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Originally published as JCO Early Release 10.1200/JCO.2005.04.6326 on May 22 2006 © 2006 American Society of Clinical Oncology. Powerful Prognostic Stratification By [18F]Fluorodeoxyglucose Positron Emission Tomography in Patients With Metastatic Breast Cancer Treated With High-Dose Chemotherapy
From the Centre for Molecular Imaging; Division of Haematology and Medical Oncology, the Peter MacCallum Cancer Centre, Melbourne; the University of Melbourne, Parkville, Victoria, Australia; and the Nuclear Medicine Department, Cancer Center Jean Perrin, Clermont Ferrand, France Address reprint requests to Rodney Hicks, MD, Centre for Molecular Imaging, The Peter MacCallum Cancer Centre, 12 Cathedral Place, East Melbourne, VIC 3002, Australia; e-mail: rod.hicks{at}petermac.org
PURPOSE: This study examines the use of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of the therapeutic response for patients treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation for metastatic breast cancer (MBC) focusing on prognostic stratification. PATIENTS AND METHODS: Forty-seven patients with MBC were treated with a maximum of three cycles of HDC. Therapeutic response was assessed with conventional imaging (CImg; including a computed tomography in all cases and ultrasound, mammography, and bone scanning as clinically indicated) and by FDG-PET study performed after the last cycle of HDC. Parameters analyzed for predicting survival were FDG-PET and CImg results, pattern of disease, prior treatment, and HDC regimen. RESULTS: Complete responses were observed in 16 patients (37%) with CImg and 34 patients (72%) with FDG-PET. The FDG-PET result was the most powerful and independent predictor of survival; patients with a negative post-treatment FDG-PET had a longer median survival than patients with a positive FDG-PET (24 months v 10 months; P < .001). By multivariate analysis the relative risk (RR) of death was higher in patients with FDG-PET-positive disease (RR, 5.3), prior anthracycline treatment (RR, 3.3), or with visceral metastasis (RR, 2.4). CONCLUSION: A single FDG-PET study performed after completion of HDC for MBC can powerfully stratify for survival. This may have implications for how we should assess outcome after conventional-dose therapy for MBC and warrants additional study.
Metastatic breast cancer (MBC) is incurable in most cases and remains a major therapeutic challenge. Beginning in the mid-1980s, trials were initiated evaluating the role of high-dose chemotherapy (HDC) with autologous bone marrow or stem cell transplantation (SCT). Results of phase II trials indicated that HDC for MBC resulted in high response rates and improvement in disease-free survival.1 However, large randomized trials of patients with MBC have failed to demonstrate any significant survival benefit.2 Although some studies have demonstrated that HDC may be beneficial for selected patients with breast cancer,3-5 any additional studies examining this approach must be performed in the context of well-designed clinical trials.6-8 Nonetheless, one consistent feature of HDC studies has been the comparatively high complete response rates observed compared with conventional-dose therapy. Thus, it is an opportunity to examine new strategies to assess response to therapy. We have previously reported our studies of repetitive cycles of HDC in patients with advanced breast cancer and sought to examine the impact of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in assessing response and predicting outcome.9-12 Indeed, the lack of demonstration of a survival benefit despite apparently high therapeutic response rates after HDC with autologous SCT for MBC emphasizes the limitations of conventional imaging (CImg) techniques for assessing response. Metabolic response evaluation using PET with the glucose analog FDG has been proposed as a technique for assessing treatment response and one of the first therapeutic monitoring trials utilizing FDG-PET involved chemo-hormone therapy for locally-advanced breast cancer.13 That study demonstrated that for those patients who subsequently achieved a clinical and radiologic response, there was an early and significant reduction in FDG uptake in lesions, whereas no change was noted in nonresponders. Subsequent studies have also suggested the potential utility of FDG-PET for therapeutic response assessment after chemotherapy.14,15 Unlike our study, these studies correlated progressive reduction in FDG uptake with favorable clinical and radiologic response and did not examine the impact on long-term outcome. We have previously demonstrated that patients with non–small-cell lung cancer, who underwent radical radiotherapy and were FDG-PET negative after therapy, had a significantly improved survival.16 In this study, we have sought to determine if a similar evaluation strategy could predict survival in patients with MBC.
