Prospective Assessment of Patterns of Failure After High-Precision Definitive (Chemo)Radiation in Head-and-Neck Squamous Cell Carcinoma

doi:10.1016/j.ijrobp.2010.01.054

International Journal of Radiation OncologyBiologyPhysics

Volume 80, Issue 2, 1 June 2011, Pages 522-531

https://doi.org/10.1016/j.ijrobp.2010.01.054 Get rights and content

Purpose

To prospectively analyze patterns of failure in patients with head-and-neck squamous cell carcinoma treated with definitive high-precision radiotherapy with a focus on location of failure relative to target volume coverage.

Methods and Materials

Sixty patients treated with three-dimensional conformal radiotherapy or intensity-modulated radiation therapy were included. Locoregional failure volume was defined on the planning data set at relapse, and dose received was analyzed by use of dose–volume histograms.

Results

Thirteen patients were deemed to have had locoregional failures, of which two did not have any viable tumor on salvage neck dissection, leaving eleven patients with proven persistent or recurrent locoregional disease. Of these, 9 patients had in-field failure, 1 marginal failure, and 1 both in-field and marginal failures. Overall, only 2 of 11 patients (18%) with relapse had any marginal failure. Of the 20 sites of locoregional failure, 15 (75%) were in-field and 5 (25%) marginal. Distant metastases were detected in 3 patients, whereas a second new primary developed in 3 others. With a median follow-up of 26 months (interquartile range, 18–31 months) for surviving patients, the 3-year local control, locoregional control, disease-free survival, and overall survival rates were 75.3%, 74%, 67.2%, and 60.5%, respectively.

Conclusions

Locoregional relapse remains the predominant pattern of failure in head-and-neck squamous cell carcinoma treated with high-precision definitive radiotherapy with the majority of failures occurring “in-field” within the high-dose volume. Marginal failures can occur, particularly in the vicinity of the spared parotid gland. The therapeutic index of high-precision conformal radiotherapy is largely dependent on adequate selection and delineation of target volumes and organs at risk.

Introduction

Definitive chemoradiotherapy (i.e., radical radiotherapy with concurrent systemic chemotherapy) is the contemporary standard of care in the nonsurgical management of head-and-neck squamous cell carcinoma (HNSCC) based on a large body of high-quality evidence 1, 2. Recently, spurred by advances in imaging, planning, and delivery, high-precision radiotherapeutic techniques such as three-dimensional (3D) conformal radiotherapy (CRT) and intensity-modulated radiation therapy (IMRT) have gained immense popularity, particularly in HNSCC, with their promise to reduce acute and late morbidity of treatment and to improve locoregional control, as well as their potential positive impact on quality of life and survival 3, 4, 5. The basic premise of high-precision conformal techniques is to improve the therapeutic index by improving target volume coverage and reducing normal tissue toxicity. The therapeutic index of highly conformal radiotherapy is largely dependent on adequate selection and delineation of gross tumor volume (GTV); in-depth knowledge of the natural history of disease including patterns of tumor extension and spread, both in the vicinity of the primary site and in the involved nodes, and the chances of the presence of occult micrometastatic disease in the regional lymph nodes for defining appropriate clinical target volumes (CTVs); and tissues and organs at risk (OARs) whose sparing is likely to result in meaningful clinical benefit (6). The sharp dose falloff and steep dose gradients inherent in high-precision radiotherapeutic techniques are poorly tolerant to errors of delineation and implementation, and highly conservative margins might result in an unacceptably increased risk of marginal recurrences with a negative impact on locoregional control and survival. Despite consensus guidelines for target volume delineation 7, 8, a major limitation is the presence of interobserver/intraobserver, intermodality, and interdiscipline variation, which can result in inconsistency, rendering comparisons difficult. Although the vast majority of recurrences after 3D-CRT or IMRT for HNSCC are truly in-field in the high-dose region, a small minority continue to be marginal, particularly in the high retropharyngeal region and in the vicinity of the spared parotid glands.

The objective of this report is to analyze the patterns of failure in patients with HNSCC treated with definitive high-precision CRT with or without concurrent weekly chemotherapy in a prospective trial with a focus on their location relative to target volume delineation and dose distribution.

