Interim FDG PET/CT for Predicting the Outcome in
Patients with
Head and Neck Cancer
Shang-Wen Chen, MD; Te-Chun Hsieh, MD; Kuo-Yang Yen, BSc; Shih-Neng Yang,
MD;
Yao-Ching Wang, MD; Chun-Ru Chien, MD, PhD; Ji-An Liang, MD; Chia-Hung Kao,
MD
INTRODUCTION
Over the past decade, definitive radiotherapy (RT) or concurrent chemoradiotherapy (CRT) has been increasingly employed in the treatment of head and neck cancer (HNC). Despite analyzing tumor volume information obtained using TNM classification of malignant tumors or computed tomography (CT) for predicting the prognosis of patients with HNC, the
implementation of individualized therapy is limited by a lack of comprehensive knowledge on individual
responses to specific treatments. 18Fluoro-2-deoxy-D-glucose
positron emission tomography (FDG-PET) is frequently used as an imaging modality in treating HNCs.
Maximum standard uptake value (SUVm) and biological tumor volumes, such as metabolic tumor volume and total lesion glycolysis, have been investigated because analyzing these values can be used to indicate the activity of biologically active tumors.1–7
After drug therapy, monitoring patients’ responses by using FDG-PET can lead to major changes in patient
management protocols by accurately differentiating responders from nonresponders. Two studies have shown
that early PET information is highly predictive of treatment success for Hodgkin lymphoma or nonsmall cell
carcinoma following drug therapy.8,9 When RT is
with high false-positive results due to the tissue healing process or alterations in FDG-uptake kinetics.10 Thus,
the most effective time for accessing tumor response during RT remains undecided. Researchers have explored
the predictive value of PET studies during early phases
of HNC treatment11–13 and suggested that a fast SUVm decrease during the first 2 weeks of
CRT indicated superior
survival rates. Thus far, there is a lack of studies regarding the impact of interim PET on late-stage RT or
CRT. For example, a cumulative dose of 40 to 50 Gy corresponds to the RT dose reported in several preoperative
protocols for HNC treatments.14–16 Recognizing patients
who are nonresponders is critical because they might benefit from intensified and innovative treatment options.17 In addition, the distinctive roles of interim
PET parameter in the T- and N-status on local failures have not yet been specified in previous studies. This study examined the clinical effects of interim PET and CT (PET/CT) during the second half of definitive RT and CRT (RT/CRT) on survival and local controls in patients with advanced HNCs originating from the pharynx. In addition, we explored the association between the volumetric and biological tumor response during RT treatments. Thus, an interim response assessment for these patients can lead to timelier implementations of optimal treatment modalities.
MATERIALS AND METHODS Patient Population
Between January 2009 and December 2012, a cohort of
51 patients with stage III to IVA pharyngeal cancer with a histological proof of squamous cell carcinoma or undifferentiated
carcinoma were prospectively enrolled in this PET/CT study (certificate number: DMR99-IRB-067). They completed definitive RT/CRT treatment courses for organ preservation schemes at China Medical University Hospital. The median age was 52 years (range: 29 to 69 y). Forty-eight patients were men and three were women. All received successive pretreatments, and interim FDG-PET/CT images were taken. The pretreatment
PET/CT scans were scheduled within 1 week before the start of RT, and the interim PET/CT was taken at the cumulative RT dose of 40 to 50 Gy. The first and second PET/CT scans were performed using the same machine and protocol. No patient was known to have a history of diabetes, and all exhibited normal serum glucose levels before the PET/CT images
were taken. The characteristics of the 51 patients are listed in Table I.
PET/CT Image Acquisition
All patients were asked to fast for at least 4 hours before
PET/CT imaging. Approximately 60 minutes after the administration of 370 MBq of FDG, the images were taken using a
PET/CT scanner (PET/CT-16 slice, Discovery STE; GE Medical Systems, Milwaukee, WI). During the uptake period, the patients were asked to rest. The PET/CT workstation provided the quantification of FDG uptake regarding SUV. Nuclear medicine physicians identified the locations and values of SUVm for all the primary tumors (SUVm-P) and metastatic neck lymph
nodes (SUVm-N). Radiation oncologists then reviewed the consistency of the PET/CT images in collaboration with the nuclear
medicine physicians. This procedure was addressed in our previous report.18 In this study, there were 51 patients with assessable pretreatment SUVm-P (pSUVm-Ps) and interim SUVm-P (iSUVm-P) values, and 46 patients with pretreatment SUVm-N (pSUVm-N) and interim SUVm-N (iSUVm-N) values. The
reduction ratio of SUVm (SRR) was calculated using the following equation: SRR512(iSUVm/pSUVm).
