	To evaluate the role of magnetic resonance imaging (MRI) in the clinical staging of prostate cancer in the definitive and salvage settings, and to identify changes in treatment recommendations.

	Between November 2008 and November 2011, 114 patients referred for radiotherapy (RT) consultation underwent a prostate-protocol MRI of the prostate and pelvis. Charts were retrospectively reviewed for demographic and clinical information.

	Eighty-six patients were evaluated for definitive treatment, 26 for salvage treatment, and 2 for RT planning in the adjuvant setting. Of the definitive subjects, MRI was performed after RT consultation in 68 patients and before consultation in 18 patients. For patients who underwent an MRI after consultation, MRI led to a change in treatment recommendation for 6 of 68 (9%) patients. Androgen deprivation therapy was added or extended in 3, prophylactic nodal RT was added to 3, and definitive nodal RT was added to 1.

	Active surveillance was no longer recommended in two persons, and brachytherapy alone was no longer an option in two persons. Of the 86 definitive treatment patients, nodal metastases were identified in 6 (7%). For the 26 salvage patients, imaging did not lead to any changes in planned treatment. MRI evaluation can influence clinical decision making for both physician and patient, but how those decisions change outcome is still unresolved.

	In most cases when treatment recommendations were modified based on MRI findings, therapy was escalated to correspond with clinical upstaging. It remains to be seen if this translates into improved disease control, and it is possible that the “Will Rogers phenomenon” (when moving an element from one set to another raises the average values of both) will result from incorporating the high-resolution MRI information into clinical decision making.

Historically, magnetic resonance imaging (MRI) has not been routinely used for the diagnosis and staging of prostate cancer (PC). Accurate staging is important because there is wide variability in recommended treatment options and expected outcomes for patients with low-risk, intermediate-risk, and high-risk PC.

Although useful for risk stratification, prostate-specific antigen (PSA) measurements can be unreliable correlates of tumor stage and disease burden.

 In addition, while digital rectal examination (DRE) can detect high-risk features such as extracapsular extension (ECE), DRE has been shown to have a low sensitivity.

 MRI has several possible roles in the management of PC, and its utility is being investigated in numerous single-institution studies. MRI findings have been correlated to pathologic features after radical prostatectomy.

 MRI is being evaluated as a tool for selecting patients who are appropriate active surveillance (AS) candidates, 

 despite some evidence that it may not be useful at predicting adverse pathologic features,

 or for predicting risk of recurrence based on high-risk features.

A better understanding of tumor extent and location within the gland may lead to improvements in therapeutic decision making and in surgical and radiotherapy (RT) treatment planning. Use of prostate MRI could also lead to delivery of more aggressive therapies because of the detection of adverse features that would otherwise remain occult.

We reviewed the use of prostate MRI to characterize its effect on the clinical stage and subsequent treatment recommendations for patients referred for RT consultation.

After Institutional Review Board approval was obtained, all patients who were evaluated in the radiation oncology department and underwent a prostate protocol MRI between November 2008 and November 2011 were identified.

In total, 114 patients met these criteria. Charts were reviewed for age at diagnosis, PSA level, date of biopsy, Gleason score, and pathologic or DRE-based T-stage. The clinical American Joint Committee on Cancer (AJCC 7th edition) Tumour, Node, Metastases (TNM) stage and the National Comprehensive Cancer Network (NCCN) risk groups were documented. Prostate protocol MRI reports were reviewed, and an MRI stage was assigned by the authors based on the extent of disease identified on imaging.

Treatment recommendations, per dictated reports, were given at the time of initial RT consultation and again after MRI information was obtained. In situations where the MRI was obtained before the RT consultation, only one set of recommendations was made.

MR imaging studies were performed on a whole body 3 Tesla Siemens Magnetom TrioTim or Verio (Siemens Medical Solutions, Erlangen, Germany) with an 8-channel pelvic phased-array coil and spine coil. Routine techniques and sequences were used, including small field of view (FOV) T2-weighted turbo spin-echo sequences in the axial, sagittal, and coronal directions, covering the prostate and seminal vesicles (SVs). Scanning parameters were TR range/TE range, 3000—3300/101-121; slice thickness 3-4 mm; an echo train length of 17-19 and 1-2 averages.

Each plane took 5 to 6 minutes to acquire with a FOV of 160 x 160 mm. A 256 x 256 pixel matrix was used. An axial T1 small FOV series was performed to detect postbiopsy hemorrhage. Whole-pelvis imaging T1 and T2 with fat saturation was performed to look for lymph node (LN) and osseous involvement. Axial whole-pelvis diffusion-weighted imaging was performed with b values of 0 and 1000.

All studies were evaluated by one of five abdominal fellowship- trained radiologists with two to 15 years of experience. Imaging was evaluated as part of usual clinical care on a PACS image viewer (iSite, Philips Healthcare, Andover, MA) 

, with full access to any previous imaging and medical records, including PSA level and biopsy results. No additional review was performed for this study.

Clinical interpretation was focused on providing information for local staging, including an assessment of the prostate capsule, SVs, and pelvic nodes. Criteria used to classify local disease included a focal T2 hypointense mass in the peripheral zone without corresponding T1 hyperintense signal, to suggest postbiopsy hemorrhage. ECE included evaluation on the T2-weighted images for direct extension into the periprostatic fat or an interruption of the T2 dark band that surrounds the prostate, or broad contact of the low-signal intensity focus of disease with the capsule (≥10 mm).

Eighty-six patients were evaluated for definitive treatment, 26 for salvage treatment, and 2 patients were evaluated for treatment planning in the adjuvant setting. Patient and tumor characteristics are described in 

. For the 86 patients with newly diagnosed PC, AJCC TNM stages before and after MRI acquisition are displayed in 

 The most common clinical stage was T1cN0M0 (50%). MRI revealed that 17 (19.8%) had findings concerning for ECE, and 13 (15.1%) had SV invasion (SVI). Of the patients with ECE diagnosed on MRI, the clinical stage was formerly T1c in 7 cases, T2a in 3, T2b in 4, T2c in 1, and T3a in 2. Of the patients with SVI on MRI, the clinical stage was formerly T1c in 4 cases, T2a in 1, T2b in 1, T2c in 3, T3a in 2, and T3b in 2. In 29 cases (34%), MRI findings agreed with the clinical examination findings. In 54 (63%) patients, MRI findings suggested more advanced disease than DRE, and in 3 (3%) cases the MRI findings were less concerning than DRE. Of the 54 who were clinically upstaged, 33 (61%) had clinical T1c disease prior to MRI. Of these, 14 had imaging findings reported as involving both lobes of the prostate gland, 7 had findings concerning for ECE, and 4 had SVI on MRI. Of the 3 who were downstaged, in two cases of clinical T2a disease, the tumor could not be detected on MRI, and in one case of clinical T3a disease, ECE could not be identified on MRI.