Patients The records of all patients who received HDC and autologous SCT for MBC and had a post-autologous SCT PET scan performed are included in this report. Forty-seven eligible patients were identified. All patients were participating in prospective trials of repetitive HDC with autologous SCT for MBC or locally advanced disease and FDG-PET scans were scheduled as part of post-treatment routine investigation.9-12 All trials were performed with approval from the institutional ethics committee and after obtaining written informed patient consent. Patients received a maximum of three consecutive cycles of HDC using one of three regimens (cyclophosphamide, thiotepa, and docetaxel, ifosamide, thiotepa and paclitaxel, or cyclophosphamide, thiotepa, and paclitaxel, delivered every 35 days). Each HDC cycle was supported by autologous SCT and filgrastim (5 µg/kg per day, subcutaneously from day 1 until the absolute neutrophil count was > 1.5 x 109/L for 3 consecutive days). The last dose of filgrastim was at least 14 days before PET to minimize reactive bone marrow changes obscuring residual bone disease. CImg included a helical, contrast-enhanced chest and abdominal computed tomography (CT) performed before and 1 month after the final cycle of HDC and autologous SCT in all patients. Ultrasound (US) was also performed in patients without liver metastases on contrast-CT and was used for follow-up only if positive. Similar, mammography was selectively performed in patients with clinical recurrence or a residual breast mass, and repeated only if positive at baseline. Bone scan and marrow biopsy were routinely performed before HDC, but were repeated only in those patients who were positive. All radiology reporting was performed as part of routine clinical management by experienced oncologic radiologists in a dedicated, comprehensive cancer center. Additional CImg was performed between cycles at the investigators' discretion. The FDG-PET study was performed 1 month after the last cycle of HDC contemporaneously with CImg.
PET Scan Acquisition and Processing Patients received 70 MBq to 120 MBq to achieve an estimated singles count rate less than 3 million counts per second in order to avoid exceeding the NaI detector count capacity. Although this is a lower dose than used for conventional PET scanners, this is the appropriate dose for this type of scanner. Emission scanning involved six overlapping bed positions, 5 minutes in duration, and was followed by eight contiguous 3-minute transmission scans using a cesium-137 source obtained from the lower neck to the upper femurs with the arms raised (if tolerated). Total imaging time was approximately 60 minutes. Emission data were processed by means of iterative reconstruction (ordered subset expectation maximization method)18 with attenuation correction.19 Images data sets were reported from the screen, both with and without attenuation correction.
FDG-PET Scan Interpretation
Assessment of Therapeutic Response by CImg Therapeutic response evaluation was assessed according the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines20 by comparison of a baseline and post-treatment CT, supplemented when CT was negative by liver US (CT/US). All CT scans were reviewed by radiologists with subspecialty expertise in oncological imaging and performed on helical CT scanners, primarily of 4-slice design. Radiologists reviewed all US studies. CT results were reported independent of the PET results but as part of routine clinical practice by one experienced oncological radiologist. Therapeutic response was defined as complete response (CR), the disappearance of all target lesions; partial response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD), at least a 20% increase in the sum of the longest diameter of target lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Supplementary evaluation of therapeutic response in bony metastases was performed by comparison of a baseline bone scan with a bone scan performed after HDC. PD was defined by visual progression in extent and in intensity of the bony uptake abnormities or by new bony lesions. PR was defined by visual partial resolution of the documented bony uptake abnormalities in the baseline study. A CR was defined by normalization of the scan appearances. SD was defined by an unchanged scan appearance. Overall therapeutic tumor response was scored as described in Table 1.
Kaplan-Meier survival estimates were calculated from the first day of the first course of HDC to death.21 Patients were categorized into a visceral metastatic disease group, and in a nonvisceral metastatic disease group, defined by those with only bony and/or nodal metastasis. Parameters analyzed for prediction of survival were FDG-PET results, CImg results (CT/US/bone scan), pattern of disease (visceral metastatic disease v nonvisceral metastatic disease), prior treatment, and type of HDC regimen. These parameters were compared by log-rank test. A multivariate analysis was also performed by Cox model and Wald test to assess the same factors for survival prediction.22
Patients The median age of the 47 patients was 44 years (range, 26 years to 60 years). Sixteen patients had an initial presentation with bony and/or nodal disease. The remaining 31 patients had visceral metastasis including pulmonary, hepatic, adrenal, marrow, and pericardial deposits. Before study entry, 35 patients (75%), 17 patients (34%), and 40 patients (83%) had received an anthracycline, paclitaxel, or cyclophosphamide, respectively (Table 2). For the HDC regimen, 12 patients received three cycles of ifosamide, thiotepa, and paclitaxel, 24 patients were treated with three cycles of cyclophosphamide, thiotepa, and paclitaxel, and nine patients received three cycles of cyclophosphamide, thiotepa, and docetaxel. Two patients tolerated only two cycles of cyclophosphamide, thiotepa, and docetaxel.
