Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes

doi:10.1016/j.ijrobp.2011.10.022

International Journal of Radiation OncologyBiologyPhysics

Volume 83, Issue 5, 1 August 2012, Pages 1521-1527

https://doi.org/10.1016/j.ijrobp.2011.10.022 Get rights and content

Purpose

We previously showed that metabolic tumor volume (MTV) on positron emission tomography—computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans.

Methods and Materials

From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume ≥50% of maximum SUV (SUV_max). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV_max over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival).

Results

The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV_max (average, −0.1 cc/week) and MTV (average, −0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03).

Conclusions

Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

Introduction

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging has been increasingly used for staging, radiotherapy target definition, and determining treatment response in head-and-neck cancers (HNC) 1, 2, 3. When combined with computed tomography (CT) imaging, PET-CT has an improved sensitivity and specificity compared with standard CT or magnetic resonance imaging 4, 5, 6.

Differential FDG uptake between tumor cells and normal tissue measured via maximum standardized uptake value (SUV_max) is an independent prognostic factor in several HNC subsites 7, 8, 9. We recently reported on a more functional preradiation PET-CT measurement tool, metabolic tumor volume (MTV), which quantifies the metabolic tumor burden. Pretreatment MTV predicted for disease progression and survival in HNC, whereas SUV_max did not (10). We also showed that postradiation MTV is a prognostic factor in HNC (11). These findings suggest that metabolic tumor burden may be a stronger independent prognostic factor than SUV 12, 13, 14, 15.

Presumably, HNC increases in size and metabolic activity over time. The rate of growth should correlate with tumor biology, with faster-growing tumors intuitively being more aggressive and fatal. The anatomic and functional imaging characteristics of PET-CT make it an excellent candidate to capture tumor growth rate, which has not been evaluated in HNC. The purpose of this study was to examine tumor growth over time without any intervening treatment, measured with SUV_max and MTV in serial preradiation PET-CT scans.

Section snippets

Patients

After Institutional Review Board approval, we reviewed the medical records of HNC patients treated with definitive radiation at Stanford University (June 2006 through November 2009). Patients with two pre-radiotherapy PET-CT scans without treatment between the two scans were included. Patients were excluded for the following reasons: distant metastatic disease at diagnosis; prior definitive surgery, chemotherapy, or radiotherapy; or salivary gland, paranasal sinus, thyroid, or skin primary

PET-CT velocity

The median time between PET-CT scans was 3.0 weeks (range, 6 days to 10.7 weeks). Of the first PET-CT scans, the median primary tumor SUV_max was 11.2 (range, 2.8–53), and the median nodal SUV_max was 10.4 (range, 0–49). The median primary tumor MTV was 4.5 cc (range, 0.5–35 cc), and the median nodal MTV was 5.9 cc (range, 0.7–29 cc). Figure 1 demonstrates the change in SUV and MTV over time. We observed significant variability between each patient’s two PET-CT scans. One would expect SUV and MTV

Discussion

Neither SUV_max nor MTV measured on serial PET-CT scans adequately captured tumor progression over time. Our results did not support the intuitive concept that HNC tumors increase in size and metabolic activity over time. As we move toward risk-adapted therapy, there will be interest in integrating PET-CT as a risk-stratifying biomarker and the incorporation of serial FDG PET-CT scans to assess treatment response. Here, we highlight potential limitations in serial PET-CT reproducibility. The