Delineation of CT-Based Tumor Volume
Concurrent chemoradiotherapy-based tumor volume definition was previously described.19 Briefly, the contouring of the tumor volume and normal and critical structures was performed without knowledge of the PET results in order to reduce bias. Radiation oncologists then delineated the pretreatment primary
gross tumor volume (pGTV-P) and the largest metastatic lymph node volume (pGTV-N). Neck lymph nodes were considered
pathological when their smallest axis diameter was>1 cm. To reduce interobserver variation, at least two radiation oncologists performed the contouring of the tumors for each patient,
and the average of the readings was used as the measured volume.
By using the same method, radiation oncologists
delineated the interim primary tumor volume (iGTV-P) and the metastatic lymph node volume (iGTV-N) based on the CT images of the interim PET/CT. The volume reduction ratio (VRR) was calculated using the following equation20: VRR51 – (iGTV/pGTV).
Treatment
Radiotherapy (RT) was performed using a sequential
intensity-modulated radiotherapy technique, as reported previously. 3 All patients received a median total RT dose of 72 Gy
(range: 67.7 to 74.4 Gy). The clinical target volume (CTV)-modeled regions were considered to be two regions representing different risks: CTV1 encompassed the primary tumors,
metastatic lymph nodes, and the regions adjacent to the gross tumor; and CTV2 consisted of the ipsilateral or contralateral neck regions at risk of harboring microscopic tumors. The dose delivered to the CTV1 and CTV2 during the first course was 50.4 Gy, with a further boost of 20.0 to 24.0 Gy to the CTV1 during the second course. The median RT duration was 56 days. Forty-one patients received CRT; their regimen consisted of cisplatin (80–100 mg/m2 on days 1, 22, and 43); three patients received combined target therapy with cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly); and seven patients received RT alone.
Follow-Up
After completion of the treatments, all the patients were followed up every 1 to 2 months over the first 2 years, and
every 3 to 4 months thereafter. A physical examination and laryngoscopy were performed during each follow-up session, and a
CT scan of the neck was conducted every 4 to 6 months for 2 years. Posttreatment PET/CT was performed in 32 patients. The timing was at 4 to 6 weeks after RT/CRT. The definition of local failure was based on the laryngoscopy results, the CT scan of the neck, or the PET/CT. When a patient had a persistent tumor or local recurrence after initial complete remission, salvage surgery was suggested, if technically feasible and allowable
by the condition of the patient.
Statistical Analysis
This study used the median values of the PET/CT- and
CT-based parameters as cutoff points. The results of the statistical analysis are presented as the mean6standard deviation.
The Mann–Whitney test was used to assess the differences of the pretreatments, interim SUVms, and SRRs between patients with or without failure. The correlation between the VRRs and SRRs was also examined using Pearson’s correlation coefficient with the significance set at 0.01. Overall survival (OS), disease-free survival (DFS), primary relapse-free survival (PRFS), and nodal relapse-free survival (NRFS) were calculated using the Kaplan-Meier method. The log-rank test and
Cox regression were performed to examine the effects of variables on survival. The salvage of any recurrence was not considered in evaluating the relapse. P values less than 0.05 were
considered statistically significant. All calculations were performed using SPSS 13.0 for Windows (SPSS Inc, Chicago, IL).
Lastly, all tests were 2-sided.
RESULTS
Measurement of PET/CT- and CT-Related Parameters
The interim PET/CT was taken when the cumulative RT dose ranged from 41.4 to 46.8 Gy (median: 43.2 Gy). The mean pSUVm-P was 11.164.9, whereas the mean iSUVm-P was 4.562.6. For 46 patients with measurable nodal diseases, the mean pSUVm-N and
iSUVm-N were 7.966.1 and 3.562.9, respectively. Consequently, the mean SRR for the primary tumor (SRR-P)
was 0.5460.33, whereas the SRR for the metastatic lymph node (SRR-N) was 0.4960.34.