Section snippets

Methods and Materials

Sixty-two previously untreated patients with squamous cell carcinoma of the oropharynx, larynx, or hypopharynx with American Joint Committee on Cancer Stage T1–T3, N0–2b, and M0 (excepting T1 glottic larynx) were accrued in an institutional review board–approved prospective Phase II randomized controlled trial comparing 3D-CRT with IMRT, with acute salivary gland toxicity as the primary endpoint. Patterns of failure, quality of life, locoregional control, disease-free survival, overall

Results

Between December 2005 and April 2008, 62 patients were accrued and randomized into the trial. Of these 62 patients, 2 refused any treatment after randomization, leaving 60 evaluable patients who constitute the data set for this analysis. The patient and disease characteristics for the cohort are summarized in Table 1. The patient group consisted of 54 men and 6 women, with a median age of 54 years (range, 31–65 years). The median radiotherapy dose to gross disease with margins (PTV70) was 70 Gy

Discussion

The primary objective of this report was to analyze patterns of failure in patients with non-nasopharyngeal HNSCC treated with high-precision definitive CRT (3D-CRT or IMRT) with a focus on the location of failures in relation to the target volume coverage. Most of the failures were truly in-field in the high-dose region, consistent with previously published data 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. In large series (Table 4) the predominant pattern of failure after CRT for

Conclusions

Locoregional relapse remains the predominant pattern of failure in non-nasopharyngeal HNSCC treated with high-precision definitive CRT with concurrent systemic chemotherapy. The majority of the locoregional failures occur in-field within the high-dose volume, that is, the region of gross disease encompassed by greater than 95% of the prescription isodose. This emphasizes the need to identify hypoxic regions within the tumor using anato-metabolic imaging for studies of dose escalation to the

References (32)

J.P. Pignon et al.
Chemotherapy added to loco-regional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of Chemotherapy on Head Neck Cancer
Lancet
(2000)
J.P. Pignon et al.
MACH-NC Collaborative Group. Meta-analyses of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomized trials and 17,346 patients
Radiother Oncol
(2009)
A. Eisbruch et al.
Balancing risk and reward in target delineation for highly conformal radiotherapy in head and neck cancer
Semin Radiat Oncol
(2009)
V. Grégoire et al.
CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines
Radiother Oncol
(2003)
V. Gregoire et al.
Proposal for the delineation of the nodal CTV in the node-positive and the post-operative neck
Radiother Oncol
(2006)
L.A. Dawson et al.
Patterns of loco-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer
Int J Radiat Oncol Biol Phys
(2000)
K.S. Chao et al.
Patterns of failure in patients receiving definitive and postoperative IMRT for head and neck cancer
Int J Radiat Oncol Biol Phys
(2003)
N. Lee et al.
Intensity-modulated radiation therapy for head-and-neck cancer: The UCSF experience focusing on target volume delineation
Int J Radiat Oncol Biol Phys
(2003)
A. Eisbruch et al.
Recurrences near base of skull after IMRT for head and neck cancer: Implications for target delineation in high neck and for parotid sparing
Int J Radiat Oncol Biol Phys
(2004)
B. Bussels et al.
Recurrences after conformal parotid-sparing radiotherapy for head and neck cancer
Radiother Oncol
(2004)

M. Yao et al.

Intensity-modulated radiation treatment for head-and-neck squamous cell carcinoma—The University of Iowa experience

Int J Radiat Oncol Biol Phys

(2005)

G.O. Schoenfeld et al.

Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer

Int J Radiat Oncol Biol Phys

(2008)

G. Sanguineti et al.

Patterns of loco-regional failure after exclusive IMRT for oropharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(2008)

D.E. Soto et al.

Correlation between pretreatment FDG-PET biological target volume and anatomical location of failure after radiation therapy for head & neck cancers

Radiother Oncol

(2008)

S. Nangia et al.

Selective nodal irradiation for head and neck cancer using intensity-modulated radiotherapy: Application of RTOG consensus guidelines in routine clinical practice

Int J Radiat Oncol Biol Phys

(2010)

J.J. Caudell et al.