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Prognostic biomarkers of disease relapse are needed for risk-adaptive therapy of oropharyngeal cancer (OPC). This work aims to identify an imaging signature to predict distant metastasis in OPC.
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Integrating tumor and nodal imaging characteristics at baseline and mid-treatment CT allows prediction of distant metastasis in OPC. The proposed imaging signature requires prospective validation and, if successful, may help identify high-risk human papillomavirus-positive patients who should not be considered for deintensification therapy.
Cancer of the Head and Neck
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In the United States it is estimated that there will be 51,540 new cases of head and neck cancer in 2018, accounting for 3% of all cancer cases and 1.5% of all cancer deaths. The three major risk factors for head and neck cancer are tobacco, human papillomavirus (HPV) infection, and alcohol. The treatment of head and neck cancer is dictated by the primary site. Most oropharyngeal cancers in the United States are now due to human papillomavirus (HPV) and as such have an improved prognosis. Early-stage oropharynx cancers can effectively be treated with surgery or RT. The standard of care for locally advanced disease is CRT; however, incorporation of transoral robotic surgery (TORS) is under active investigation. Surgery is generally considered the preferred initial treatment modality for oral cavity lesions with adjuvant RT with or without chemotherapy for patients with high-risk features on surgical pathology. In patients with laryngeal cancer, the goal of first-line therapy should be to preserve the function of the larynx, without sacrificing tumor control. Early-stage laryngeal cancer can effectively be treated with either surgery or RT. In early stage disease, the anatomic location and extent of disease will dictate if surgery is feasible. The treatment of choice in most locally advanced larynx cancers is concurrent chemotherapy and radiation. Management of head and neck cancers requires a multidisciplinary approach with effective integration of multiple specialties to achieve the desired goals of cure and functional organ preservation.
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The metabolic tumor volumes were defined as the tumor volume that was greater than or equal to 50% of maximum standardized uptake value. They found that increased MTV significantly predicted risk of disease progression, cancer-specific mortality, and overall risk of death [14]. As in our study, Chu et al. did not find that metabolic nodal velocity was significantly correlated with outcomes.
Volumetric tumor growth velocity (TGV) reflects in vitro tumor aggressiveness, but its prognostic value has not been investigated in vivo. We examined the prognostic impact of TGV on oncologic outcomes in patients with oropharyngeal squamous cell cancer (OSCC).
101 OSCC patients with two pretreatment CTs with time gap of 2 or more weeks treated at a single institution between 2004 and 2008 were identified. Primary tumor and nodal targets were segmented in scans. Linear growth rates were calculated. Recursive partitioning analysis (RPA) identified cut point associated with outcomes.
Median follow-up was 59 months (range 7–118). Median primary TGV was 0.65% increase per day (range 0–9.37%). RPA identified TGV cut point associated with local control (LC) of 1% per day. Patients with higher TGV had decreased 5-year LC (73% vs. 98%, p = 0.0004), distant control (DC, 62% vs. 91%, p = 0.0007), and overall survival (OS, 38% versus 93%, p < 0.0001). In multivariate analysis including demographics, tumor stage, subsite, and treatment factors, TGV ⩾ 1% per day independently predicted worsened LC (p = 0.02), DC (p = 0.003), and OS (p < 0.0001). However, this TGV cutoff was not significantly predictive of LC, DC, or OS for a subset of presumed HPV-positive patients.
OSCC TGV ⩾ 1% per day is a substantive negative prognostic indicator for disease control and overall survival, particularly in HPV non-associated tumors. This novel CT-based volumetric assessment of TGV suggests a simple methodology for risk stratification of patients.
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To assess the relationship between tumor-specific growth rate (TSGR) and oropharyngeal cancer (OPC) outcomes in the HPV era.
Primary tumor volume differences between a diagnostic and secondary scan separated $⩾$ 7 days without interval treatment were used to estimate TSGR, defined as percent volume growth/day derived from primary tumor volume doubling time for 85 OPC patients with known p16 status and smoking pack-years managed with (chemo)radiation. Variables were analyzed using Kruskal–Wallis or Fisher’s exact test as appropriate. Log-rank tests and Cox proportional models analyzed endpoints. Using concordance probability estimates (CPE), TSGR was incorporated into RTOG 0129 risk grouping (0129RG) to assess whether TSGR could improve prognostic accuracy.
Median time between scans was 35 days (range 8–314). Median follow up was 26 months (range 1–76). The 0129RG classification was: 56% low, 25% intermediate, and 19% high risk.
Median TSGR was 0.74%/day (range 0.01–4.25) and increased with 0129RG low (0.41%), intermediate (0.57%) and high (1.23%) risk, respectively (p = 0.015). TSGR independently predicted for TF (TSGR: HR (95%CI) = 2.79, 1.67–4.65, p < 0.001) in the Cox model.
On CPE, prognostic accuracy for TF, disease-free survival and overall survival was improved when 0129RG was combined with TSGR. Dichotomizing 0129RG by median TSGR yielded no observed recurrences in low risk patients with TSGR < 0.74% and demonstrated significant difference for intermediate risk (8% vs. 50% for TSGR < 0.74% vs. $⩾$ 0.74%, respectively, p < 0.001).
Tumor-specific growth rate correlates with increasing 0129RG and predicts treatment failure, potentially improving the prognostic strength and risk stratification of established 0129 risk groups.
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The identification of robust prognostic and predictive biomarkers would transform the ability to implement an individualised approach to radiotherapy. In this regard, there has been a surge of interest in the use of functional imaging to assess key underlying biological processes within tumours and their response to therapy. Importantly, functional imaging biomarkers hold the potential to evaluate tumour heterogeneity/biology both spatially and temporally. An ever-increasing range of functional imaging techniques is now available primarily involving positron emission tomography and magnetic resonance imaging. Small-scale studies across multiple tumour types have consistently been able to correlate changes in functional imaging parameters during radiotherapy with disease outcomes. Considerable challenges remain before the implementation of functional imaging biomarkers into routine clinical practice, including the inherent temporal variability of biological processes within tumours, reproducibility of imaging, determination of optimal imaging technique/combinations, timing during treatment and design of appropriate validation studies.
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These findings were also seen in studies by Murphy and colleagues92 and Tang and colleagues.93 Another study by Chu and colleagues94 suggests that when the MTV tumor volume is assessed on serial PET/CT scans before RT initiation, the calculated MTV tumor velocity (absolute change in MTV/time in weeks) was predictive of disease-free survival and overall survival. There has also been work correlating the pathologic tumor volume on surgical specimens from postoperative patients who have H&N cancer with the imaging-defined volume.

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: K. P. Chu and J. D. Murphy contributed equally to this study.

: Supported in part by R01-CA118582-04 (Q.T.L., E.E.G.), and by 5P01-CA67166-15 (Q.T.L., E.E.G.).

: Conflict of interest: none.

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Clinical InvestigationPrognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

PET-CT velocity

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Eur J Surg Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lung Cancer

Impact of [18F]-2-fluorodeoxyglucose-positron emission tomography/computed tomography on previously untreated head and neck cancer patients

Laryngoscope

Tumor volume in pharyngolaryngeal squamous cell carcinoma: Comparison at CT, MR imaging, and FDG PET and validation with surgical specimen

Radiology

Comparison of whole-body PET/CT, dedicated high-resolution head and neck PET/CT, and contrast-enhanced CT in preoperative staging of clinically M0 squamous cell carcinoma of the head and neck

J Nucl Med

Standardized uptake value of 2-[(18)F] fluoro-2-deoxy-D-glucose in predicting outcome in head and neck carcinomas treated by radiotherapy with or without chemotherapy

J Clin Oncol

Prediction of survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer

J Nucl Med

Prognostic value of metabolic tumor volume measured by 18F-fluorodeoxyglucose positron emission tomography in patients with esophageal carcinoma

Ann Surg Oncol

Clinical Investigation
Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes