation Oncology 2011, 6:120 Page 4 of 6 http://www.ro-journal.com/content/6/1/120 Institute, Cary, NC). Proportions were compared using Table 3 Actuarial survival rates related to +/- systemic therapy and tGTV volume the Chi-square test. Univariate analyses were performed with a Cox proportional hazards regression model in Parameters (n) 3y-OAS 3y-DFS 3y-DMFS 3y-LRC StatView . Actuarial survival data were calculated using entire cohort (112) 58% 50% 70% 61% Kaplan-Meier curves and log-rank tests implemented in no systemic therapy (14) 25% 17% 50% 25% StatView . Stratification of variables was done with help any systemic therapy (98) 61% 53% 72% 64% of log rank (Mantel-Cox) calculation. p-value < 0.0001 0.01 0.1 (NS) 0.04 P values < 0.05 were considered statistically < 130 cc (91) 58% 51% 75% 62% significant. > 130 cc (21) 30% 38% 40% 40% p-value 0.1 (NS) 0.2(NS) 0.001 0.05 Results no systemic therapy (14) 25% 17% 50% 25% - Disease control any systemic therapy, > 130 30% 40% 50% 45% After a mean/median follow up time of 26/21 months, 51 cc (19) patients (46%) were alive with no evidence of disease any systemic therapy, < 130 63% 55% 78% 76% (ANED) when last time seen. The related follow up cc (79) times, time to treatment failure and Kaplan Meier actuar- p-value 0.0001 0.03 0.01 0.04 ial survival curves are shown in Table 2, 3, and Figure 1. OAS: overall survival DMFS: distant metastasis free survival Distant spread (M+) developed in 32/112 patients DFS: disease free survival (29%); lesions suspicious for M+ were pre-therapeuti- LRC: loco-regional control cally diagnosed in 12/32 patients (38%), which reached the same 2-year overall survival rate of 65% as the initi- ally M0-subgroup; 8ofthe 12 patients were still alive mean 11 months post treatment (4-21). In 15/32 (47%), tGTV < 130 cc resulted in a tendency towards superior distant metastases remained the only sign of disease (i. OAS, DFS and LRC rate, with a significant difference in e., M+ with loco-regional control) mean 21 months (5- the distant metastasis rate. 84)postIMRT. In 7of32patients(6% of theentire cohort) new and isolated distant disease during the - Impact of systemic therapy post-treatment follow up period were found. Patients who where eligible to undergo any systemic Thirty-six patients (32%) experienced local failure, in therapy (i. e., 1-7 cycles of concomitant cisplatin or 21 of them (58%), the primary tumour persisted (persis- cetuximab, and/or induction chemotherapy, n = 98 tent disease defined as macroscopic persistence or re- (88%)), versus those who were not (n = 14 (12%) - in growth to macroscopic disease during the first 3 months most cases due to co-morbidity and/or age) were found from treatment start). Nodal failure occurred in 25 to achieve significantly superior 3-year survival rates (22%) patients, in 13/25 (52%) as persistent disease. (Table 3, Figure 2). The tGTV was similar in both - Impact of the tumour volume The expected inverse association between tumour volume and disease control was tested using the retro- spectively chosen cut-off value of 130 cc (Table 3): Table 2 Duration of follow up and interval of disease free survival, analysed according to the status of patients when last time seen Status follow up, months time to disease, months last time seen (n) mean/median (range) mean/median (range) ANED (51, 46%) 37/36 (3-91) 0 INED (10, 9%) 26/19 (5-60) 0 AD (12, 11%) 10/7 (2-23) 4/8 (0-11) DOD (39, 35%) 16/12 (4-53) 5/4 (0-28) ANED: alive with no evidence of disease INED: inter-current dead without disease Figure 1 Kaplan Meier actuarial survival rates of the entire AD: alive with disease cohort. LRC: loco-regional control rate. MFS: metastasis free survival DOD: died of disease rate. DFS: disease free survival rate. OAS: overall survival. na: not assessable Studer et al. Radiation Oncology 2011, 6:120 Page 5 of 6 http://www.ro-journal.com/content/6/1/120 Discussion 1 1 The previously defined ‘unfavourable’ SCC HNC patient subgroup with large tGTV > 70 cc [1] has been updated .8 .8 (Table 1, Figure 1) and further analyzed, using the advantage of volumetric staging to define further volu- .6 .6 D DF FS S,, an any y c c h he em mot othe her ra ap py y ( (n n= =9 98) 8) metric subgroups. The aim of this report was to analyze whether a subgroup of patients with large tGTV > 70 cc .4 .4 referred for curative treatment can be defined which only marginally benefits from intensive curative treat- .2 .2 ment. Weaknesses of this report are its retrospective D DF FS S,, n no o c che hem mot othe her r a apy py ( ( n n= =1 14 4) ) approach, retrospective subgroup analysis, and the use p= p=0 0..0 01 1 0 0 of different chemotherapeutic schedules and chemother- apeutic dose-intensity, respectively. The strength of this 0 0 20 20 40 40 60 60 80 80 10 100 0 report is a homogeneous IMRT contouring and treat- m mo on ntth hs s ment delivery performed according to prospectively Figure 2 Kaplan-Meier actuarial disease free survival (DFS) rates of subgroups with and without any systemic therapy. defined treatment schedules in all patients, and in the relatively large sample size. Our outcome results are comparable with selected recently published data on ‘non-resectable’ HNC treated groups (mean 99 cc vs 103 cc, NS), while the mean age with radio-chemotherapy, with DFS/OAS rates of expectedly significantly differed (60 years (range 41-81) in patients with combined modality treatment, vs 73 approximately 50/60% versus ~25/45% [6], 65/70% [7], years (range 58-87) in the IMRT only subgroup, p = 50/65% [8]. 