Predicting Outcome in Patients with Rhabdomyosarcoma: Role of [18F]Fluorodeoxyglucose Positron Emission Tomography

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Radiation Oncology biology

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Clinical Investigation

Predicting Outcome in Patients with Rhabdomyosarcoma: Role of [18F] Fluorodeoxyglucose Positron Emission Tomography Dana L. Casey, BA,* Leonard H. Wexler, MD,y Josef J. Fox, MD,z Kavita V. Dharmarajan, MD,*,x Heiko Schoder, MD,z Alison N. Price, MD,y,jj and Suzanne L. Wolden, MD* Departments of *Radiation Oncology, yPediatrics, and zNuclear Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; xDepartment of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York; and jjDepartment of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania Received Jun 26, 2014, and in revised form Jul 30, 2014. Accepted for publication Aug 2, 2014.

Summary The ability of positron emission tomography (PET) to serve as a predictive marker of outcomes other than local control in rhabdomyosarcoma (RMS) is unclear. We retrospectively analyzed the predictive value of PET at different time points throughout treatment in 107 RMS patients. Baseline PET, PET after induction chemotherapy, and PET after radiation were all predictive of progression-free survival. Our data suggest that PET is an early indicator of outcomes in patients with RMS.

Purpose: To evaluate whether [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) response of the primary tumor after induction chemotherapy predicts outcomes in rhabdomyosarcoma (RMS). Methods and Materials: After excluding those with initial tumor resection, 107 patients who underwent FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center from 2002 to 2013 were reviewed. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated according to FDG-PET response and maximum standardized uptake value (SUV) at baseline (PET1/SUV1), after induction chemotherapy (PET2/SUV2), and after local therapy (PET3/SUV3). Receiver operator characteristic curves were used to determine the optimal cutoff for dichotomization of SUV1 and SUV2 values. Results: The SUV1 (<9.5 vs 9.5) was predictive of PFS (PZ.02) and OS (PZ.02), but not LC. After 12 weeks (median) of induction chemotherapy, 45 patients had negative PET2 scans and 62 had positive scans: 3-year PFS was 72% versus 44%, respectively (PZ.01). The SUV2 (<1.5 vs 1.5) was similarly predictive of PFS (PZ.005) and was associated with LC (PZ.02) and OS (PZ.03). A positive PET3 scan was predictive of worse PFS (PZ.0009), LC (PZ.05), and OS (PZ.03). Conclusions: [18F]fluorodeoxyglucose positron emission tomography is an early indicator of outcomes in patients with RMS. Future prospective trials may incorporate FDG-PET response data for risk-adapted therapy and early assessment of new treatment regimens. Ó 2014 Elsevier Inc.

Reprint requests to: Suzanne L. Wolden, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065. Tel: (212) 639-5148; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 5, pp. 1136e1142, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.08.005

Conflict of interest: none

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Introduction Response to induction therapy serves as an early predictor of outcomes in many pediatric tumors, including Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma (1-5). However, initial response to chemotherapy, as measured via computed tomography (CT) or magnetic resonance imaging (MRI), was a poor predictor of failurefree survival in patients with rhabdomyosarcoma (RMS) treated on Intergroup Rhabdomyosarcoma Study (IRS)-IV (6) and Children’s Oncology Group (COG) study D9803 (7). The value of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in assessing response and predicting outcomes has been recently described in Ewing sarcoma, osteosarcoma, and adult soft-tissue sarcoma (812). Although FDG-PET plays a valuable role in the staging of RMS (13, 14), its predictive value has not been well established (15). At our institution we previously analyzed the role of FDG-PET in predicting local control among a cohort of patients with RMS (16). The association between initial response to chemotherapy on FDG-PET and outcomes other than local control remains unknown. The ability of FDG-PET to serve as an early indicator of progression-free survival (PFS) could allow for riskadapted alterations in therapy as well as early assessment of novel treatment regimens. The primary objective of this study was to investigate the role of postinduction chemotherapy PET as a predictive marker of outcomes in RMS. We secondarily sought to analyze the predictive value of FDG-PET at other time points throughout treatment, including at baseline and after all local control therapy.

Methods and Materials Patient population This is a single-institution, retrospectively ascertained cohort of all RMS patients who underwent evaluation by FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center (MSKCC) between January 2002 and December 2013. There were no age or stage criteria for inclusion in the cohort. Of the 140 RMS patients who underwent FDG-PET during this timeframe, we excluded 26 patients with clinical group I or II disease. These patients by definition did not have measurable disease at the time of chemotherapy initiation, interfering with our primary objective to measure response to induction chemotherapy. We excluded another 7 patients who did not undergo a postinduction chemotherapy FDG-PET, leaving 107 patients for analysis. Seventy-four of 107 patients were included in our previous analysis evaluating the ability of FDG-PET to predict local control. In addition to FDG-PET, initial workup for all patients consisted of CT or MRI of the primary site, CT of the chest, abdomen, and pelvis, and bone marrow aspirate and biopsy to evaluate for metastatic

PET predicts outcomes in RMS 1137

disease. A waiver of authorization was received from the MSKCC institutional review board to conduct the analyses in this study.

Treatment All patients received multiagent chemotherapy therapy on or according to one of the following protocols: an MSKCC phase II pilot protocol IRB #03-099 consisting of irinotecan, carboplatin, cyclophosphamide, doxorubicin, and vincristine (nZ73), or COG protocols ARST0331 (nZ4), ARST0431 (nZ3), ARST0531 (nZ5), and D9803 (nZ6). Nine patients were treated on a National Cancer Institute pilot study of alternating vincristine, doxorubicin, cyclophosphamide with etoposide and ifosfamide. The remaining patients (nZ7) received a combination of standard chemotherapy agents off protocol. Sixty-four percent of patients underwent definitive radiation therapy (RT) for local control, 35% underwent surgery and RT, and 1 patient progressed before local therapy could be administered.

FDG-PET imaging Details regarding FDG-PET techniques used at our institution have been previously described (17). Scans were first interpreted visually to determine presence of abnormal FDG uptake in the primary tumor. If activity in the region of interest was greater than the background activity and unexplained by normal physiologic or inflammatory processes, the scan was considered positive. The standardized uptake value (SUV) of the primary tumor was defined as the activity in the region of interest per unit volume divided by injected dose per unit body weight (16). Semiquantitative analysis was done by recording the maximum SUV. For analysis, we defined PET1 as the baseline FDGPET at diagnosis before chemotherapy initiation; PET2 as the postinduction chemotherapy FDG-PET at week 12 (median) before local control therapy; and PET3 as the first FDG-PET after local control therapy, no longer than 4.5 months after RT. The corresponding maximum SUVs were labeled SUV1, SUV2, and SUV3. For PET2 and PET3 scans, PET positivity (residual uptake greater than background unexplained by normal physiologic or inflammatory processes) or negativity (no residual uptake) of the primary site of disease was recorded along with the maximum SUV.

Statistical analysis Three methods were used for dichotomization of SUV results: (1) receiver operating characteristic (ROC) curves were used to determine the optimal SUV1 and SUV2 cutoff values; (2) PET1 scans were dichotomized around an SUV1 value of 6.0 and PET2 scans around an SUV2 value of 2.5, as done previously in the literature for sarcomas (9, 10, 12); and (3) PET2 and PET3 scans were categorized as PET

1138 Casey et al. positive versus PET negative for ease of clinical use. We did not look at SUV continuously owing to the variability in PET methodology and analysis that makes such comparisons challenging. The ratio of SUV2/SUV1 was also calculated and considered favorable if <0.5. Progressionfree survival was calculated as the time from diagnosis to first relapse. Relapses included local, regional, and/or distant failure or progression. Overall survival (OS) was calculated as the time from diagnosis to death from any cause. Patients without relapse or death were censored at the time of last follow-up. The Kaplan-Meier method was used to assess the PFS and OS, and a competing-risks analysis was used to assess the cumulative incidence of local failures. Survival curves among different subgroups of patients were compared with the Mantel logerank test. Cumulative incidence curves were compared with Gray’s method.

Results The characteristics of the patients who met study criteria are listed in Table 1. The median age at diagnosis was 10.9 years (range, 0.2-44.0 years). Primary site was favorable (stage I) in 6 patients, 4 of whom were classified as COG low risk and 2 as intermediate risk. Most patients presented with poor prognostic features, including alveolar histology (56%), unfavorable primary site (94%), stage III-IV disease (92%), and group IV disease (42%). All 107 patients underwent evaluation by FDG-PET after induction chemotherapy (PET2) at a median time of 12.3 weeks (range, 7-31 weeks) from chemotherapy initiation. Eighty-six had evaluable baseline PET scans (PET1), and 94 had evaluable postelocal therapy PET scans (PET3). Forty-four patients (41%) relapsed at a median time of 1.1 years from diagnosis (range, 0.2-3.3 years). Sites of failure were as follows: 11 local, 29 distant, 3 simultaneous local and distant, and 1 regional. Median follow-up of surviving patients was 5.3 years (range, 0.3-10.6 years), with 8 patients lost to follow-up. Among the entire cohort, the 3-year PFS and OS rates were 55% and 63%, respectively. The PFS and OS rates were 66% and 73% in those with localized disease, versus 38% and 48% in patients with metastatic disease (PZ.009 and PZ.005, respectively). Age (<10 years vs 10 years) and primary site (favorable vs unfavorable) were also associated with PFS (PZ.0001 and PZ.05, respectively). Table 2 provides a complete list of potential prognostic factors of PFS, OS, and local control on univariate analysis.

Baseline PET (PET1) The median SUV1 among the 86 patients with analyzable PET1 scans was 8.1 (range, 0-22). Receiver operating characteristic curves revealed an optimal SUV1 cutoff value for PFS of 9.5. Primary-site SUV1 was associated

International Journal of Radiation Oncology  Biology  Physics Table 1 patients

Demographic and clinical characteristics of the 107

Characteristic Gender Male Female Age (y) <10 10 Primary site Parameningeal GU BP Extremity Orbit GU non-BP Head and neck Other Histology Embryonal Alveolar Pleomorphic Mixed IRS group I II III IV Stage I II III IV Local control therapy Definitive RT Radiation þ surgery No local therapy*

n (%) 53 (50) 54 (50) 51 (48) 56 (52) 36 9 25 3 2 1 31

(34) (8) (23) (3) (2) (1) (29)

45 60 1 1

(42) (56) (1) (1)

0 0 63 (59) 44 (41) 6 2 55 44

(6) (2) (51) (41)

69 (64) 37 (35) 1 (1)

Abbreviations: GU BP Z genitourinary bladder/prostate; GU nonBP Z genitourinary non-bladder/prostate; IRS Z Intergroup Rhabdomyosarcoma Study; RT Z radiation therapy. * Patient progressed before local therapy could be administered.

with outcomes: 3-year PFS was 62% (95% confidence interval [CI] 48-76%) in those with SUV1 <9.5, versus 39% (95% CI 21-56%) in those with SUV1 9.5 (PZ.02; Fig. 1). The SUV1 was similarly predictive of OS (PZ.02), but not of local control. When a cutoff value of 6.0 was used, SUV1 remained predictive of PFS (PZ.02) and OS (PZ.006).

Postinduction chemotherapy PET (PET2) The median SUV2 was 2.6 (range, 0.7-13) among patients with positive PET2 scans, with 45 patients experiencing a complete response after induction chemotherapy (defined as negative PET2 scan). Of the 62 patients with positive PET2 scans, 32 patients (52%) relapsed, versus 12 of 45 (27%) with negative scans. Positivity versus negativity on PET2 was predictive of outcomes: 3-year PFS in those with

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Prognostic factors for local failure (LF), relapse-free survival PFS and overall survival (OS)

Factor PET1 SUV1 <9.5 SUV1 9.5 PET1 SUV1 <6 SUV1 6 PET2 Negative Positive PET2 SUV2 <1.5 SUV2 1.5 PET2 SUV2 <2.5 SUV2 2.5 SUV2/SUV1 Ratio <0.5 Ratio 0.5 PET3 Negative Positive Age (y) <10 10 Histology Embryonal Alveolar Tumor size (cm) <5 5 Primary site Favorable Unfavorable Stage Localized Metastatic

n

3-y LF (%)

P

3-y PFS (%)

P

3-y OS (%)

P

55 31

13 17

.53

62 39

.02

72 46

.02

30 56

7 18

.15

69 44

.02

82 51

.006

45 62

6 21

.03

72 44

.01

77 53

.06

54 53

6 22

.02

71 40

.005

75 51

.03

73 34

6 31

.0008

64 38

.01

65 58

.20

71 15

11 27

.10

54 52

.87

60 73

.66

67 27

10 26

.05

67 33

.0009

72 49

.03

51 56

9 20

.10

76 36

.0001

79 46

.0005

45 60

23 7

.04

65 48

.07

72 54

.07

36 65

7 18

.13

64 53

.22

69 63

.40

6 101

0 15

.31

100 52

.05

100 60

.05

63 44

16 12

.77

66 38

.009

73 48

.005

Abbreviations: PET1 Z baseline positron emission tomography; PET2 Z PET after induction chemotherapy; PET3 Z PET after local control therapy; SUV Z standardized uptake value.

negative PET2 scans was 72% (95% CI 58-86%), versus 44% (95% CI 31-57%) in those with positive PET2 scans (PZ.01; Fig. 2a). Receiver operating characteristic curves revealed an optimal SUV2 cutoff value for PFS of 1.5: 3year PFS was 71% (95% CI 58-84%) in those with SUV2 <1.5, versus 40% (95% CI 26-53%) with SUV1 1.5 (PZ.005; Fig. 2b). Similar results were found when a cutoff value of 2.5 was used (PZ.01). To achieve a more homogenous subgroup, we excluded 21 patients whose PET2 scans were outside of 12  2 weeks and reperformed calculations above. Receiver operating characteristic curves revealed an optimal SUV2 value of 0.9 for the subgroup. An SUV2 <0.9 as well as PET negativity remained predictive of improved PFS (PZ.04 and PZ.05, respectively). Additionally, we looked at only those patients who were treated on the same institutional prospective protocol, IRB #03-

099, and underwent PET2 scans at 12  2 weeks. Among the 62 patients who met criteria, PET2 positivity versus negativity as well as SUV2 <0.7 versus 0.7 (ROC cutoff) were predictive of PFS (PZ.04 and PZ.04, respectively). However, dichotomization by an SUV2 value of 2.5 was no longer predictive of outcomes. Restricting the analysis to patients with nonmetastatic disease, SUV2 <2.5 remained predictive of improved PFS (PZ.04). There was an insignificant trend toward improved PFS when the optimal cutoff for PFS as determined by ROC curves was used: 3-year PFS in those with SUV2 <2.2 was 75%, versus 47% in those with SUV 2.2 (PZ.08). A similar trend was seen when patients with localized disease were dichotomized by PET2 positivity versus negativity. Negativity on PET2, SUV2 <1.5, and SUV2 <2.5 were all predictive of local control (PZ.03, PZ.02, and

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Fig. 1. Progression-free survival based on baseline positron emission tomography maximum standardized uptake value (SUV1). PZ.0008, respectively). An SUV2 <1.5 was also predictive of improved OS (PZ.03). The median SUV2/SUV1 was 0.2 (range, 0-1.2). The SUV2/SUV1 was not associated with local control, PFS, or OS.

Postelocal therapy PET (PET3) Median time at PET3 was 7.3 weeks after local therapy (range, 1.1-18.7 weeks). Of the 27 patients with positive PET3 scans, 14 patients experienced an increase in SUV from PET2 to PET3, 12 patients had a decrease in SUV, and 1 patient’s SUV remained the same. The median SUV3 among those with a positive PET3 was 2.6 (range, 1.1-8.2). Sixty-seven percent of patients (18 of 27) with a positive scan at the end of local therapy relapsed. The PFS at 3 years was 67% (95% CI 55-79%) in those with a negative PET3 scan, versus 33% (95% CI 16-51%) in those with a positive PET3 scan (PZ.0009; Fig. 3). Positivity on PET3 was also associated with worse local control (PZ.05) and OS (PZ.03). Among patients with positive PET3 scans, there was no difference in PFS according to whether the SUV had increased or decreased from PET2 to PET3 (PZ.35). Additionally, an increase in FDG activity from PET2 to PET3 was not associated with clinical progression in 13 of 14 patients and was attributed instead to treatment effect.

Fig. 2. Progression-free survival based on postinduction chemotherapy positron emission tomography (PET2). Dichotomization by (a) PET2 positivity versus negativity; and (b) standardized uptake value (SUV2) of 1.5. to expand upon our previous report and evaluate the role of FDG-PET (most importantly PET after induction chemotherapy) as a predictor of patient outcomes. We found that baseline PET, PET after induction chemotherapy, and PET after local therapy were all predictive of PFS. Additionally,

Discussion Well-established prognostic factors for RMS include primary site, age, histology, tumor size, regional lymph node involvement, clinical group, and the presence or absence of distant metastases. We previously found that postradiation PET negativity was predictive of local control in a series of 94 RMS patients, whereas baseline and pre-RT PET negativity suggested statistically insignificant trends toward local control (16). The aim of the present study was

Fig. 3. Progression-free survival based on postelocal therapy positron emission tomography (PET3).

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we confirmed our previous findings that postradiation FDG-PET predicts local control (16), and with a larger sample size and more follow-up, found that postinduction chemotherapy PET also has the ability to predict local control. This is the first report analyzing the value of PET after induction chemotherapy in assessing response and predicting PFS in patients with RMS. Previous reports have found a similar predictive value of PET response assessments for esophageal carcinoma (18), melanoma (19), lung cancer (20), lymphoma (1, 21), ovarian cancer (22), Ewing sarcoma (9), osteosarcoma (12), and soft-tissue sarcoma (11). For example, in Ewing sarcoma, SUV2 (<2.5 or 2.5) was predictive of PFS, whereas SUV1 and SUV2:1 were not (9); and in extremity soft-tissue sarcoma, SUV1 <6 and a favorable FDG-PET response after induction chemotherapy were both associated with improved survival (11). Our data suggest that FDG-PET after induction chemotherapy has the potential to act as an intermediate endpoint biomarker for both research and clinical practice, as has been suggested in adult soft-tissue sarcoma (23). For research purposes, FDG-PET response may serve as a noninvasive marker of tumor response that could allow for earlier assessment of new treatment regimens. This would be especially beneficial in intermediate- and high-risk RMS, for which the discovery and evaluation of alternative chemotherapeutic agents and/or the intensification of local therapies are particularly relevant concerns for patients at greater risk of systemic or local treatment failure. For example, a stereotactic boost directed to PET2-positive residual disease could be a method of intensifying local therapy in patients at risk of local relapse. The FDG-PET response may also allow for further risk-stratification and alteration of postinduction treatment, depending on whether the patient had an unfavorable or favorable response. The ability of such modifications in treatment to then translate into improved outcomes must be further evaluated in a prospective study. It is important to recognize when planning adaptive treatment that a positive PET scan after induction therapy should not be equated with relapse, and a negative PET scan should not be equated with survival. For example, although a negative PET at week 12 in our cohort was associated with improved PFS, 27% of patients with a negative PET2 still relapsed. Additionally, although most patients with a positive PET3 relapsed, it seems that most events were metastatic (local failure of 27% in patients with a positive PET3). Thus, persistent FDG activity after local control therapy should not alone be an indication of local relapse. European RMS protocols already call for alterations in therapy based on initial response to chemotherapy as measured via anatomic methods (CT or MRI) (24-27). However, the limitations of anatomic imaging in measuring tumor response have been previously described for softtissue sarcoma (28), and data from IRS-IV showed that tumor response assessment by anatomic imaging at week 8

PET predicts outcomes in RMS 1141

was not associated with failure-free survival (6). Similar results were found at week 12 in patients treated on COG D9803 (7), as well as after the completion of all therapy on IRS-IV (29). Taken together with our data, functional imaging with FDG-PET may be more appropriate for measuring treatment response in RMS. This may be due to PET’s superior ability to differentiate necrotic tissue from viable tumor. We used ROC curves to determine the cutoff values for SUV1 and SUV2 that would allow for the optimal balance between sensitivity and specificity. We also analyzed our data with cutoff values previously used in sarcoma literature (6.0 for SUV1, 2.5 for SUV2) (9, 12), as well as the practical dichotomization by presence or absence of FDG uptake for PET2 and PET3 scans. Dichotomization by PET positive versus PET negative, as is done in Hodgkin lymphoma (1), is more feasible for clinical use when techniques are not as stringently defined. Among the entire cohort, dichotomization by all 3 methods discussed above showed a consistent association between response on postinduction chemotherapy PET and PFS. However, among smaller subgroups, not all methods of dichotomizations were predictive. For example, among the subgroup of patients with localized disease, only SUV2 <2.5 was predictive of outcomes. This may be in part due to the smaller sample size after excluding patients with metastatic disease, because the other methods for dichotomization both showed statistically insignificant trends. Whether an optimal cutoff value exists must be further explored and may be specific to an individual cohort. Additionally, the optimal timing for evaluation of response as defined by PET was not addressed in this study and must be further explored. The size of our cohort was relatively large compared with similar series and may partly explain the discrepancies in results between the St. Jude experience (which contained 38 patients) and ours (15, 30). The major limitation of our report is the retrospective design and consequent: (1) variation in timing of postinduction chemotherapy FDG-PET; and (2) lack of uniform therapy. However, among the subgroup of patients who underwent PET2 scans at approximately the same time, FDG-PET response continued to be predictive of outcomes. Additionally, among the homogenously treated subgroup of patients on an in-house prospective protocol, the association between postinduction chemotherapy PET and PFS remained significant. Further supporting the predictive value of PET, findings at baseline, postinduction chemotherapy, and post-RT PET were congruent with one another. Other limitations include the lack of an independent cohort in which to validate our findings, the range of timing at which PET3 scans were obtained, and the length of time over which our cohort spanned (11 years); the validity of comparing SUV results between different PET scanners and over an extended period of time is unknown. The predictive power of FDG-PET should be validated in a larger, multi-institutional, prospective trial. In summary, response on FDG-PET at week 12 was correlated with

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outcomes in patients with RMS. Our findings suggest that future protocols may be able to use FDG-PET response data for improved risk-stratification, modification of subsequent therapy, and/or evaluation of the effectiveness of new treatment regimens.

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