Margin on gross tumor volume and risk of local recurrence in head and neck cancer

Int J Radiat Oncol Biol Phys

(2010)

Cited by (16)

Incidence of contralateral regional failure in the electively irradiated contralateral neck of patients with head and neck squamous cell carcinoma
2019, Clinical and Translational Radiation Oncology
Citation Excerpt :
Notably, data on the incidence of RF in the electively treated neck is scarce. In the few published reports, the incidence of RF in electively irradiated lymph node regions varied between 1 and 11% [14–19]. However, none of these studies mentioned the exact incidence of cRF in the electively irradiated contralateral neck.
The vast majority of patients with head and neck squamous cell carcinoma (HNSCC) routinely undergo elective nodal irradiation (ENI) to both sides of the neck. Little is known about the extent to which bilateral ENI prevents regional failure (RF) and contralateral RF (cRF) in particular, while such knowledge is necessary to evaluate the results of more selective approaches like unilateral ENI. We investigated the rate and pattern of RF after bilateral ENI, the rate of cRF in the electively irradiated contralateral neck, and tried to identify risk factors for development of cRF.
Retrospective cohort study of a consecutive series of 605 patients with T1-4N0-3 HNSCC treated between 2008 and 2017 with primary (chemo)radiation and bilateral ENI.
Median follow-up was 43 months (range 1.4–126). Three-year cumulative incidence of RF was 12.7%. Three-year cumulative incidences of ipsilateral RF (iRF) and cRF were 10.6% and 2.8%, respectively. All cRF occurred within the electively treated volume. Salvage treatment was possible in 65% and 59% of patients with iRF and cRF, respectively (p = 0.746). The 3-year overall survival rates after RF in patients with iRF and cRF were 27.4% and 41.2%, respectively (p = 0.713). Three-year cancer-specific survival rates were 31.6% and 48.1%, respectively (p = 0.634). In multivariate analysis, no significant predictive factors were identified for cRF after bilateral ENI.
Contralateral regional failure is rare, but still occurs in 2.8% of patients treated with bilateral ENI. The possibilities for salvage treatment, the rates of overall survival and cancer-specific survival were comparable to patients with iRF.
Prospective Qualitative and Quantitative Analysis of Real-Time Peer Review Quality Assurance Rounds Incorporating Direct Physical Examination for Head and Neck Cancer Radiation Therapy
2017, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
The majority of RT plans in that study were 3-dimensional (3D) conformal, and we demonstrated that PE is critical in the process of target volume delineation in those cases. Currently, in the era of intensity modulated radiation therapy (IMRT) and proton therapy (IMPT) with their high level of treatment precision, target volume definition is increasingly critical, particularly in head and neck cancer (8, 9). As a continuation of efforts to characterize the impact of a real-time peer review QA process, we performed an update of that previous study to assess the changes made during peer review in the setting of exclusive IMRT planning.
Our department has a long-established comprehensive quality assurance (QA) planning clinic for patients undergoing radiation therapy (RT) for head and neck cancer. Our aim is to assess the impact of a real-time peer review QA process on the quantitative and qualitative radiation therapy plan changes in the era of intensity modulated RT (IMRT).
Prospective data for 85 patients undergoing head and neck IMRT who presented at a biweekly QA clinic after simulation and contouring were collected. A standard data collection form was used to document alterations made during this process. The original pre-QA clinical target volumes (CTVs) approved by the treating-attending physicians were saved before QA and compared with post-QA consensus CTVs. Qualitative assessment was done according to predefined criteria. Dice similarity coefficients (DSC) and other volume overlap metrics were calculated for each CTV level and were used for quantitative comparison. Changes are categorized as major, minor, and trivial according to the degree of overlap. Patterns of failure were analyzed and correlated to plan changes.
All 85 patients were examined by at least 1 head and neck subspecialist radiation oncologist who was not the treating-attending physician; 80 (94%) were examined by ≥3 faculty members. New clinical findings on physical examination were found in 12 patients (14%) leading to major plan changes. Quantitative DSC analysis revealed significantly better agreement in CTV1 (0.94 ± 0.10) contours than in CTV2 (0.82 ± 0.25) and CTV3 (0.86 ± 0.2) contours (P=.0002 and P=.03, respectively; matched-pair Wilcoxon test). The experience of the treating-attending radiation oncologist significantly affected DSC values when all CTV levels were considered (P=.012; matched-pair Wilcoxon text). After a median follow-up time of 38 months, only 10 patients (12%) had local recurrence, regional recurrence, or both, mostly in central high-dose areas.