0.01). Eleven of the 14 patients who underwent radiation We found a statistically significantly inferior outcome only (79%), died from disease during the first 20 in patients not being able to undergo any systemic ther- months; however, in 8 of them, substantial subjective apy (Table 3 and Figure 2). This result is limited by the loco-regional benefit was documented for a mean dura- unbalanced sample sizes (14 vs 98), and the significant tion of 17 months (range 4-20). The remaining three difference in mean age (expectedly, as higher age and patients who experienced no benefit suffered from per- related frequent severe co-morbidity are usual reasons sistent local disease. Three patients with tGTV > 130 cc to not apply systemic therapy). It is known that higher treated with radiation alone died from disease after 2, 3, age per se may inversely influence outcome [9] - age could therefore be an independent reason for inferior and 10 months, respectively. outcome. A potential difference of the impact of sys- Only 2/14 (14%) patients treated with IMRT alone temic therapy on very advanced (’unresectable’)versus remained alive with no evidence of disease, vs 41/78 less advanced stages (lower tumor load) HNC is not (52%) treated with any systemic therapy for tGTV < 130 well known to our best knowledge. The subgroup with cc, vs 8/19 (42%) treated for tGTV > 130 cc, tGTV > 70 cc and unable to undergo systemic therapy respectively. still achieved 2-year DFS/OAS rates of approximately 30% (Figure 2), justification enough to consider a cura- - Additional potentially prognostic parameters tive IMRT approach also for this subgroup. The initial pre-treatment WHO performance status As in previous investigations on volumetric based out- (Table 1) was not found to be of prognostic value (49% come prediction [1] (Table VI in reference [1]) and [2], vs 50% 3-year DFS, p = 0.26). Similarly, there was no an inverse association between tGTV and disease con- gender-related outcome difference (p = 0.3). Analysis based on T and N stages or TN grouping resulted in trol was also found in the here assessed patient segment non-significantly different or nearly identical Kaplan with ‘very large tumor volume’: patients with tGTV > Meier survival curves. Also the primary tumour site 130 cc tended towards inferior outcome, with nearly (mesopharynx versus hypopharynx) or age (grouped in 40% achieving 3-year disease control (versus > 50% in decades: < 50 vs 50-60 vs 61-70 vs > 70 years) showed patients with tGTV < 130 cc (NS), Table 3); again, this no prognostic value. Patients suspicious of distant outcome data justify offering a curative combined mod- metastasis did not worse compared with initially M0- ality treatment to compliant patients with very large patients (see above). Any potential impact of the human tumor volumes. papilloma virus (HPV) status on the disease control in Eight of 12 patients suspicious of initial M+ status were still alive at mean ~1 year (range 4-21 months) this ‘very large tumour volume’ patient cohort could not post treatment, enjoying beneficial treatment effects; the be assessed, as the HPV status was not available in most imaging diagnosis of limited M+ status should not be of our patients. Cu Cum m.. S Su ur r v viiv v a all Studer et al. Radiation Oncology 2011, 6:120 Page 6 of 6 http://www.ro-journal.com/content/6/1/120 participated in the data acquisition. All authors read and approved the final used as a criterion to exclude patients from loco-regio- manuscript. nal curative IMRT approach. Radiation is known as most effective local therapy for advanced non-resectable Conflicts of interest The authors declare that they have no competing interests. loco-regional disease, however requiring high doses, if possible enhanced by systemic therapy. In order to keep Received: 3 June 2011 Accepted: 22 September 2011 side effects as low as possible, IMRT should be used Published: 22 September 2011 also in patients with radiologically suspicious distant References lesions. Whether further investigation should be per- 1. Studer G, Lutolf UM, El-Bassiouni M, Rousson V, Glanzmann C: Volumetric formed on suspicious M1 lesions has to be decided case staging (VS) is superior to TNM and AJCC staging in predicting outcome by case. of head and neck cancer treated with IMRT. Acta Oncol 2007, 46:386-394. 2. Studer G, Seifert B, Glanzmann C: Prediction of distant metastasis in head The most unfavourable subgroup seems characterized neck cancer patients: implications for induction chemotherapy and pre- by (elderly) patients with a tumour load of > 130 cc and treatment staging? Strahlenther Onkol 2008, 184:580-585. unable to undergo any systemic treatment - this group 3. Studer G, Zwahlen RA, Graetz KW, Davis BJ, Glanzmann C: IMRT in oral cavity cancer. Radiat Oncol 2007, 2:16. however was too small to draw reliable conclusions 4. Induction chemotherapy plus radiation compared with surgery plus from it (this question is under prospective evaluation at radiation in patients with advanced laryngeal cancer. The Department our institution). of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991, 324:1685-1690. 