Response Of 43 patients evaluated by CT/US, 16 patients (37%) and 15 patients (35%) achieved CR or PR, respectively. The CT/US remained stable for 5 patients (12%) while 7 patients (16%) had PD (Table 3). Twenty-seven patients with bone involvement were evaluated by bone scan. Two patients achieved CR (7%), 16 patients achieved PR, and nine patients had SD or PD (Table 3).
As assessed by FDG-PET, 34 patients (72%) were deemed to have a CMR after the final cycle of HDC. With respect to evaluation of bone disease by FDG-PET, 23 of 27 patients (85%) had a CMR after treatment including three patients with a deterioration, as assessed by bone scan. As it was not practical for all patients to have pre-autologous SCT FDG-PET scans, assessment of FDG-PET response based on a percentage decrease in FDG-uptake was not part of the formal evaluation of treatment efficacy. Nonetheless, in an attempt to examine the issue of metabolic response, qualitative changes in pre- versus post-autologous SCT FDG-PET imaging were assessed in 41 patients who had a positive FDG-PET scan before HDC as well as a post-treatment scan performed. Applying standard criteria for metabolic response by PET23 to these patients, 28 patients (68%) achieved CR, seven patients had a partial metabolic response, and six patients demonstrated either SD or PD. Of the six patients who did not have a FDG-PET scan performed before HDC but had a negative FDG-PET after HDC, two patients subsequently demonstrated a FDG-PET positive relapse (indicating that their metastatic disease was FDG avid) and in the remaining four patients, the FDG avidity of the disease remains unknown (no follow-up FDG-PET performed at relapse) but non-FDG avid disease in this population seems unlikely.
Survival
Due to relatively small numbers of complete responders by CImg, the relationship between survival and therapeutic response obtained by CImg were compared both for CR versus incomplete response patients (nonCR), and by combining all objective responders and nonresponders into dichotomous groups defined as CR + PR versus SD + PD. Overall therapeutic response by CImg and bony tumor response assessed by bone scan did not result in a statistically significant improvement in survival; patients responding to the HDC (CR + PR) had a numerically longer survival than nonresponding patients but failed to reach statistical significance (21 months v 10 months; P = .065). Although the survival rate was significantly different at 12 months (77% v 42%; P < .05), there was no difference at 24 months. With respect to response of visceral organs evaluated by CT/US, the presence of visceral metastasis reduced overall survival (median survival 16 v 28 months; P = .065), with a statistically different survival rate at 12 months (61% v 87.5%; P < .05). Patient survival was inferior if patients had received an anthracycline-based chemotherapy some time before the HDC (Table 4). Moreover, patients with a negative FDG-PET (CMR) following HDC had a significantly longer survival than patients with a positive FDG-PET (nonCMR) scan (median survival time 24 months v 10 months respectively; P < .001; Table 4; Fig 2). In a multivariate analysis, the FDG-PET result was the most powerful and an independent predictive factor of survival (Table 5). A positive PET scan 1 month after HDC increases the relative risk of death by five-fold. The median survival of the 23 patients with bone disease who had a CMR was 22 months with a 2-year predicted survival of 48%.
Of the 41 patients who had a pre- and post-treatment FDG-PET performed, in whom response was assessable, there was trend toward a better survival in those who demonstrated at least a partial metabolic response compared with those with SD or PD (12 month survival of 57% v 16%; P = .09).