Comprehensive peer review planning clinic is an essential component of IMRT QA that led to major changes in one-third of the study population. This process ensured safety related to target definition and led to favorable disease control profiles, with no identifiable recurrences attributable to geometric misses or delineation errors.
Elective nodal irradiation and patterns of failure in head and neck cancer after primary radiation therapy
2016, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
In contrast, Spencer et al (11) conducted a prospective study and found that eliminating RT to the contralateral RP region and high level II area is safe and improves the quality of life for patients with HNC and clinically uninvolved necks undergoing IMRT. Gupta et al (20) agreed, suggesting that it might be adequate to include the subdiagastric space as the cranial-most target in the contralateral, clinically uninvolved neck, because no RP first failure was observed in their 32 patients with OP cancer. In our national guidelines, RP inclusion is indicated in the following situations: (1) initially positive RP nodes on either side; (2) tumor in the posterior pharyngeal wall; and (3) nasopharyngeal carcinoma (not included in the present study).
The delineation of elective clinical target volumes in head and neck cancer (HNC) is important; however, the extent of lymph node levels necessary to include is debated. A comprehensive analysis of recurrence patterns in a large cohort of patients with HNC was performed, with an emphasis on recurrence in the retropharyngeal region and level IB.
From 2005 to 2012, 942 patients with oropharyngeal, hypopharyngeal, laryngeal or oral cavity carcinomas were curatively treated with primary radiation therapy. The median follow-up period was 34 months, and 77% of the patients underwent intensity modulated radiation therapy. The retropharyngeal region was only routinely included in cases of involvement of the posterior pharynx wall and level IB only in cases of involvement of the oral cavity. In patients with regional recurrence, the anatomic site of the recurrence was assessed from the surgical descriptions or computed tomography scans and compared with the original radiation treatment plan (available from 2007 onward). The p16 status was available for 282 oropharynx carcinoma cases, with 65% p16-positive.
Of the 942 patients, 376 (40%) developed recurrences: 228 (24.2%) local, 123 (13.1%) regional, and 109 (11.6%) distant. In 700 patients with available treatment plans, retropharyngeal and level IB recurrence was observed in 2 and 7 patients, respectively. Eight patients (1.1%) had recurrence in a lymph node level not included in their primary treatment plan. For oropharynx carcinoma, the locoregional control rate (90% vs 70%) but not distant control rate (92% vs 87%), was significantly better in the p16-positive than in the p16-negative patients. Although fewer recurrences developed in the p16-positive group, patients with recurrence of p16-positive tumors were more likely to develop recurrence in distant sites.
Retropharyngeal or level IB recurrence after primary HNC radiation therapy is rare. Thus, inclusion of these regions in the elective treatment volumes should be limited to patients with involvement of the posterior pharyngeal wall or oral cavity.
Patterns of Failure after Intensity-modulated Radiotherapy in Head and Neck Squamous Cell Carcinoma using Compartmental Clinical Target Volume Delineation
2014, Clinical Oncology
To determine the pattern of disease recurrence in non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) patients treated with radical intensity-modulated radiotherapy (IMRT) with or without chemotherapy, and to correlate the sites of locoregional recurrence with radiotherapy target volumes.
In total, 136 patients treated with radical IMRT with or without chemotherapy between 2008 and 2011 for non-nasopharyngeal HNSCC were retrospectively identified. A compartmental approach to clinical target volume (CTV) delineation was routinely utilised during this period and IMRT was delivered using a 5–7 angle step and shoot technique. Locoregional recurrences were reconstructed on the planning computed tomography scan by both deformable image coregistration and by visual assessment, and were analysed in relation to target volumes and dosimetry.