5. Studer G, Peponi E, Kloeck S, Dossenbach T, Huber G, Glanzmann C: In sum Surviving Hypopharynx-Larynx Carcinoma in the Era of IMRT. Int J Radiat � patients with tGTV > 70 cc treated with IMRT and Oncol Biol Phys 2010. 6. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, systemic therapy achieved 3-year DFS and OAS of Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, approximately 50% and 60%, respectively Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL: Cisplatin, � (elderly) patients with tGTV > 70 cc treated with fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007, 357:1695-1704. IMRT alone represented a subgroup which only margin- 7. Tribius S, Kronemann S, Kilic Y, Schroeder U, Hakim S, Schild SE, Rades D: ally benefits from curative IMRT (3-year OAS/DFS Radiochemotherapy including cisplatin alone versus cisplatin + 5- ~25%/< 20%, 3-year DFS 17%); nevertheless, most fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck. Strahlenther Onkol 2009, 185:675-681. patients experienced subjective benefit from radiation in 8. Tobias JS, Monson K, Gupta N, Macdougall H, Glaholm J, Hutchison I, terms of symptom relief, which is considered justifying Kadalayil L, Hackshaw A: Chemoradiotherapy for locally advanced head IMRT at least aiming effective palliation and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial. Lancet Oncol 2010, 11:66-74. � (elderly) patients with very large tGTV > 130 cc 9. Pignon JP, le Maitre A, Maillard E, Bourhis J: Meta-analysis of treated with IMRT alone did worst (1-y OAS 0%), how- chemotherapy in head and neck cancer (MACH-NC): an update on 93 ever, a larger sample size is needed for corroboration randomised trials and 17,346 patients. Radiother Oncol 2009, 92:4-14. doi:10.1186/1748-717X-6-120 Conclusions Cite this article as: Studer et al.: Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large volume Tumour volume and eligibility to undergo systemic head neck cancer. Radiation Oncology 2011 6:120. therapy were found important prognostic factors in patients with large tGTV load > 70 cc. Larger sample sizes are required to test, if patients with tGTV > 130 cc and unable to undergo systemic therapy should be prevented from curative treatment approaches. Radiobiological parameters may identify other criteria to defineapalliativesubgroupamong thepatientswith very large tumour volumes. Submit your next manuscript to BioMed Central and take full advantage of: Author details Department of Radiation Oncology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. Department of Oncology, University Hospital • Convenient online submission Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. • Thorough peer review • No space constraints or color figure charges Authors’ contributions GS conceived of the study and carried out its design, CG and GS draw the • Immediate publication on acceptance contours in all cases, approved all dose distribution plans and were • Inclusion in PubMed, CAS, Scopus and Google Scholar responsible for the initial decision of a curative treatment approach in the individual patients. CG was involved in the data analysis and interpretation. • Research which is freely available for redistribution TR decided on and supervised IC application in the assessed patients, and Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large volume head neck cancer

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Copyright © 2011 by Studer et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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10.1186/1748-717X-6-120
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Abstract

Background: Former prospective analyses revealed gross tumor volume (GTV) as the most reliable parameter to statistically significantly predict disease control in head neck cancer (HNC) patients treated with definitive intensity modulated radiation therapy (IMRT) +/-concomitant systemic therapy. The most ‘unfavourable’ subgroup was characterized by total GTV (tGTV) of > 70 cc, translating in ~50 and 65% 3-year disease free (DFS) and overall survival (OAS, vs 68% and 88% in tGTV < 70 cc, p = 0.001 and 0.0001), and ~25% distant spread (vs 6% for tGTV < 70 cc, p < 0.0001). The aim of this report was to analyze whether there is a subgroup out of patients with tGTV > 70 cc, which only marginally benefits from intensive curative treatment. Results: Between 03/2002-03/2011, 112 HNC patients with tGTV > 70 cc were definitively irradiated with curative intention. Mean tGTV was 104 cc (71-251). 98/112 (88%) patients underwent systemic therapy. Parameters with potential impact on disease outcome were retrospectively tested. The 3-year local-regional control (LRC), DFS and OAS rates were 61%, 50%, and 58%. The used cut-off value of 130 cc revealed an inverse association between tGTV and outcome. Patients able to undergo any systemic therapy (n = 98, mean tGTV0 103 cc, mean age 60 years) showed a satisfying and significantly superior outcome compared to the subgroup with radiation alone (n = 14, mean tGTV 99 cc, mean age 73 years), with 53% vs 17% 3-year DFS (p = 0.01). Radiation alone for tGTV > 130 cc failed to aim its curative goal in 3/3 patients. Conclusion: Patients with tGTV > 70 cc unable to undergo any systemic therapy represented a subgroup in which disease control was achievable in < 20% following curatively intended IMRT. Prospective testing of a larger sample size is needed to evaluate, if radiation alone for tGTV >~130 cc fails to meet its curative aim. Keywords: loco-regionally advanced HNC, tumour volume as prognostic factor, systemic therapy in advanced HNC, IMRT in advanced HNC Background and 65% 3-year disease free (DFS) and overall survival Former analyses revealed gross tumor volume (GTV) as (OAS, vs 68% and 88% for tGTV < 70 cc, p = 0.001/ the most reliable prognostic parameter for outcome in 0.0001), with distant spread in ~25% (vs 6% if tGTV < head and neck cancer (HNC) patients treated with 70 cc, p < 0.0001) [2]. This ‘unfavourable’ subgroup represents one quarter of simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) +/- concomitant systemic all squamous cell carcinoma (SCC) HNC patients therapy [1]: the ‘unfavourable’ subgroup was character- referred to our institution for definitively IMRT in cura- ized by total GTV (tGTV) of > 70 cc, translating in ~50 tive intention (112/458 (23%), 03/2011). Many patients presenting with such advanced tumours are suffering form alcohol abuse with related co-morbidities and fre- * Correspondence: gabriela.studer@usz.ch quently limited compliance. For this cohort with consid- Department of Radiation Oncology, University Hospital Zurich, Raemistrasse erable risk for treatment failure and tolerance problems, 100, 8091 Zurich, Switzerland Full list of author information is available at the end of the article © 2011 Studer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Studer et al. Radiation Oncology 2011, 6:120 Page 2 of 6 http://www.ro-journal.com/content/6/1/120 the risk-benefit ratio of intensive treatment approaches Table 1 Characteristics of the analyzed cohort with curative intention remains difficult to estimate in Parameters Patients advance. Our philosophy is to try to prevent patients N patients included 112 (100%) from usually quickly developing severe loco-regional definitive SIB-IMRT 112 (100%) symptoms due to large tumor volumes. conc. syst Tx, IC, no syst Tx 75 (70%), 24 (21%), 14 (12%) The aim of this report was to analyze whether there is time interval 3/2002 - 03/2011 a subgroup identifiable which only marginally benefits male/female (%) 96/16 (86/14) from intensive curative treatment. age, mean/median (range) 62/61 years (33-87) Between March 2002 and March 2011, 112 HNC WHO performance status 0/1/2 78 (70%)/33 (29%)/1 (1%) patients with tGTV > 70 cc were treated using a pro- Diagnosis (%) spectively defined curative radiation therapy schedule. oropharynx 62 (55%) Patients diagnosed with other than squamous cell carci- hypopharynx 22 (20%) noma or with nasopharyngeal cancer were excluded (n oral cavity 10 (9%) = 24). In 98/112 patients (88%), systemic therapy was larynx 5 (4%) administered. Table 1 shows patient and tumour charac- others 9 (8%) teristic. A second (n = 24), third (n = 2) or even fourth CUP 4 (4%) (n = 1) malignancy was diagnosed prior or after comple- T (number),% recurrence 5, 4% (101 cc, 10-206) tion of treatment of the HNC in 27 patients of the (mean volume, range) cohort (24%). Twelve patients (10%) were initially diag- CUP 4, 4% (0 cc) nosed with or suspicious for small distant metastases T1 6, 5% (7 cc, 4-13) (lung in most cases). This was not considered a contra- T2 15, 13% (34 cc, 5-63) indication for a curative loco-regional IMRT approach. T3 23, 20% (60 cc, 10-122) Patients with small or questionable M1 lesions were T4 59, 53% (77 cc, 12-206) included into this analysis, as for those patients the N (number),% recurrence 1, 1% (5 cc) same difficult question (loco-regionally curative treat- (mean volume, range) ment or not?) has to be answered in the clinical routine, N0 10, 6% (0 cc) and as suspicion for/limited initial M+ status did not N1a-2b 39, 13% (34 cc, 1-125) turn out as an inverse parameter allowing to exclude N2c 37, 64% (30 cc, 1-119) patients from loco-regionally curative treatment (see N3 25, 23% (83 cc, 28-160) results). Gross Tumor Volumes (GTV) The selection of patients considered as ‘still potentially mean primary GTV (range) 62 cc (0-206) loco-regionally radio-curable’ remains somewhat arbi- mean nodal GTV (range) 41 cc (0-160) trary and influenced by personal experience, however, mean total GTV (range) 104 cc (71-251) was consistent over the analyzed time period, as all Follow up, mean/median (range) months patients were evaluated by the same radiation oncolo- all patients 26/21 (3-91) gists (CG and GS). Main criteria for the decision to sup- alive patients (n = 58) 30/24 (5-85) port a curative treatment approach were 1) the anatomic dead patients (n = 39) 18/13 (4-60) tumor extent, including the GTV relation to surround- SIB-IMRT: simultaneously integrated boost intensity-modulated radiation ing critical structures, with respect to the boost dose therapy volume, 2) oral cavity tumors (as definitive radiation of Conc. CT: concomitant chemotherapy oral cavity tumors resulting in low disease control [3]), IC: induction chemotherapy CUP: carcinoma of unknown primary and 3) taking patients’ compliance and interest in undergoing a time consuming therapy with risk for tol- between 01/2002-12/2004 and 01-11/2005; n = total erance problems into account. In patients who pre- 172), the volumetric staging system (VSS) was found to sented with very advanced loco-regional disease with represent the most important predictor for local-regio- doubtful curative radio-therapeutic options, induction nal outcome [1]. This VSS bases on two cut-offs (15 cc chemotherapy (IC) was provided if possible (n = 24). and 70 cc), resulting in three volumetric subgroups: pri- The aim of the IC was to ease the decision to initiate a mary GTV or total GTV (tGTV) of 1-15 cc (favourable) potentially curative versus palliative loco-regional treat- vs 16–70 cc (intermediate) vs > 70 cc (unfavourable). ment approach, based on the response to IC [4]. While the primary GTV was used to predict local con- trol rates, tGTV was shown to best predict nodal con- - Volumetric staging trol, distant metastasis free, disease free and overall In a former evaluation based on 88 retrospectively and survival, respectively. The volumetric criterion has since 84 prospectively analysed IMRT patients (treated Studer et al. Radiation Oncology 2011, 6:120 Page 3 of 6 http://www.ro-journal.com/content/6/1/120 2.00 been applied prospectively on our definitive IMRT � SIB : daily dose 2.00 Gy (PTV1)/1.70 Gy (PTV2)/ patients to estimate disease outcome. 1.54 Gy (PTV3); total dose: 68-70.00 Gy (n = 20); 2.11 In thecurrent work, wefocus on theabovedescribed � SIB : daily dose 2.11 Gy (PTV1)/1.80 Gy (PTV2)/ unfavourable subgroup with tGTV > 70 cc. Additional 1.64 Gy (PTV3); total dose: 69.60 -71.7 Gy (n = 76); 2.20 volumetric sub-grouping (cut-off 130 cc) and the impact � SIB : daily dose 2.20 Gy (PTV1)/2.00 Gy (PTV2)/ of systemic therapy were retrospectively tested, aiming 1.80 Gy (PTV3); total dose: 66.00 -72.6 Gy (n = 16). to try to identify a palliative subgroup out of the ‘unfa- The dose was normalized to the mean dose in PTV1. vourable’ cohort with tGTV > 70 cc (outcome data were For intensity optimization 95% of the prescribed dose first analyzed by retrospectively testing two cut-offs, 100 should encompass at least 95% of the PTV and 100% of cc and 130 cc, resulting in nearly identical outcome the prescribed dose encompassed the GTV. No more results for patients with tGTV 71-100 cc and 101-130 than 20% of any PTV would receive > 110% of its pre- cc, while patients with tGTV > 130 cc did worse; this scribed dose, while no more than 1% of any PTV would finding lead to the retrospective use of one single cut- receive < 93% of the desired dose. off value of 130 cc). If the normal tissue volume or the exposed mucosal Volumetric three-dimensional measurements (cc) of tissue volume was felt to be too large to receive 70 Gy contoured GTVs were calculated by the Varian Treat- by using the above described standard PTV1 (GTV plus ment Planning System (TPS, Eclipse V8.5, Varian Med- 1-1.5 cm), the dose to PTV1 was reduced to 66-68 Gy, ical Systems, Palo Alto, CA) volume algorithm. with no change to the prescription dose delivered to the GTV (’GTV-PTV’). Methods - IMRT planning - Chemotherapy Patients were immobilized from head to shoulders with a) Cisplatin commercially available thermoplastic masks and an indi- Systemic standard concomitant cisplatin based therapy vidually customized bite block. CT images (2 mm slice was given to eligible patients (n = 76, 68%); our pre- thickness) were acquired from the upper aspect of the ferred cisplatin regimen of 40 mg/m2 i. v. per radiation orbita to the level of the carina. Contrast agent enhance- week was used in all cases. ment was used whenever possible. b) Cetuximab The target volumes were drawn on each axial planning Since April 2006, cetuximab has been used for patients CT slice, based on diagnostic CT images, supplemented who were not eligible to undergo cisplatin chemother- with fused diagnostic MRI and/or PET-CT scans. The apy. Most frequent reasons for initial cetuximab therapy GTV included the gross extent of the primary disease or switch from standard cisplatin based chemotherapy and involved lymph nodes. PTV1 (planning target to cetuximab were decreased hearing, tinnitus, or volume) was defined by adding a 1 - 15 mm margin to impaired renal function (n=26, 23%).Anintravenous the GTV, dependent on the proximity of the lesion to loading dose of 400 mg/m cetuximab was administered critical structures. PTV2 covered areas at high risk for in the week prior to the commencement of radiation, potential microscopic disease. PTV3 included the clini- followed by 250 mg/m2 per radiation week. cally negative cervical lymphatic nodes down to the c) Induction Chemotherapy (IC) supra-clavicular fossa (elective PTV). Organs at risk were In 24 (21%) compliant patients with no serious medical outlined in three dimensions with an estimated planning contra-indications for