Overall, the mean pGTV-P was 28.1625.0 mL,
whereas the mean iGTV-P volume was 17.4616.5 mL. For the 46 patients with nodal tumors, the mean pGTVN and iGTV-N was 19.0623.6 mL and 14.1618.3 mL, respectively. Accordingly, the calculated mean VRR for the primary tumor (VRR-P) was 0.3560.19, and the VRR for the nodal tumor (VRR-N) was 0.3660.22. The
correlation study indicated a closer association between the SRRs and VRRs for metastatic neck lymph nodes (r50.40; P50.008) than those for primary tumors (r50.20; P50.16) (Supporting Fig. S1).
Treatment Outcome
Among the 51 patients, the median follow-up duration was 23 months (range: 7 to 53 mo). Twenty-nine
patients survived (27 without evidence of disease; 2 with evidence of tumor relapse), whereas 22 patients died due to recurrent tumors. Primary and nodal recurrences were observed in 15 and 14 patients, respectively. Table II summarizes the outcomes for all patients. In summary, the 2-year OS, DFS, PRFS, and NRFS values
were 58%, 54%, 67%, and 70%, respectively. Prognostic Value of PET/CT- and CT-Related Parameters and Reduction Ratio
As listed in Table III, no differences were observed in the pSUVm-P or pSUVm-N values between patients
with and without relapse. However, high iSUVm values were associated with treatment failures. The mean
iSUVm-P was 5.662.9 for patients with primary failures and 3.962.3 for those without the failure
(P50.029); whereas the mean iSUVm-N was 5.164.0 in patients with nodal failures, compared with 2.861.9 in those without failure (P50.012). The mean SRR-P for patients with and without primary failures was
0.6360.23 and 0.4060.34, respectively (P50.038). The mean SRR-N exerted no impact on nodal recurrence. By contrast, higher values of iGTV-N and VRR-N were associated with an increased risk of nodal failures. The
mean iGTV-N and VRR-N were 25.7637.2 and
0.2260.16, respectively, in patients with nodal failures, compared with 9.1610.8 and 0.4260.21 in those without recurrence (P 50.039 and P50.002).
In this study, the median values of PET/CT-related parameters were used as cutoffs of the analysis. The results of the Cox regression analysis are summarized in Table IV. An SRR-P<0.64 was the only predictor
for inferior OS and DFS (P50.035, hazard ratio [HR]52.64, 95% confidence interval [CI] 1.08–6.49; P50.045, HR52.33, 95% CI51.02–5.35, respectively). As depicted in Figures 1 and 2, patients who had tumors with an SRR-P<0.64 had a considerably lower 2-year OS and DFS compared with those who had SRR-P_0.64 (47% vs. 66%; 41% vs. 64%). An SRR-P<0.64 exerted a marginal impact on PRFS (P50.051, HR52.87, 95% CI50.99–8.26). The 2-year PRFS for patients with an SRR-P<0.64 and SUR-P_0.64 was 54% and 78%, respectively (P50.041) (Fig. 3). Using an SRR-P<0.64 as a cutoff to predict primary recurrence, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 46.2%, 84.0%, 75.0%, 60.0%, and 64.7%, respectively.
Prognostic Value of Interim PET/CT on Various Cancer Origins and Neck Recurrence
Using the Mann-Whitney U test, further analysis
was conducted to assess the separate predictive roles of the PET/CT-related parameters in cancers originating from the oropharynx and hypopharynx. In patients with oropharyngeal cancer (n520), the iSUVm-P had a marginal impact on primary recurrence (P50.07). In
patients with hypopharyngeal cancer (n521), a high iSUVm-P and a low SRR-P were associated with failure (P50.015 and P50.04).
Of the 46 patients with accessible CT- and PET/CTrelated nodal parameters, although patients with small
iSUVm-N had a superior NRFS in the univariate analysis (P50.043), the only independent predictor for NRFS was a VRR-N<0.37 (P50.009; HR55.55; 95%
CI51.52–20.4) (Supporting Fig. S2). The other PET/CTrelated factors showed no major impact on nodal failure.
DISCUSSION
The early identification of factors predictive of
treatment outcomes in cancer patients is of great interest because such research might allow therapy to be tailored to the characteristics of individual tumors before
the ending of definitive treatments. Although traditional TNM classification or pretreatment tumor volume has been widely used as a predictor of prognosis in HNC patients, these parameters might not accurately reflect RT outcomes because of great variations in the radiosensitivity between tumors, even between those with the
same origins. Compared with pretreatment PET/CT parameters, the clinical implications regarding the value of parameters on interim PET during RT is a great challenge. It involves the optimal timing of the images due
to RT-induced local inflammation. This study is a pilot investigation conducted to reveal the effects of SRR and iSUVm in primary tumors and metastatic neck lymph nodes on the treatment outcome at a cumulative RT dose of 40 to 50 Gy. Recognized pretreatment parameters such as SUVm, metabolic tumor volume, total lesion glycolysis, and CT-based tumor volumes can be implemented
concurrently as response predictors for RT/CRT outcomes.