		Table 1. Demographics and Tumor Characteristics of the Study Population

		Table 2. Clinical Staging of 86 Patients Treated with Definitive Radiotherapy

MRI reported newly found nodal metastases in 6 (7%) patients, and pelvic LNs were “concerning” in an additional two. Distant metastases (DM) were not identified in any patient. MRI was performed after RT consultation in 68 patients and before consultation in 18 patients. For patients who underwent an MRI after consultation, MRI led to a change in treatment recommendation for 6 of 68 (8.8%) 

. Two patients were initially considered for brachytherapy monotherapy but after MRI they underwent surgery or combined modality treatment with external beam radiation therapy (EBRT) and androgendeprivation therapy (ADT). Two patients were considered for AS, but after MRI underwent definitive treatment. In four patients, EBRT to the prostate and SVs was recommended at the time of diagnosis, but after MRI, the field was extended to include the pelvic LNs. In three cases, ADT was not considered at diagnosis but was recommended after consideration of MRI findings. For the 26 patients evaluated in the salvage setting, the mean time from definitive surgical treatment to MRI was 4.4 years (range 0.5 to 21 years). Retained SVs were identified in seven (26.9%) patients. For the 28 patients evaluated in the salvage and adjuvant settings, no nodal or DM were identified, and imaging did not lead to changes in planned treatment.

MRI use for prostate cancer staging, decision making, and treatment planning is supported by most payers and treatment guidelines,

The mantra of “Don’t order a test unless you will action the result” is a refrain most medical students learn early in their training. This study was undertaken specifically to evaluate how the diagnostic MRI altered clinical decision making, despite the absence of level 1 evidence that proves or disproves its merit in changing oncologic outcomes. There are no universally adopted guidelines to inform the clinician on how MRI results should affect patient care. At our institution, in the definitive treatment setting it is our bias that MRI findings of SVI, grossly evident extracapsular extension, lymphadenopathy, or very-high-volume disease should be considered a very-high-risk feature. In these cases, it is our bias that patients should have pelvic lymph nodal radiation, dose-escalation with brachytherapy if possible, as well as ADT as part of their definitive treatment. With the exception of lymphadenopathy, CT scans perform poorly at discriminating these particular features. Conversely, in low-risk and favorable intermediate-risk patients, we consider very-low volume or no evidence of disease on MRI to be a favorable prognostic feature that may support the use of monotherapies or AS when taken in context with other clinical parameters. Reports of “capsular abutment concerning for extracapsular extension” are generally considered nonactionable.

Irrespective of how these findings affect the choice of therapy delivered, these authors feel that properly performed MRI sequences can greatly assist in the contour definition of the prostate and surrounding anatomy for both radiation oncologist and surgeon to assist in high-quality treatment planning. In this series of patients, most were found to have more advanced disease on MRI than what DRE implied. Bilateral gland involvement, ECE, and SVI were identified on MRI more often than DRE detected rates of T2c, T3a, and T3b disease. This is consistent with published reports, such as that by Fuchsjager et al,

 who evaluated 224 patients who underwent an endorectal MRI before EBRT for PC. On MRI, bilateral gland involvement, ECE, and SVI were identified in 24.6%, 40.2%, and 7.1%, respectively, compared to 0%, 7.6%, and 5.4% with DRE-based T2c, T3a, and T3b disease, respectively. Numerous studies have demonstrated a correlation between these MRI findings and biochemical failure after RP or EBRT.

A study of 977 men demonstrated that PSA failure was predicted by preoperative PSA, MRI T-stage, percentage of positive prostate biopsies, Gleason score, and 1992 AJCC clinical stage in men undergoing RP.

		Table 3. Change in Treatment Recommendation Because of Findings on Prostate Protocol MRI

		AS, active surveillance; EBRT, external beam radiotherapy; ADT, androgen deprivation therapy; RP, radical prostatectomy; Brachy, brachytherapy; SV, seminal vesicles; LAN, lymphadenopathy; mo, months; NED, no evidence of disease; *Brachy not indicated because of history of transurethral resection of the prostate. #High-risk NCCN group because of elevated PSA only, and elevated PSA possibly attributable to BPH.

reported on 279 men with intermediate-high risk PC who underwent an endorectal MRI prior to combination EBRT and brachytherapy. ECE on MRI and Gleason score were the only independent predictors of recurrence. Fuchsjager et al found that pretreatment PSA and ECE on MRI were significant predictors of PSA relapse.12 ECE and SVI on MRI predict for poor outcome, and it is therefore appropriate that these features should be considered when treatment recommendations are made.

Use of pelvic MRI for identifying LN involvement is more controversial than the role of MRI in diagnosing locally advanced disease. A meta-analysis of series evaluating the diagnostic accuracy of MRI in diagnosing LN metastases revealed that the sensitivity and specificity of MRI were 0.39 and 0.83, respectively, compared to 0.42 and 0.82, respectively, for CT imaging.

 MRI is limited in detecting LN metastases because the imaging criteria in routine practice depend on a size threshold of ≥10 mm in short axis for elongated nodes or ≥8 mm in short axis for rounded nodes suggesting malignancy. Nodes with malignant deposits often measure less than these thresholds, accounting for the low sensitivity of conventional MRI in malignant LN detection.

While many studies have analyzed the prognostic significance of the high-risk features detected on MRI, it is more challenging to understand how frequently and significantly this information changes treatment recommendations. In our series of 86 patients with newly diagnosed PC, MRI findings had an impact on treatment decision making in six (8.8%) definitively treated patients. Usually, this resulted in an escalation of therapy to address a higher clinical T-stage than what was previously thought. Whether or not this results in a change in outcome remains to be seen. At best, the practice of changing the treatment recommendation based on the imaging findings may lead to more cures; at worst, these men may suffer additional treatment-related morbidity and cost with no therapeutic gain. Improvements in diagnostic imaging techniques will lead to improved resolution of tumor burden on MRI than can be appreciated on most physical examinations. Hence, it is possible that the “Will Roger’s phenomenon,” which describes the apparent improvement in average outcomes in two cohorts when moving elements of one into another, will be seen by incorporating the high-resolution information that MRI affords. That is, if patients previously thought to be low-risk were now reclassified into the highrisk category with DRE occult disease, both the low- and high-risk groups may demonstrate improved outcome over historical controls. A similar phenomenon was noted when Gleason pattern interpretation shifted over time.

 Therefore, the outcomes of patients diagnosed and treated using MRI information cannot be readily compared to historic controls. One barrier to incorporating MRI findings with clinical stage is the current challenge in diagnosing ECE on MRI. A change in stage from T1/T2 to T3 disease can lead to an increase in RT field size (prostate/SVs vs pelvic field), a change in duration of ADT (none vs months to years), and omission of alternative treatment options such as brachytherapy monotherapy or AS. The detection and interpretation of ECE can be challenging. The diagnostic criteria for ECE include concrete findings such as periprosatic fat infiltration with or without direct extension into the neurovascular bundle, and softer features, including areas of capsular bulging, obliteration of the rectoprostatic angle, and capsular contact of tumor extending ≥10 mm.

 which compared local staging and detection of ECE at 3.0 T with and without endorectal coils, found a sensitivity of 33.3% versus 31.3%, specificity of 96.6% versus 97.5%, and accuracy of 63.% versus 61.4%, respectively. In no case was the difference statistically significant. The high specificity argues that the prostate MRI protocol is very accurate for detecting disease when it is present, which may account for the change in management decisions that is attributed to the MRI. Recent studies have demonstrated that sensitivity of MRI in local staging improves in poorly differentiated PC.

This again suggests that the MRI is useful in detecting patients who are at risk of clinical understaging, without increasing the likelihood of overtreatment.

Contrary to patients with newly diagnosed PC, in our limited series of patients evaluated for adjuvant or salvage RT, MRI did not add clinical information that altered our treatment approach. There were no cases of LN involvement or DM, no marginal local recurrences, and the instances of retained SVs seen would have likely been detected on planning CT simulation. In a recent publication by Liauw, endorectal MRI identified a radiographic local recurrence in 21 of 88 (24%) men with clinically undetectable, post-RP biochemical recurrence with a mean pretreatment PSA of 0.30 ng/mL.

 Retained SVs were identified in 14% and LN involvement in 5%. Other institutions have demonstrated that MRI allows for detection of locally recurrent disease in most cases. In a series by Sella et al,

 soft tissue local recurrences as identified on MRI were considered confirmed if a positive biopsy was obtained and if the PSA decreased after RT or if the mass progressed on follow-up imaging. However, in the Sella et al series, the indication for MR imaging was not given, and it is possible that imaging was obtained to confirm the presence of a mass or nodule identified on physical examination. In addition, the authors did not state if a retained SV in the setting of an elevated PSA was considered a local recurrence. The discrepancy between these series and ours could lie in the study methodology. In the work published by Sella et al and Liauw et al, MRI images were retrospectively reviewed for study purposes. This has the potential to bias the reading radiologists and lead to a greater documentation of locally recurrent disease. In our study, MRI results were obtained retrospectively from the initial radiologist’s diagnostic report, and therefore the local recurrence detection rate more accurately represents average rates in practice.

		Figure 1: Representative MRI axial images: (a) T3b disease, (b) pelvic lymphadenopathy, (c) retained seminal vesicle, and (d) T4 disease.

Limitations of this study include its retrospective nature. Identification of high-risk features on MRI could lead to delivery of more aggressive treatment, yet this may not have been explicitly stated in the dictated notes. In this case, we may be underestimating the effect of MRI on treatment decision making. Change in treatment recommendations based on MRI findings is a subjective measure; however, it is important to recognize the possible impact of MRI on cancer staging and consider how this may affect treatment outcomes. Use of MRI to detect PC in the definitive and salvage settings is significantly different, and each of these topics warrants review. Additionally, the clinical routine prostate MRI protocol at our institution is performed at 3.0 T without an endorectal coil. The literature has been inconclusive as to whether 1.5 T imaging with an endorectal coil is clearly superior to 3.0 T without an endorectal coil when a multiparametric approach is used.

This study demonstrates how advanced imaging in PC detection can influence treatment planning and delivery. In most cases, when treatment recommendations were modified based on MRI findings, therapy was escalated to correspond with clinical upstaging. It remains to be seen if this translates into improved disease control. It is possible that the “Will Rogers phenomenon” will result from incorporating the high-resolution MRI information into clinical decision making.

University of Utah, Department of Radiation Oncology, (JT, BT, KK, DS) University of Utah, Department of Radiology (MH) University of Utah, Department of Surgery, Division of Urology (WL)

 Jonathan Tward, University of Utah, Department of Radiation Oncology, 1950 Circle of Hope, Room 1570, Salt Lake City, UT 84112. Tel: 801-581-2396 Fax: 801-585-2666 Email: jonathan.tward@hci.utah.edu

: Jonathan D. Tward consulted for Myriad Genetics, provided expert testimony for Garlington, Lohn & Robinson, and received an HCI Directors translational research initiative grant. Dennis C. Shrieve provided expert testimony for a law firm and receives book royalties from Lippincott. Marta E. Heilbrun has a grant from RSNA/ NIBIB and receives book royalties from Amirsys publishing. For the remaining authors, no conflicts of interest were declared.

			Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1.2016.

			Thompson IM, Ankerst DP, Chi C, et al. Operating characteristics of prostate- specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. 

			Schroder FH, van der Maas P, Beemsterboer P, et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. 

			Obek C, Louis P, Civantos F, Soloway MS. Comparison of digital rectal examination and biopsy results with the radical prostatectomy specimen. 

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 2009;192(6):1471-1480. doi: 10.2214/AJR.09.2527.

			Renard-Penna R, Roupret M, Comperat E, et al. Accuracy of high resolution (1.5 tesla) pelvic phased array magnetic resonance imaging (MRI) in staging prostate cancer in candidates for radical prostatectomy: results from a prospective study. 

2013;31(4):448-454. doi: 10.1016/j.urolonc. 2011.02.017.

			Puech P, Potiron E, Lemaitre L, et al. Dynamic contrast-enhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. 

. 2009;74(5):1094-1099. doi: 10.1016/j.urology.2009.04.102.

			Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. 

. 2015;67(4):627- 636. doi: 10.1016/j.eururo.2014.10.050.

			Guzzo TJ, Resnick MJ, Canter DJ, et al. Endorectal T2-weighted MRI does not differentiate between favorable and adverse pathologic features in men with prostate cancer who would qualify for active surveillance. 

. 2012;30(3):301-305. doi: 10.1016/j.urolonc.2010.08.023.

			D’Amico AV, Whittington R, Malkowicz SB, et al. Combination of the preoperative PSA level, biopsy gleason score, percentage of positive biopsies, and MRI T-stage to predict early PSA failure in men with clinically localized prostate cancer. 

			Joseph T, McKenna DA, Westphalen AC, et al. Pretreatment endorectal magnetic resonance imaging and magnetic resonance spectroscopic imaging features of prostate cancer as predictors of response to external beam radiotherapy. 

. 2009;73(3):665-671. doi: 10.1016/j. ijrobp.2008.04.056.

			Fuchsjager MH, Pucar D, Zelefsky MJ, et al. Predicting post-external beam radiation therapy PSA relapse of prostate cancer using pretreatment MRI. 

. 2010;78(3):743-750. doi: 10.1016/j. ijrobp.2009.08.040.

			Riaz N, Afaq A, Akin O, et al. Pretreatment endorectal coil magnetic resonance imaging findings predict biochemical tumor control in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy.

. 2012;84(3):707-711. doi: 10.1016/j. ijrobp.2012.01.009.

			McKenna DA, Coakley FV, Westphalen AC, et al. Prostate cancer: role of pretreatment MR in predicting outcome after external-beam radiation therapy-- initial experience. 

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			Hovels AM, Heesakkers RA, Adang EM, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. 

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			Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. 

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Articles

Researchers evaluate the role of magnetic-resonance imaging in the clinical staging of prostate
cancer in the definitive and salvage settings, and to identify changes in treatment recommendations.

The Effect of Prostate MRI on Cancer Staging and Radiotherapy Treatment Recommendations

	Radiation therapy (RT) is often used in combination with chemotherapy for myeloid sarcoma (also known as granulocytic sarcoma or chloroma). In certain clinical situations, it may be appropriate to use RT as a primary treatment, and it has been used in select cases for isolated tumors, particularly those that require rapid symptom relief. Here we describe our experience of treatment of myeloid sarcoma in the porta hepatis with RT alone. This appears to be the only reported case of primary radiation management of a hepatic myeloid sarcoma.

	In this case report, we evaluated a 50-year-old woman with a newly diagnosed myeloid sarcoma at the porta hepatis. The patient had a known GATA2 mutation with monocytopenia and mycobacterial infection (Mono-Mac) syndrome, and a history of myelodysplastic syndrome-refractory anemia with excess blasts. She had had an unrelated hematopoietic stem cell transplantation (HCST) 1.5 years prior. Her post-transplant course was complicated by skin and gut graft-versus-host disease that required prolonged oral steroids and extracorporeal phototherapy. On presentation, she had a primary biliary obstruction that was initially treated with common bile duct stenting. However, the mass was found to invade and reobstruct the stent. At the time of evaluation for radiation, she was recovering from obstruction-induced cholangitis and sepsis; she had no myeloid disease involvement on bone marrow biopsy. After multidisciplinary evaluation, we elected to use the recently proposed low-dose radiation regimen of 24 Gy in 12 fractions. We designated our gross target volume (GTV) as areas concerning for disease involvement on computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). We designated our clinical target volume (CTV) as a uniform 1-cm expansion on the GTV, and our planning target volume (PTV) as an additional 5-mm uniform expansion to the CTV. We delivered 24 Gy over 12 fractions using intensity-modulated radiation therapy.

	We observed a total radiographic response 1 month after treatment, along with improvement in the patient’s symptoms and liver function tests. Six months after treatment there was no evidence of myeloid disease involvement on bone marrow cytopathology and cytogenetics. Unfortunately, she had a perirectal reoccurrence of the myeloid sarcoma at 10 months, representing an out-of-field reoccurrence. The bone marrow remained normal. This recurrence was proximal to a site of prior RT induced enteric fistula following brachytherapy with cesium for cervical cancer; thus, we were unable to re-treat this site with RT. The patient underwent re-induction chemotherapy for a second HCST, however she died of multi-organ failure one month later, 11 months following RT for the porta hepatis myeloid sarcoma.

	From our experience, treating myeloid sarcoma at the porta hepatis with 24 Gy over 12 fractions is a well-tolerated treatment that achieved a complete, durable response with minimal toxicity. We propose that clinicians consider radiation as a primary treatment option in clinical situations such as the one described here.

Myeloid sarcoma (also known as granulocytic sarcoma or chloroma) is a rare, extramedullary tumor of immature myeloid cells. The word chloroma comes from the Greek chloros, meaning green, and derives from the presence of myeloperoxidase. Not all deposits exhibit the characteristic green tint, so the terms “myeloid” or “granulocytic sarcoma” are now more commonly used.

 Myeloid sarcomas can present synchronously, after, and, rarely, prior to the onset of leukemia.

Most often, myeloid sarcoma is found concurrently in a patient with previously or recently recognized acute myeloid leukemia (AML) and is often considered an AML equivalent in terms of disease trajectory even when the bone marrow is uninvolved.

 The low frequency of presentation, frequent misdiagnosis, and the variable location and symptomatology have resulted in limited reported clinical experience. Historically, the role of radiation therapy (RT) for patients with myeloid sarcoma has been to provide timely symptom palliation.

Although treatments are generally well tolerated and efficacious, the patient’s prognosis is often poor.

 The significant heterogeneity of disease sites and patient characteristics pose a challenge to the development of a standard treatment algorithm.

Chemotherapy represents the primary treatment modality for patients with myeloid sarcoma, however RT is frequently used as an adjuvant treatment. It has been observed that the addition of radio therapy to chemotherapy was associated with a prolonged failure-free survival, particularly in the central nervous system. 

The treatment guidelines for myeloid sarcoma remain highly individualized and are largely determined by performance status, response to systemic chemotherapy, the presence of systemic disease, the patient’s relapse status, and if the patient has previously received a HSCT.

 Generally, RT may play an important role in circumstances of inadequate response to chemotherapy, recurrence after allogeneic transplant, or when the situation requires rapid symptom relief.

For patients who present with isolated myeloid sarcoma as the symptom of a relapse of a hematologic disease after transplant, treatment options are typically considered as donor lymphocyte infusion, tapering of immunosuppression, RT, and/or clinical trial. Particular attention is given to RT as treatment in circumstances that require rapid symptom relief because of vital structure compression.

Primary RT (as a monotherapy) has been utilized, although the data remains limited by small numbers of cases.

For instance, investigators at the City of Hope reported a cohort of 41 patients who received radiation between 1999 and 2011, of which 5 patients were treated with RT alone for palliative purposes. However, the limited sample size precluded a more thorough analysis of prognostic factors and outcomes.3 For our patient, advanced age and limited performance status resulted in primary RT monotherapy being employed with good effect.

In regards to dose response, myeloid sarcomas are highly radiosensitive, with response rates reported with as low a dose as 4 Gy, but in certain cases, doses up to 30 Gy are needed. Dr. Chak et al led the initial investigations into RT dose response in myeloid sarcoma (n = 33 patients, 54 RT courses), observing that the complete response (CR) rate was closely associated with RT dose (CR rate: <10 Gy, 18%; 10-19.99 Gy, 43%; 20-29.99 Gy, 86%; >30 Gy, 89%).

 Recently, Drs. Yahalom and Bakst from Memorial Sloan Kettering Cancer Center in New York City proposed treatment guidelines based on their experiences with 22 patients treated with radiation between 1990 and 2010, in which they were able to obtain outstanding response and long-term local control, with only 1 patient developing progressive disease at the irradiated site (mean follow-up = 11 months).

Based on their experience, they propose at least 20 Gy, and ideally 24 Gy in 12 fractions as an appropriate regimen. A study by Dr. Chen et al at the National Taiwan University Hospital looked at their experience treating 20 patients (43 lesions total) with myeloid sarcoma: 65% of cases had a CR to treatment, with 25% having a partial response, as defined as >50% disease reduction on imaging. Factors affecting CR on multivariate analysis included younger age and BMT prior to RT; patients with AML had a marginally significant trend toward a higher CR rate. One factor which appeared to effect the rate of CR on multivariate analysis was HSCT prior to RT (89 vs 44% rate of CR, 

 Anecdotally, some radiation oncologists have had experiences where there appears to be a dose-response relationship between the size of the myeloid sarcoma and the total dose of irradiation required for control.

A 50-year-old woman with a history of graft-versus-host disease (GVHD) of the skin and liver, the Mono Mac syndrome, and myelodysplastic syndrome refractory anemia with excess blasts (MDS RAEB-2) presented with worsening malaise and rising liver function tests. She had received a matched unrelated donor peripheral blood stem cell transplant 3.5 years earlier for MDS. Her post-transplant course was complicated by skin and gut GVHD requiring extra-corporeal photopheresis. She also had a history of cervical cancer status post lymphadenectomy and radiation therapy (external beam with intra-cavitary brachytherapy boost). Her post-RT course was complicated by radiation cystitis and proctitis and a rectovesicular fistula, which had required diversion but was successfully reversed. Immunosuppression for the chronic GVHD included cyclosporine and replacement dose hydrocortisone for adrenal insufficiency.

Diagnostic workup with ultrasound and MRI revealed a common bile duct obstruction. PET imaging revealed hypermetabolic foci in the periportal and pericholecystic areas. After endoscopic placement of a temporary stent, an operative biopsy revealed an extrahepatic mass that invaded the gall bladder and cystic duct. Initial histology suggested a poorly differentiated carcinoma, but further analysis in hematopathology revealed this to be a primitive myeloid lineage tumor of patient origin. Flow cytometry and chimerism studies confirmed that the cells were host, indicating a relapse of her MDS RAEB-2.

Because the intraoperative cholangiogram showed complete blockage of the common bile duct, a common bile duct stent was placed. On post-op day 3, she had fevers and right-upper quadrant pain. At this time CT scans demonstrated that the common bile duct stent appeared occluded, and percutaneous biliary drainage was carried out. Cholangitis and Klebsiella sepsis developed, which was successfully treated. ERCP was performed and a bare metal stent was placed to achieve biliary drainage.

After multidisciplinary evaluation including a normal bone marrow, we elected to use the recently proposed lowdose radiation regimen of 24 Gy in 12 fractions. We designated the GTV as areas concerning for disease involvement on CT, MRI, and PET. We designated our clinical target volume (CTV) as a uniform 1-cm expansion on the GTV, and our planning target volume (PTV) as an additional 5-mm uniform expansion to the CTV. We delivered 24 Gy over 12 fractions using volumetric-arc based intensity- modulated radiation therapy 

Six weeks following completion of treatment, there was no clinical or radiographic evidence of disease 

, with a complete imaging response on PET-CT. The liver enzymes returned to normal. Moreover, the bone marrow remained normal on both cytopathology and cytogenetics. At ten months after completion of treatment, her condition worsened, with hematuria, hydronephrosis, and bacteremia. Multiple studies were performed; cystoscopy showed recurrent hemorrhagic cystitis similar to toxicity she had from brachytherapy for cervical cancer. PET scan revealed a left perineal lesion and a circumferential rectal mass 

Biopsy confirmed myeloid sarcoma as the histology, representing an out-of-field disease reoccurrence. Bone marrow was again performed and showed hypocellular marrow with no evidence of disease reoccurrence. Radiation was unable to be given for local disease control because there would be significant overlap with her prior radiation treatment fields for cervical cancer, for which she suffered significant late toxicity, including an enteric fistula and chronic hemorrhagic cystitis. The patient received conditioning for a second transplant using the original unrelated donor cells. However, the patient developed liver failure, which was multifactorial but likely secondary to graft-versushost disease, urinary obstruction, and multi-organ failure, and died 11 months after completion of the RT treatment.

Given the improvements in systemic therapy, including HSCT for diseases associated with myeloid sarcoma (MDS, AML), treatment of local disease may become increasingly important and prevalent. Based on preclinical studies, radiation recruits CD8+ T cells to nonlymphoid tissues and this enhances the graft-versus-leukemia effect after allogeneic transplantation. 12 This patient’s course is consistent with the observation that patients who have received prior HSCT may have a robust and durable response to local RT. In regard to side-effect mitigation, a conformal treatment approach appeared to be useful. The most common reported acute toxicities have been hematologic and gastrointestinal, particularly when large volumes are involved.3 We used IMRT to minimize dose to the surrounding abdominal organs at risk, and our patient was able to tolerate treatment well without any toxicity.

In summary, durable local control of her extra-medullary disease relapse was obtained for 11 months with minimal side-effects of RT treatment. The patient remained free from local recurrence at the RT site and from systemic disease until her death. Our patient had a response and trajectory which was better than what most of the literature would predict. While prompt local control with radiation may certainly have played a role, the specific etiology of the myeloid sarcoma, given this patient’s complex clinical background, may be of significance. Consent: Our patient provided both verbal and written consent to the production of this case report.

National Institutes of Health (CS, AM, DH, AK) and National Cancer Institute (MM, JC, KC)

Aradhana Kaushal MD, NIH, NCI, Radiation Oncology Branch (ROB), Bldg. 10 CRC Rm. B2-3561, 10 Center Dr. MSC 1682, Bethesda, MD 20892. Tel: 301-496-5457 Fax: 301-480-5439. E-mail: kaushala@mail.nih.gov

			Halperin EC BL, Perez CA, Wazer DE. Perez and Brady’s Principles and Practice of Radiation Oncology. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2013.

			Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the world health organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. 

. 2009;114(5):937-951. doi: 10.1182/ blood-2009-03-209262.

			Hall MD, Chen YJ, Schultheiss TE, Pezner RD, Stein AS, Wong JY. Treatment outcomes for patients with chloroma receiving radiation therapy. 

 2014;58(4):523-527. doi: 10.1111/1754-9485.12172.

			Paydas S, Zorludemir S, Ergin M. Granulocytic sarcoma: 32 cases and review of the literature. 

			Pileri SA, Ascani S, Cox MC, et al. Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients. 

			Tsimberidou AM, Kantarjian HM, Estey E, et al. Outcome in patients with nonleukemic granulocytic sarcoma treated with chemotherapy with or without radiotherapy. 

			Bakst R, Wolden S, Yahalom J. Radiation therapy for chloroma (granulocytic sarcoma). 

. 2012;82(5):1816-1822. doi: 10.1016/ j.ijrobp.2011.02.057.

			Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. 

. 2011;118(14):3785-3793. doi: 10.1182/blood-2011-04-347229.

			Asna N, Cohen Y, Ben-Yosef R. Primary radiation therapy for solitary chloroma of oral tongue. 

			Vachhani P, Bose P. Isolated gastric myeloid sarcoma: a case report and review of the literature. Case reports in hematology. 

. 2014;2014:541807. doi: 10.1155/2014/541807.

			Chak LY, Sapozink MD, Cox RS. Extramedullary lesions in non-lymphocytic leukemia: Results of radiation therapy. 

			Chen W-Y, Wang C-W, Chang C-H, et al. Clinicopathologic features and responses to radiotherapy of myeloid sarcoma. 

. 2013;8:245. doi: 10.1186/1748- 717X-8-245.

Treating myeloid sarcoma at the porta
hepatis with 24 Gy over 12 fractions is a well-tolerated
treatment that achieved a complete, durable response with
minimal toxicity.

Primary Radiation Therapy for Myeloid Sarcoma of the Porta Hepatis

		Re-irradiation is an increasingly employed strategy for locally recurrent head and neck cancer, and in select cases may result in long-term disease-free survival. However, disease surveillance following re-irradiation poses several unique challenges. Following de novo radiation for primary head and neck cancer, the utility of imaging modalities that may augment physical exams is well-studied. Positron emission tomography and computed tomography (PET/CT) scanning has a negative predictive value in excess of 90% in this setting, and provides valuable prognostic information to patients and physicians. Although it is tempting to extrapolate these results, the increased tissue inflammation and necrosis, and the increased risk of distant metastases following re-irradiation, could complicate imaging interpretation, and the performance of PET/CT following re-irradiation has not been thoroughly evaluated.

		In the present study, the authors explore the prognostic significance of PET/CT following re-irradiation in a cohort of recurrent head and neck cancer patients. They identify a positive predictive value for PET/CT of >95%, suggesting PET/CT may be a valuable component of surveillance in this setting. Evidence-based surveillance algorithms are lacking for many cancer types, and in an era of value-based care, well-designed studies that demonstrate the value of specific imaging studies are needed. This study is an important first step in assessing the utility of PET/CT following re-irradiation for recurrent head and neck cancer.

	Positron emission tomography/computed tomography (PET/CT) has been widely used to assess tumor response following chemoradiotherapy of head and neck cancer. In general, a negative post-treatment PET/CT is associated with a good prognosis. Nevertheless, in the setting of re-irradiation, an increasingly adopted salvage treatment modality, this association remains unclear. In this report, we explored the prognostic significance of PET/CT following re-irradiation.

	The records of patients who underwent re-irradiation for recurrent or new primary head and neck cancer as well as PET/CT scans before and at 1.5 to 4.0 months after treatment were reviewed. Re-irradiation was given with intensity-modulated radiation therapy at a median dose of 60 GY with a cumulative dose of 130 GY. Concurrent chemotherapy was given in all but three patients. Semi-quantitative analyses of PET/CT were re-performed. Metabolic response was assessed using PET response criteria in solid tumors (PERCIST) criteria.

	Included for analyses were 54 patients; 16 patients (30%) had a negative post-treatment PET/CT and 38 patients (70%) had a positive scan. At a median follow-up time of 55 months, 44 patients had died. Among those with negative PET/CT, the median overall survival was 38.7 months, compared with 9.4 months among those with positive PET/CT (

 <.001), corresponding to estimated 5-year survival rates of 42.2% and 3.6%, respectively. The positive predictive value of PET/CT for 5-year mortality was 96.4%, while the negative predictive value was 42.2%. By PERCIST criteria, a statistically significant survival advantage was observed only among patients with a complete metabolic response, but not partial metabolic response.

	Based on our limited experiences, PET/CT after re-irradiation can be useful for prognostic purposes. Although a negative post-treatment PET/CT may not reliably portend a good prognosis, a positive PET/CT practically rules out the possibility of long-term survival.

Re-irradiation is a well-recognized salvage therapy for head and neck cancer patients who develop recurrent disease or new primary cancer in a previously irradiated area. In the absence of distant metastatic disease, about 10 to 20% of such patients may become long-term survivors after re-irradiation, with or without salvage surgery.

 Data from a randomized phase III study has shown that, after a salvage surgery, treatment with adjuvant re-irradiation along with concurrent chemotherapy improves progression-free survival (PFS) when compared with observation alone.

For this clinical scenario, therefore, the National Comprehensive Cancer Center Guideline currently recommends that re-irradiation be considered as one of the limited treatment options including additional surgery, palliative chemotherapy, or best supportive care.

Nevertheless, there remains a paucity of published experiences on the prognostication of patients following this treatment. While some clinical factors such as interval since previous radiation, tumor bulk at re-irradiation, salvage surgery, nodal disease, comorbidity, and organ dysfunction may help estimate the likelihood of long-term survival,

 this prognostic schema does not take into account the value of tumor response after re-irradiation.

During the past decade, an imaging modality with [18F]-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) integrated with computerized tomography (PET/CT) has been increasingly used for tumor staging and radiotherapy planning, as well as tumor response assessment.

Specifically, in the tumor response assessment of head and neck cancer patients following chemoradiation, PET/CT is highly prognostic. A negative PET/CT indicating a complete metabolic response (CMR) has been associated with an absence of future disease recurrence with a negative predictive value—the probability that a person who is a test negative is a true negative&mdash; typically over 90%.

While the usefulness of post-treatment PET/CT has been well demonstrated among first-time irradiated patients, this has not been systematically investigated among re-irradiated patients. In the re-irradiation setting, some unique issues that may affect the accuracy of PET/CT will need to be considered. First, in the re-irradiation setting, there is generally a heightened prevalence of tissue necrosis, infection, or aspiration, which can cause tissue hypermetabolism, thereby causing a false-positive finding on PET/CT.

 Second, due to a partial-volume effect, PET/ CT may not reliably detect sub-centimeter lesions.

This is especially relevant because, in the re-irradiation setting, there may be an increased prevalence of small-volume metastatic disease, considering the aggressive biology of the recurrent cancer and the fact that pre-treatment scans have already screened out patients with obvious metastatic disease from being candidates for re-irradiation.

Given these considerations, we sought to investigate the prognostic significance of PET/CT scans in the salvage re-irradiation setting. Our primary objective was to evaluate long-term 5-year survival based on the response observed from post-treatment PET/CT scans. Our secondary objectives were to describe the degree to which metabolic responses by PET response criteria in solid tumors (PERCIST) criteria among a subgroup of patients with gross disease at the start of re-irradiation predicted survival, and to evaluate if the prognostic significance of PET/CT will remain significant and independent from other clinical factors that have been already recognized as survival predictors after salvage re-irradiation therapy.

After approvals from the Institutional Scientific Review Committee and Institutional Review Board, eligible patients with locally recurrent squamous cell carcinoma of the head and neck treated with definitive re-irradiation during January 2005 to 2012 with a curative intent were retrospectively identified. For patients who underwent salvage surgery, at least one of the following high-risk pathological features must have been present: positive surgical margins, multiple lymph node involvement, perineural invasion, or soft tissue invasion. Re-irradiation was defined as a significant (>50%) overlap of the previously irradiated field. Human papilloma virus (HPV) testing was performed among select patients with oropharygeal primary using p-16 immunohistochemistry or Fluorescence in-situ hybridization in which positivity was based on diffuse and intense reaction. Staging was per the American Joint Committee on Cancer 7th edition.

Comorbidity was assessed by Charlson’s index.

 Organ dysfunction was defined as feeding tube dependency, functioning tracheostomy, or soft tissue defect including history of osteonecrosis. Prophylactic feeding tube placement before re-irradiation was not considered as organ dysfunction. This study included the previously reported outcomes from nine patients.

Re-irradiation was confined to the local relapse region (no elective uninvolved lymph node included) and was given as 2-Gy fraction daily using linear accelerator with intensity modulated radiation (IMRT) technique. Target tumor volume was planned based on computed tomography (CT) scans. In addition, for patients with gross disease, PET/CT images were fused with planning CT images to delineate the area of 18F-FDG avidity. Gross tumor volume was first derived and a margin of 5 mm each was added for clinical target volume and planning target volume with appropriate reduction to avoid critical structure. Concurrent chemotherapy or immunotherapy was prescribed as followed: cisplatin was given as 75-100 mg/m

 weekly; carboplatin was given as AUC 5-6 every 3 weeks or AUC 1-2 weekly; and cetuximab was given as a 500 mg/m

 loading dose one week before re-irradiation, then 250 mg/ m

 weekly. All chemotherapy was discontinued at the completion of re-irradiation. Pre-treatment tumor size was measured on contrasted CT scans. Tumor burden reflected the sum of the maximal diameter of the primary tumor plus the diameter of cervical adenopathy. For patients with no gross disease before re-irradiation, their tumor burden was recorded as zero.

Patients underwent PET/CT within 4 months after completion of re-irradiation. In addition, among those with gross disease before re-irradiation, pre-treatment PET/CT was performed for staging purposes before re-irradiation. At our institution, patients were scanned on a Biograph PET system (Siemens Medical Solutions) or Discovery VCT PET/CT system (GE Medical Systems), maintained to manufacturer specification. All patients underwent overnight fasting, and serum glucose below 200 mg/dl was confirmed prior to imaging. PET/CT image acquisition occurred at approximately 90-120 minutes after 18F-FDG administration at 3 MBq/kg (81 μCi/kg) body by intravenous injection. PET emission data were obtained in 3D mode for two minutes at each bed position. CT studies for attenuation correction and anatomic co-registration were performed without contrast in a low dose protocol (30 mA, 120 kV) covering the area from base of the skull to the proximal thighs. Quantification at review was performed on images compliant with the Digital Imaging and Communication in Medicine standard, using ADW 4.2 (GE Medical Systems) processing software.

 Available digitized images of fused PET/CT scans were reviewed by one nuclear medicine physician who was unaware of patient clinical outcome. Semi-quantitative evaluation was based on maximum standardized uptake value (SUVmax) calculated as the ratio of measured activity concentration over an assumed homogeneous distribution of the applied radioactivity

 on the spherical region of interest at the most intense lesion.

The SUVmax was used as a measurement index, measured using volumetric region-of-interest technique with standard image analysis software. Metabolic response was assessed according to PERCIST version 1.0.20 CMR or negative PET/CT was defined as a complete resolution of 18F-FDG uptake within the target lesion rendering it indistinguishable from surrounding background blood-pool levels with no new 18F-FDG-avid lesions. Partial metabolic response was a reduction of a minimum of 30% in the target tumor standardized uptake value (SUV). Progressive metabolic disease is a 20% increase in SUV or emergence of new 18F-FDG-avid lesions consistent with neoplasm. For the purpose of graded PERCIST response category, only patients with available baseline PET/CT performed within 3 months before the beginning of re-irradiation were included and for those with multiple PET/CT during the period, only values obtained from the test performed closest to the re-irradiation initiation was used.

Descriptive statistics, including median and range for continuous variables and frequency and percentage for categorical variables, were obtained. Pearson’s Chi-square or Fisher’s exact test were used to compare categorical variables with Monte Carlo estimation as appropriate. To address a non-normal distribution, the non-parametric Mann-Whitney test was used to compare duration from previous re-irradiation and tumor burden between groups.

Overall survival (OS) was calculated from re-irradiation until death or last follow-up and PFS was from re-irradiation until death, progression, or last follow-up, whichever occurred first. Death was verified by the National Social Security Death Index. Survival estimates were obtained by the method of Kaplan-Meier. The point estimates of survival were used to compute the performance characteristics of PET/CT in predicting disease progression or death at 2 and 5 years. The log-rank test was used to compare the survival between groups. The Cox-proportional hazards regression model was fitted to examine the independent impact of CMR on survival outcomes, adjusted for other prognostic factors. All 

-values were 2-tailed and the significant level was set at 

 <0.05. All analyses were performed on SAS version 9.4 (Cary, NC) or SPSS version 22 (Chicago, IL).

Patient, Treatment, and Tumor Characteristics Data from 54 patients were analyzed. On the basis of post-treatment PET/CT, 16 patients (30%) achieved CMR and 38 patients (70%) failed to achieve CMR. The characteristics of patients with or without CMR were comparable 

. The majority of patients in both groups were males who had no active smoking history or significant comorbidity. Organ dysfunction was present at baseline in 15 patients (28%): Feeding tube dependency was observed in 11 patients, functioning tracheostomy in 4 patients (2 patients were also feeding tube-dependent), and osteonecrosis in 2 patients.

For treatment-related characteristics, salvage surgery occurred in 13 patients (24%) prior to re-irradiation. A higher proportion of patients who underwent salvage surgery achieved CMR than those with gross tumors at re-irradiation: 43% versus 16%, 

 = 0.03. There was a higher proportion of cetuximab usage observed in the group of patients without CMR: 10 patients versus zero patient, 

 = .07. In both groups, the median time interval between the initial and present radiotherapy was 3 years and the dosage or duration of re-irradiation was comparable.

With regard to tumor-related characteristics, the overall median tumor burden before re-irradiation was 2.4 cm. Consistent with a higher proportion of patients who underwent salvage surgery being in the CMR group, lower tumor burden was also observed in the CMR group: 1.5 cm versus 2.9 cm, 

 = .01. In both groups, the most common disease sites were the oropharynx and oral cavity. HPV or p-16 staining was performed in 11 patients; 8 patients (73%) tested positive.

There were 13 patients (24%) whose physical examination was suspicious for residual disease. Post-treatment PET/CT of 54 patients was performed at a median of 2.9 months (range 1.5 to -4.0 months) after re-irradiation completion. The median acquisition time of PET/CT was 1.8 hours. The observed median SUVmax was 5.9.

CMR was observed in 16 patients (30%) and failure to achieve CMR occurred in 38 patients (70%). Among the 38 patients who failed to achieve CMR, 30 patients (80%) had persistent hypermetabolism in the treatment field and 8 patients (20%) developed a new site of disease outside the treatment field, including 3 patients with distant metastases. To date, death had occurred in 44 patients, corresponding to a median OS of 14 months (95% CI: 11.4-16.5). The median follow-up time was 55.4 months (range 7.5-96.1). Progressive disease or death had occurred among 46 patients, corresponding to a median PFS of 7.2 months (95% CI: 4.5-9.9). The estimated 5-year OS and PFS rates were 15.7% and 13.2%, respectively.

Prognostic Significance of PET/CT in the Context of Other Variables

When considering survival by post-treatment PET/CT results, patients who achieved CMR had a significantly better median OS than those who did not: 38.7 months versus 9.4 months, 

. This corresponded to estimated 2-year OS rates of 75% versus 16.4% and 5-year OS rates of 42.2% versus 3.6%, respectively. In addition, patients who achieved CMR had a significantly better PFS than their counterparts: 29.2 months versus 5.6 months, 

. This corresponded to estimated 2-year PFS rates of 62.5% versus 5.8% and 5-year PFS rates of 40.5% versus 5.8%, respectively. Based on these estimates, the performance of PET/CT in predicting survival outcomes at 2- and 5-year time points were calculated 

. Positive PET/CT predicted progression or death with higher positive predictive values than negative predictive values. The positive predictive value—the probability that a person who is a test positive is a true positive&mdash; ranged from 83.6% to 96.4%, while the negative predictive value&mdash; the probability that a person who is a test negative is a true negative&mdash;ranged from 40.5% to 75%.

We evaluated the predictive value of PET/CT on survival in the context of other prognostic factors 

. In a univariable analysis, positive PET/CT was associated with an increased risk of death with % ratio (HR) 4.9 (95% CI: 2.3, 10.5) and an increased risk of progression or death with HR 4.9 (2.3, 10.3).

In a multivariable analysis incorporating other known prognostic factors of re-irradiation, positive PET/CT remained predictive of overall mortality with HR 7.2 (95% CI: 2.7-19.6) and of progression or death with HR 6.8 (95% CI: 2.6-17.5, 

 <0.001). In this multivariable model, the second best predictor of survival was the lack of salvage surgery, with HR 3.97 (0.77, 20.41), though this association did not reach statistical significance (

We performed a subgroup analysis among patients who did not undergo salvage surgery. Of these, there were 33 patients with available baseline PET/CT, thus allowing for a graded metabolic response assessment based on the PERCIST percentage change in the tumor metabolism.

Among these patients, their pre-treatment PET/CT scans were performed at a median of 2.1 weeks (range 1 to 11.8) prior to re-irradiation. The median acquisition time of these scans was 1.9 hours (range 1.3 to 3.7). The median pre-treatment SUVmax was 9.7 (range 2.4 to 27.4). After re-irradiation, the median SUVmax was 6.1 (range 0 to 15.7). This change in tumor metabolism was equal to a median reduction of 46% (range -86% to +100%) 

. There were 7 patients with higher-than-baseline tumor metabolism and 6 of them met the criteria for progressive disease. According to PERCIST, 8 patients (24%) achieved CMR, 14 patients had a partial metabolic response (42%), 5 patients (15%) had a stable metabolic disease, and 6 patients (18%) developed progressive metabolic disease.

To explore the association between tumor response and OS, we compared the survival outcomes among the 4 patient groups classified by PERCIST category. While patients with CMR emerged as the group with the best survival outcome, there was little difference in the survival among those with partial metabolic response, stable metabolic disease, or progressive metabolic disease 

This pattern of association was also observed with the PFS outcome 

. Overall, when comparing patients with and without CMR, those with CMR had significantly better survival outcomes. The median OS was 28.2 months (95% CI: 15.2 to 41.3) among those with CMR, compared with 13.2 months (95% CI: 7.9 to 18.5) among those without CMR, respectively (

 = 0.034), and the median PFS was 15.4 months (95% CI: 5.1 to 11.3), compared with 6.1 months (95% CI: 4.9 to 7.2), respectively (

In this study we reported on the utility of PET/CT in the salvage re-irradiation for head and neck cancer. We found that CMR, a negative post-treatment PET/CT, occurred in only 30% of patients. CMR was not strongly predictive of long-term survival; however, failure to achieve CMR was strongly predictive of disease progression or death. This observation remained robust even after accounting for other known prognostic factors including salvage surgery. Overall, failure to achieve CMR projected about a 7-fold increase in the risk of death or progression. Therefore, the potential clinical utility of PET/CT in the re-irradiation setting appears to lie in its high positive predictive value.

In contrast to the observation derived from the chemoradiation among radiation-naïve patients, a negative post-treatment PET/CT in the re-irradiation setting does not necessarily portend a good prognosis. This likely reflects the natural history of patients who develop recurrent or new primary head and neck cancer in that they are more likely to have future recurrence or may develop complications that can lead to an increased mortality even if disease is initially controlled. This observation suggests that patients with a negative post-treatment PET/CT will still need to be considered for an intensive follow-up. Furthermore, for patients with positive post-treatment PET/CT, our limited experiences indicate that they will likely develop disease progression or death. For such patients, additional treatment should be considered if deemed appropriate.

While there appears to be a distinction in how PET/ CT can be applied in clinical practice between the radiation- naïve setting and the re-irradiation setting, the sensitivity and specificity—which are intrinsic qualities of the test&mdash;of PET/CT still remain quite comparable. In previously reported series, the sensitivity and specificity of PET/ CT to predict survival in the radiation-naïve setting are, respectively, in the range of 70 to 80% and 80 to 90%.

 In our study, both the sensitivity and specificity estimates are also in the 70 to 80% range, depending on the referenced survival time point. The key difference between the two settings, however, is the prevalence of outcome; that is recurrence or death, which is higher in the re-irradiation setting than in the initial radiation setting. For instance, the estimated 5-year OS rate in our study was only 16%, compared to 60 to 70% in the first-time radiation setting.

 Such high prevalence of outcome, therefore, translates into the high positive predictive value of positive post-treatment PET/ CT observed in the current study.

Although, to our knowledge, this is the only report of PET/CT utility in the salvage re-irradiation setting with semi-quantitative re-analysis, a number of limitations should be considered. First, due to a small sample size, there may not be adequate statistical power to detect any survival difference by PERCIST response category, specifically to detect the survival advantage associated with partial metabolic response. Second, there was a variation in the timing of the PET/CT performance ranging from two to four months after re-irradiation. Although the optimal timing of post-treatment PET/CT remains to be defined, false positivity and false negativity rates may be affected by the timing of PET/CT. Finally, in our practice, patients with an obvious clinical progression of disease may not necessarily undergo post-treatment PET/CT, and therefore patient selection to undergo the scan can affect the positive or negative predictive values of PET/CT. Although the vast majority of the PET/CT scans were done for surveillance purposes, some scans were performed in an attempt to differentiate between residual disease and radiation-induced tissue necrosis. Due to the retrospective nature of this study, we were unable to confirm the intent of PET/CT scan in all cases.

In summary, our experiences herein illustrate the prognostic significance of 18F-FDG PET/CT scan in the salvage re-irradiation setting. Failure to achieve CMR is highly predictive of disease progression or death. In addition, this prognostic significance of PET/CT is superior to other known pre-treatment prognostic indicators. A study with a larger sample size will be needed to understand the prognostic significance by PERCIST criteria.

Department of Head and Neck Oncology (TT, TP, JM, JK, JC, AT), Department of Thoracic Oncology (TT), Department of Radiation Oncology (JC, AT), Department of Diagnostic Imaging (EE), University of South Florida, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Tawee Tanvetyanon, MD, MPH, 12902 University of South Florida Magnolia Dr., Tampa, FL 33612. Phone: 813-745-7640, Fax: 813-745-3027. E-mail: tanvett@moffitt.org

Researchers explored the prognostic significance of PET/CT following re-irradiation in patients with head and neck cancer.

February 2016 | Contemporary Radiation Oncology

The Effect of Prostate MRI on Cancer Staging and Radiotherapy Treatment Recommendations

Primary Radiation Therapy for Myeloid Sarcoma of the Porta Hepatis

Prognostic Significance of Post-Treatment PET/CT Following Salvage Re-irradiation of Head and Neck Cancers

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