This study provides the first results of the FDG-PET utility in patients with MBC undergoing HDC with autologous SCT. We demonstrated that a single FDG-PET scan performed 1 month after HDC is strongly predictive of survival. FDG-PET was able to stratify the patient population into two subgroups, FDG-PET negative or CMR group (72%), corresponding to a median survival of 24 months, and a FDG-PET positive disease or nonCMR group (28%), who had a poorer median survival of only 10 months (P < .001). Eighty-three percent of CMR patients were alive at 12 months compared with 38% of nonCMR patients. Conversely, CImg, which demonstrated a CR rate of 37%, was unable to predict survival duration in a clinically meaningful way. Although PET was read in concert with the CT images, this was only for correlative purposes and where there was discordance, the PET result was used exclusively. With respect to bone disease, others have demonstrated the value of FDG-PET imaging in such patients.24 In this study we found that although only two of 27 patients achieved a CR with bone scan, some 23 patients (85%) achieved FDG-PET negativity, including three who had a deterioration as assessed by bone scan, presumably representing a flare response in these cases. Similar to the entire group with CMR, these patients had a prolonged median survival of 22 months. Thus, although by conventional criteria these negative PET results would be considered false-negative based on the fact that all patients eventually relapsed, the lack of metabolic signal nevertheless provides useful prognostic information. This is presumably because low FDG-uptake at sites of known disease is an indicator of either a significant biologic effect of drug therapy on cellular metabolism or a reduction of viable cell burden, and possibly both. In addition to the prognostic importance of FDG-PET negativity, we, like others,25 found that visceral disease and prior treatment with an anthracycline was associated with a poorer outcome. Our study did not evaluate the role of FDG-PET scanning in patients at the time of relapse and before embarking on the HDC and autologous SCT regimen. This was largely a logistical issue as patients were often referred to our facility from other oncology centers having already commenced, or having recently progressed on conventional-dose treatment. However, previous studies evaluating the role of FDG-PET in monitoring response to conventional-dose chemotherapy for either locally-advanced breast cancer26 or in patients with MBC27-29 demonstrated that an early reduction in FDG uptake, generally expressed as a percentage reduction in a semi-quantitative measure termed the standardized uptake value, was predictive of subsequent morphological or clinical response. Thus, additional studies evaluating the role of FDG-PET imaging before HDC or other novel treatment strategies seem warranted, particularly in identifying patients most likely to benefit from such therapies. In the context of controversial role of HDC and autologous SCT, our data provide evidence that FDG-PET can identify a subgroup of patients for whom HDC appears to have achieved a relative prolongation of survival. Similar results have been demonstrated in the context of patients with non-Hodgkin's lymphoma undergoing HDC and autologous SCT.30 The finding of FDG-PET-negativity presumably reflects lower tumor volume and hence may open the way for additional refinement of treatment paradigms in this patient group. Indeed, novel approaches such as the use of molecular targeted therapy, antiangiogenic therapy, and cancer vaccination strategies are currently being explored in states of minimal residual disease31-33 and thus CMR patients would seem an appropriate population to target such strategies. Finally, the prognostic importance of post-treatment FDG-PET CMR has clearly been demonstrated for aggressive non-Hodgkin's lymphoma.34 That study, like ours, showed that FDG-PET scanning demonstrates a response rate double that of CImg, and that FDG-PET is superior for predicting survival. By examining a group of MBC patients who had undergone HDC and autologous SCT, we were able to evaluate a group of patients who had higher response rates (by both CImg and FDG-PET) than those typically seen with conventional dose therapy. Thus statistically, because of its increased power, we were able to demonstrate a difference with a relatively small number of patients. Larger prospective studies are now needed to evaluate the role of FDG-PET (and preferably FDG-PET/CT) in patients with MBC undergoing conventional-dose therapy.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Reece DE, Foon KA, Chatterjee MB, et al: Use of the anti-idiotype breast cancer vaccine 11D10 in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer. Clin Breast Cancer 4:S152-157, 2003 (suppl 3) 32. Hempel P, Muller P, Oruzio D, et al: Combination of high-dose chemotherapy and monoclonal antibody in breast-cancer patients: A pilot trial to monitor treatment effects on disseminated tumor cells. Cytotherapy 2:287-295, 2000[CrossRef][Medline] 33. Morabito A, Sarmiento R, Bonginelli P, et al: Antiangiogenic strategies, compounds, and early clinical results in breast cancer. Crit Rev Oncol Hematol 49:91-107, 2004[Medline] 34. Juweid ME, Wiseman GA, Vose JM, et al: Response assessment of aggressive non-Hodgkin's lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol 23:4652-4661, 2005 Submitted October 17, 2005; accepted April 11, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