Similar to the timing of our interim PET/CT protocol, Farrag et al. first investigated a cohort of 43 HNC patients whose interim PET was performed at the end of the fourth week (47 Gy/20 fraction) during the RT/CRT, and observed that the OS and DFS were inferior in patients with higher interim SUVms.17 In contrast,
Brun et al. reported 47 HNC patients in whom the metabolic rates of the tumors were examined using interim
PET in weeks 1 to 3 of RT.12 Their results showed that the low and high metabolic rates at
the interim PET
were associated with complete remission in 96% and 62% (P50.007), with 5-year overall survival in 72% and 35% (P50.004). Hentschel et al. assessed various timings of interim PET/CT in a cohort of 37 patients with
HNC.13 They suggested that an SRR of_50% from
before treatment to week 1 or 2 (10 or 20 Gy) of the concurrent CRT was a potential prognosticator for 2-year
OS. However, none of these studies explored the distinctive role of interim SUVm values or that of SRR in the
T- and N-status on local failures, respectively. In addition, the difference between the SRR and the reduction ratio of CT-based volumes has not been examined. Our study is the first to compare the predictive role between the iSUVm and SRR. In addition, we defined the separate
prognostic values of the T- and N-related parameters in the final outcome. Although the optimal
cutoff values must be determined by conducting research with a large cohort, this study indicated that HNC
patients with a higher iSUVm or a lower SRR during the late-phase of RT/CRT were also associated with inferior outcomes.
In addition, our study is the first to reveal the relationship between anatomical and biological changes. The
primary goal of cancer treatment is to produce sustained remission, which is mainly based on changes in tumor volume. Functional changes often precede structural changes in tissues; thus, the identification of residual viable tumor by analyzing anatomical images is somewhat difficult, particularly when tumor cells are
replaced by stromal cells without a considerable loss in volume.10 Geets et al. investigated 10 patients with
pharyngo-laryngeal squamous cell carcinoma treated using CRT and showed that PET-based tumor volumes
segmented from interim treatment images were considerably smaller than those obtained using anatomical
imaging modalities.21 Alternatively, measurable anatomical
changes throughout fractionated RT for treating HNCs were reported to occur mainly during the second half of treatment.22 Given that the VRR of the primary
tumor at 40 to 50 Gy might be a potential predictor for
primary failure in patients with oropharyngeal or hypopharyngeal cancers,20 there are two additional implications
in this study. First, at a cumulative RT dose of 40 to 50 Gy, SRR or iSUVm can supplement VRR as a response marker for local control. Second, according to our findings, there is a need to investigate the actual molecular mechanism of the disparities between volumetric
and biological changes during RT, particularly that of the primary tumor.
Despite limitations such as the small sample size, this study demonstrated the feasibility of using interim SUVm and SRR for implementing an organ preservation scheme when PET/CT becomes a part of the response marker. Based on our data, we recommend that the
most effective treatment modification, such as dose escalation or consideration of adjunctive surgery, should be
considered for patients exhibiting an SRR-P<0.64 or a higher iSUVm at a cumulative RT dose of 40 to 50 Gy. In contrast, a routine follow-up protocol after CRT can be applied for those with an SRR-P>0.64. Because using only one phase of molecular images to represent the final outcome might be problematic, the results must be tested on a large cohort of patients and by using various phases of interim images to determine how effectively the response markers are working. Furthermore, more correlation studies between the interim PET/CT
and other known biomarkers should be conducted. Nonetheless, our findings can help oncologists quickly assess
the feasibility of salvage surgery or conduct doseescalation schemes for patients with high-risk features.
CONCLUSION
In summary, interim PET/CT at a cumulative RT dose of 40 to 50 Gy can be used as a predictor for OS and DFS in patients with pharyngeal cancer under definitive RT/CRT. A high interim SUVm was associated with local recurrence. In addition, patients with a low SRR-P should be considered to be at risk for primary failure.