The median follow-up was 31 (range 3–53) months. Two year local control, regional control, disease-free survival, distant metastasis-free survival and overall survival were 86, 93, 78, 89 and 79%, respectively. One hundred and twenty of 136 (88%) patients achieved a complete response to treatment and 7/120 (6%) have subsequently had a locoregional recurrence. Analysis of these recurrences revealed five to be infield; one to be marginal to the high-dose CTV; one to be out-of-field. Overall the marginal/out-of-field recurrence rate was 2/136 (1.5%).
IMRT utilising a compartmental approach to CTV delineation was associated with a low rate of marginal/out-of-field recurrence.
Intensity-modulated radiation therapy for head and neck cancer: Systematic review and meta-analysis
2014, Radiotherapy and Oncology
Intensity-modulated radiation therapy (IMRT) provides the possibility of dose-escalation with better normal tissue sparing. This study was performed to assess whether IMRT can improve clinical outcomes when compared with two-dimensional (2D-RT) or three-dimensional conformal radiation therapy (3D-CRT) in patients with head and neck cancer.
Only prospective phase III randomized trials comparing IMRT with 2D-RT or 3D-CRT were eligible. Combined surgery and/or chemotherapy were allowed. Two authors independently selected and assessed the studies regarding eligibility criteria and risk of bias.
Five studies were selected. A total of 871 patients were randomly assigned for 2D-RT or 3D-CRT (437), versus IMRT (434). Most patients presented with nasopharyngeal cancers (82%), and stages III/IV (62.1%). Three studies were classified as having unclear risk and two as high risk of bias. A significant overall benefit in favor of IMRT was found (hazard ratio – HR = 0.76; 95% CI: 0.66, 0.87; p < 0.0001) regarding xerostomia scores grade 2–4, with similar loco-regional control and overall survival.
IMRT reduces the incidence of grade 2–4 xerostomia in patients with head and neck cancers without compromising loco-regional control and overall survival.
Target delineation in stereotactic body radiation therapy for recurrent head and neck cancer: A retrospective analysis of the impact of margins and automated PET-CT segmentation
2013, Radiotherapy and Oncology
Citation Excerpt :
Use of deformable registration to analyze patterns of failure has also been previously described in the setting of IMRT for primary SCCHN [17]. Failure was defined as initial disease progression or complete response/partial response/stable disease followed by progression, as described in previous patterns-of-failure analyses [12,18–20]. A trained radiologist interpreted each post-treatment PET-CT and made the determination of recurrent tumor volume based on anatomic features, contrast enhancement, and changes in PET FDG-avidity.
Few guidelines exist on stereotactic body radiation therapy (SBRT) treatment planning for recurrent head and neck cancer. We assessed the impact of retrospectively adding margins/automated PET volumes to the gross tumor volume (GTV) in patients with post-SBRT recurrences.
We reviewed 89 patients with recurrent head and neck cancer treated with SBRT using no margin around the GTV. GTVs were recontoured with 1–5 mm margins. PET-CT planned GTVs were also recontoured by adding PET-standardized uptake value (SUV)_3.5, SUV_4.5, SUV_{40% max}, and signal/background ratio (SBR) to the original GTV. We deformably registered recontoured GTVs to post-SBRT scans and assessed fraction of recurrence volume (RV) falling within the GTV, the “RV-GTV overlap.”
With non-PET-CT planning, median RV-GTV overlap increased from 11.7% to 48.2% using 5 mm margins, and median GTV size increased by 41.8 cc (156%). With PET-CT planning, RV-GTV overlap increased from 45% to 93.6% using 5 mm margins, and GTV size increased by 34.8 cc (140%). Adding SUV_3.5 and SBR increased RV-GTV overlap from 45% to 73.3% and 73.6%, with GTV size increases of 0.8 (3%) and 3.1 cc (11%), respectively.
Recontouring increased recurrence coverage and also GTV size. Margins up to 5 mm may reduce failures but could possibly increase toxicities. Automated PET contours may reduce near-miss failures with smaller increases in GTV size.

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: The index trial was partially supported by Siemens Ltd, USA, and the ¹⁸F-fluorodeoxyglucose–positron emission tomography scans were partly supported by a grant from an individual donor (name withheld on donor request).

: Conflict of interest: none.

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Clinical InvestigationProspective Assessment of Patterns of Failure After High-Precision Definitive (Chemo)Radiation in Head-and-Neck Squamous Cell Carcinoma

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conclusions

Lancet

Radiother Oncol

Semin Radiat Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Prospective Assessment of Patterns of Failure After High-Precision Definitive (Chemo)Radiation in Head-and-Neck Squamous Cell Carcinoma