IC, who presented with very organ-at-risk volume (PRV) margin of 2-10 mm. We advanced loco-regional disease (mean 120 cc, range 73- used an extended-field IMRT (EF-IMRT) technique, 177) with poor curability, IC was offered. The aim of IC where the primary was treated in one phase along with was to ease the decision to initiate potentially curative the regional lymph nodes. Irradiation was delivered with radiation therapy, based on the response to IC. Most five or seven coplanar beam angles by a 6-MV dynamic frequently used IC drug combination was taxotere/cis- multi-leaf collimator (MLC) system (sliding-window platin/5-fluoro-uracil. technique; Varian Medical Systems, Palo Alto, CA, USA). In some patients, volumetric modulated arc therapy Statistics (VMAT) technique on a Truebeam Varian linear accel- Theinfluenceof thetumourvolume(tGTV)and sys- erator was applied. All patients signed an informed con- temic therapy was retrospectively tested. In addition, sent as approved by our local ethical board. univariate analysis of the impact of TN stages, age, diag- nosis, distant metastasis at initial diagnosis, and pre- - Prescription Dose therapeutic performance status were performed. Statisti- As previously described [5], SIB-IMRT was performed cal calculations were performed using the statistics pro- using the following schedules (five fractions/week each): gram implemented in StatView (version 4.5; SAS Studer et al. Radiation Oncology 2011, 6:120 Page 4 of 6 http://www.ro-journal.com/content/6/1/120 Institute, Cary, NC). Proportions were compared using Table 3 Actuarial survival rates related to +/- systemic therapy and tGTV volume the Chi-square test. Univariate analyses were performed with a Cox proportional hazards regression model in Parameters (n) 3y-OAS 3y-DFS 3y-DMFS 3y-LRC StatView . Actuarial survival data were calculated using entire cohort (112) 58% 50% 70% 61% Kaplan-Meier curves and log-rank tests implemented in no systemic therapy (14) 25% 17% 50% 25% StatView . Stratification of variables was done with help any systemic therapy (98) 61% 53% 72% 64% of log rank (Mantel-Cox) calculation. p-value < 0.0001 0.01 0.1 (NS) 0.04 P values < 0.05 were considered statistically < 130 cc (91) 58% 51% 75% 62% significant. > 130 cc (21) 30% 38% 40% 40% p-value 0.1 (NS) 0.2(NS) 0.001 0.05 Results no systemic therapy (14) 25% 17% 50% 25% - Disease control any systemic therapy, > 130 30% 40% 50% 45% After a mean/median follow up time of 26/21 months, 51 cc (19) patients (46%) were alive with no evidence of disease any systemic therapy, < 130 63% 55% 78% 76% (ANED) when last time seen. The related follow up cc (79) times, time to treatment failure and Kaplan Meier actuar- p-value 0.0001 0.03 0.01 0.04 ial survival curves are shown in Table 2, 3, and Figure 1. OAS: overall survival DMFS: distant metastasis free survival Distant spread (M+) developed in 32/112 patients DFS: disease free survival (29%); lesions suspicious for M+ were pre-therapeuti- LRC: loco-regional control cally diagnosed in 12/32 patients (38%), which reached the same 2-year overall survival rate of 65% as the initi- ally M0-subgroup; 8ofthe 12 patients were still alive mean 11 months post treatment (4-21). In 15/32 (47%), tGTV < 130 cc resulted in a tendency towards superior distant metastases remained the only sign of disease (i. OAS, DFS and LRC rate, with a significant difference in e., M+ with loco-regional control) mean 21 months (5- the distant metastasis rate. 84)postIMRT. In 7of32patients(6% of theentire cohort) new and isolated distant disease during the - Impact of systemic therapy post-treatment follow up period were found. Patients who where eligible to undergo any systemic Thirty-six patients (32%) experienced local failure, in therapy (i. e., 1-7 cycles of concomitant cisplatin or 21 of them (58%), the primary tumour persisted (persis- cetuximab, and/or induction chemotherapy, n = 98 tent disease defined as macroscopic persistence or re- (88%)), versus those who were not (n = 14 (12%) - in growth to macroscopic disease during the first 3 months most cases due to co-morbidity and/or age) were found from treatment start). Nodal failure occurred in 25 to achieve significantly superior 3-year survival rates (22%) patients, in 13/25 (52%) as persistent disease. (Table 3, Figure 2). The tGTV was similar in both - Impact of the tumour volume The expected inverse association between tumour volume and disease control was tested using the retro- spectively chosen cut-off value of 130 cc (Table 3): Table 2 Duration of follow up and interval of disease free survival, analysed according to the status of patients when last time seen Status follow up, months time to disease, months last time seen (n) mean/median (range) mean/median (range) ANED (51, 46%) 37/36 (3-91) 0 INED (10, 9%) 26/19 (5-60) 0 AD (12, 11%) 10/7 (2-23) 4/8 (0-11) DOD (39, 35%) 16/12 (4-53) 5/4 (0-28) ANED: alive with no evidence of disease INED: inter-current dead without disease Figure 1 Kaplan Meier actuarial survival rates of the entire AD: alive with disease cohort. LRC: loco-regional control rate. MFS: metastasis free survival DOD: died of disease rate. DFS: disease free survival rate. OAS: overall survival. na: not assessable Studer et al. Radiation Oncology 2011, 6:120 Page 5 of 6 http://www.ro-journal.com/content/6/1/120 Discussion 1 1 The previously defined ‘unfavourable’ SCC HNC patient subgroup with large tGTV > 70 cc [1] has been updated .8 .8 (Table 1, Figure 1) and further analyzed, using the advantage of volumetric staging to define further volu- .6 .6 D DF FS S,, an any y c c h he em mot othe her ra ap py y ( (n n= =9 98) 8) metric subgroups. The aim of this report was to analyze whether a subgroup of patients with large tGTV > 70 cc .4 .4 referred for curative treatment can be defined which only marginally benefits from intensive curative treat- .2 .2 ment. Weaknesses of this report are its retrospective D DF FS S,, n no o c che hem mot othe her r a apy py ( ( n n= =1 14 4) ) approach, retrospective subgroup analysis, and the use p= p=0 0..0 01 1 0 0 of different chemotherapeutic schedules and chemother- apeutic dose-intensity, respectively. The strength of this 0 0 20 20 40 40 60 60 80 80 10 100 0 report is a homogeneous IMRT contouring and treat- m mo on ntth hs s ment delivery performed according to prospectively Figure 2 Kaplan-Meier actuarial disease free survival (DFS) rates of subgroups with and without any systemic therapy. defined treatment schedules in all patients, and in the relatively large sample size. Our outcome results are comparable with selected recently published data on ‘non-resectable’ HNC treated groups (mean 99 cc vs 103 cc, NS), while the mean age with radio-chemotherapy, with DFS/OAS rates of expectedly significantly differed (60 years (range 41-81) in patients with combined modality treatment, vs 73 approximately 50/60% versus ~25/45% [6], 65/70% [7], years (range 58-87) in the IMRT only subgroup, p = 50/65% [8]. 0.01). Eleven of the 14 patients who underwent radiation We found a statistically significantly inferior outcome only (79%), died from disease during the first 20 in patients not being able to undergo any systemic ther- months; however, in 8 of them, substantial subjective apy (Table 3 and Figure 2). This result is limited by the loco-regional benefit was documented for a mean dura- unbalanced sample sizes (14 vs 98), and the significant tion of 17 months (range 4-20). The remaining three difference in mean age (expectedly, as higher age and patients who experienced no benefit suffered from per- related frequent severe co-morbidity are usual reasons sistent local disease. Three patients with tGTV > 130 cc to not apply systemic therapy). It is known that higher treated with radiation alone died from disease after 2, 3, age per se may inversely influence outcome [9] - age could therefore be an independent reason for inferior and 10 months, respectively. outcome. A potential difference of the impact of sys- Only 2/14 (14%) patients treated with IMRT alone temic therapy on very advanced (’unresectable’)versus remained alive with no evidence of disease, vs 41/78 less advanced stages (lower tumor load) HNC is not (52%) treated with any systemic therapy for tGTV < 130 well known to our best knowledge. The subgroup with cc, vs 8/19 (42%) treated for tGTV > 130 cc, tGTV > 70 cc and unable to undergo systemic therapy respectively. still achieved 2-year DFS/OAS rates of approximately 30% (Figure 2), justification enough to consider a cura- - Additional potentially prognostic parameters tive IMRT approach also for this subgroup. The initial pre-treatment WHO performance status As in previous investigations on volumetric based out- (Table 1) was not found to be of prognostic value (49% come prediction [1] (Table VI in reference [1]) and [2], vs 50% 3-year DFS, p = 0.26). Similarly, there was no an inverse association between tGTV and disease con- gender-related outcome difference (p = 0.3). Analysis based on T and N stages or TN grouping resulted in trol was also found in the here assessed patient segment non-significantly different or nearly identical Kaplan with ‘very large tumor volume’: patients with tGTV > Meier survival curves. Also the primary tumour site 130 cc tended towards inferior outcome, with nearly (mesopharynx versus hypopharynx) or age (grouped in 40% achieving 3-year disease control (versus > 50% in decades: < 50 vs 50-60 vs 61-70 vs > 70 years) showed patients with tGTV < 130 cc (NS), Table 3); again, this no prognostic value. Patients suspicious of distant outcome data justify offering a curative combined mod- metastasis did not worse compared with initially M0- ality treatment to compliant patients with very large patients (see above). Any potential impact of the human tumor volumes. papilloma virus (HPV) status on the disease control in Eight of 12 patients suspicious of initial M+ status were still alive at mean ~1 year (range 4-21 months) this ‘very large tumour volume’ patient cohort could not post treatment, enjoying beneficial treatment effects; the be assessed, as the HPV status was not available in most imaging diagnosis of limited M+ status should not be of our patients. Cu Cum m.. S Su ur r v viiv v a all Studer et al. Radiation Oncology 2011, 6:120 Page 6 of 6 http://www.ro-journal.com/content/6/1/120 participated in the data acquisition. All authors read and approved the final used as a criterion to exclude patients from loco-regio- manuscript. nal curative IMRT approach. Radiation is known as most effective local therapy for advanced non-resectable Conflicts of interest The authors declare that they have no competing interests. loco-regional disease, however requiring high doses, if possible enhanced by systemic therapy. In order to keep Received: 3 June 2011 Accepted: 22 September 2011 side effects as low as possible, IMRT should be used Published: 22 September 2011 also in patients with radiologically suspicious distant References lesions. Whether further investigation should be per- 1. Studer G, Lutolf UM, El-Bassiouni M, Rousson V, Glanzmann C: Volumetric formed on suspicious M1 lesions has to be decided case staging (VS) is superior to TNM and AJCC staging in predicting outcome by case. of head and neck cancer treated with IMRT. Acta Oncol 2007, 46:386-394. 2. Studer G, Seifert B, Glanzmann C: Prediction of distant metastasis in head The most unfavourable subgroup seems characterized neck cancer patients: implications for induction chemotherapy and pre- by (elderly) patients with a tumour load of > 130 cc and treatment staging? Strahlenther Onkol 2008, 184:580-585. unable to undergo any systemic treatment - this group 3. Studer G, Zwahlen RA, Graetz KW, Davis BJ, Glanzmann C: IMRT in oral cavity cancer. Radiat Oncol 2007, 2:16. however was too small to draw reliable conclusions 4. Induction chemotherapy plus radiation compared with surgery plus from it (this question is under prospective evaluation at radiation in patients with advanced laryngeal cancer. The Department our institution). of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991, 324:1685-1690. 5. Studer G, Peponi E, Kloeck S, Dossenbach T, Huber G, Glanzmann C: In sum Surviving Hypopharynx-Larynx Carcinoma in the Era of IMRT. Int J Radiat � patients with tGTV > 70 cc treated with IMRT and Oncol Biol Phys 2010. 6. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, systemic therapy achieved 3-year DFS and OAS of Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, approximately 50% and 60%, respectively Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL: Cisplatin, � (elderly) patients with tGTV > 70 cc treated with fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007, 357:1695-1704. IMRT alone represented a subgroup which only margin- 7. Tribius S, Kronemann S, Kilic Y, Schroeder U, Hakim S, Schild SE, Rades D: ally benefits from curative IMRT (3-year OAS/DFS Radiochemotherapy including cisplatin alone versus cisplatin + 5- ~25%/< 20%, 3-year DFS 17%); nevertheless, most fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck. Strahlenther Onkol 2009, 185:675-681. patients experienced subjective benefit from radiation in 8. Tobias JS, Monson K, Gupta N, Macdougall H, Glaholm J, Hutchison I, terms of symptom relief, which is considered justifying Kadalayil L, Hackshaw A: Chemoradiotherapy for locally advanced head IMRT at least aiming effective palliation and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial. Lancet Oncol 2010, 11:66-74. � (elderly) patients with very large tGTV > 130 cc 9. Pignon JP, le Maitre A, Maillard E, Bourhis J: Meta-analysis of treated with IMRT alone did worst (1-y OAS 0%), how- chemotherapy in head and neck cancer (MACH-NC): an update on 93 ever, a larger sample size is needed for corroboration randomised trials and 17,346 patients. Radiother Oncol 2009, 92:4-14. doi:10.1186/1748-717X-6-120 Conclusions Cite this article as: Studer et al.: Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large volume Tumour volume and eligibility to undergo systemic head neck cancer. Radiation Oncology 2011 6:120. therapy were found important prognostic factors in patients with large tGTV load > 70 cc. Larger sample sizes are required to test, if patients with tGTV > 130 cc and unable to undergo systemic therapy should be prevented from curative treatment approaches. Radiobiological parameters may identify other criteria to defineapalliativesubgroupamong thepatientswith very large tumour volumes. Submit your next manuscript to BioMed Central and take full advantage of: Author details Department of Radiation Oncology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. Department of Oncology, University Hospital • Convenient online submission Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. • Thorough peer review • No space constraints or color figure charges Authors’ contributions GS conceived of the study and carried out its design, CG and GS draw the • Immediate publication on acceptance contours in all cases, approved all dose distribution plans and were • Inclusion in PubMed, CAS, Scopus and Google Scholar responsible for the initial decision of a curative treatment approach in the individual patients. CG was involved in the data analysis and interpretation. • Research which is freely available for redistribution TR decided on and supervised IC application in the assessed patients, and Submit your manuscript at www.biomedcentral.com/submit

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Radiation OncologySpringer Journals

Published: Sep 22, 2011

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