J Radiat Oncol (2013) 2:315-321DOI 10.1007/s13566-013-0111-x Concurrent whole brain radiotherapy and short-coursechloroquine in patients with brain metastases: a pilot trial Harriet B. Eldredge & Albert DeNittis &James B. DuHadaway & Michael Chernick &Richard Metz & George C. Prendergast Received: 15 July 2013 / Accepted: 6 August 2013 / Published online: 16 August 2013 overall survival. Patients were stratified by IDO2 allelic Objective The immune modulatory drug chloroquine (CQ) has been demonstrated to enhance survival following radio- Results After a median clinical follow-up of 5 months (range, therapy in patients with high-grade glioma in a clinical trial, 0.5-31), 16 patients were evaluable for radiologic response but the efficacy in patients with brain metastases is unknown.
which was complete response in two patients, partial response We hypothesized that short-course CQ during whole brain in 13 patients, and stable disease in one patient. There were no radiotherapy (WBRT) would improve response to local ther- treatment-related grade≥3 toxicities or treatment interruption apy in patients with brain metastases.
due to toxicity. Median and mean overall survival was 5.7 and Methods A prospective, single-cohort study was performed 8.9 months, respectively (range, 0.8-31). A trend toward combining WBRT with concurrent CQ to assess both the increased overall survival was observed in patients with feasibility of and intracranial response to combined therapy wild-type IDO2 compared to patients with heterozygous or in patients with brain metastases. Safety, tolerability, and homozygous configurations that ablate IDO2 enzyme activity overall survival of this combination were also examined, along with allelic status of IDO2 (indoleamine 2,3- Conclusions WBRT with concurrent, short-course CQ is dioxygenase 2), an immune modulatory enzyme inhibited by well-tolerated in patients with brain metastases. The high chloroquine that may affect survival outcomes. CQ therapy intracranial disease control rate warrants additional study.
(250 mg by mouth daily) was initiated 1 week before WBRT(37.5 in 2.5 Gy daily fractions) in patients with newly diag- Keywords Brain metastases. Chloroquine.
nosed brain metastases from biopsy-proven, primary lung, Immunotherapy. Immunomodulation. Indoleamine breast, or ovarian solid tumors (n =20). The primary endpoint 2,3-dioxygenase (Ido). Non-small cell lung cancer (Nsclc).
was radiologic response 3 months after combined CQ and WBRT therapy. Secondary endpoints included toxicity and H. B. Eldredge : A. DeNittisDepartment of Radiation Oncology, Lankenau Medical Center, Brain metastases are a major cause of morbidity and mortality in patients with cancer, affecting up to 200,000 patients a year in the US alone [The majority of brain metastases originate A. DeNittis J. B. DuHadaway M. ChernickG. C. Prendergast (*) from common cancer-like lung (40-50 %), breast (15-25 %), Lankenau Institute for Medical Research, 100 Lancaster Avenue, and melanoma (10 %). These lesions may occur synchronous- ly with other sites of systemic metastasis(es), but they occur frequently as the only site of disease in patients with excellent performance status and systemic disease control [While New Link Genetics Corporation, Ames, IA 50010, USA patients with a single or limited number of brain metastasesmay benefit from neurosurgical resection or stereotactic ra- diosurgery (SRS), many patients present with multiple, diffuse Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,PA 19107, USA intracranial metastases that are not amenable to such therapies due to tumor location, number of lesions, or comorbid these genetic variations may therefore vary an individual's conditions] Thus, a viable option for the treatment of ability to respond to drugs that target IDO2 since not all many brain metastases patients, even those with poor perfor- individuals express a fully active enzyme. CQ has been found mance status, is whole brain radiotherapy (WBRT) which to be a potent and selective inhibitor of IDO2 (R.M., represents a standard of care ]. Given the prevalence of this unpublished observations), prompting the notion that CQ condition and its dismal prognosis, the treatment of brain might enhanced the efficacy of WBRT in a manner associated metastases should continue to evolve.
Regardless of treatment, the survival times of patients with Based on the improved clinical outcomes reported with brain metastases remain extremely poor with a median sur- concurrent use of CQ and partial brain radiotherapy in some vival of 3.4 months. The 6-month, 1-, and 2-year survival rates patients with high-grade glioma [, we hypothesized for these patents are 36, 12, and 4 %, respectively The that CQ might potentiate the therapeutic effect of WBRT for Radiation Therapy Oncology Group (RTOG) recursive brain metastases. In this study, patients are stratified by IDO2 partitioning analysis (RPA) and the later updated Graded genotype in the event that IDO2-inactivating SNPs blunt Prognostic Assessment (GPA) have identified prognostic fac- tors of patients with brain metastases to stratify the heteroge-nous population into prognostic classes. Using these criteria,patients with the most favorable prognostic factors still only have a predicted median survival of 11 months Ulti-mately, 30-50 % of patients with brain metastases will die of Patient selection After Institutional Review Board approval their central nervous system disease [, , reinforcing the of the protocol, all patients provided informed consent. Adult urgent need for improved therapies to treat this condition.
patients with a histologically confirmed primary solid malig- One way to potentially enhance standard WBRT would be nancy and evidence of single or multiple brain metastases on to use radiation sensitizers. Chloroquine (CQ) is a potential contrast-enhanced computed tomography (CT) or magnetic radiation sensitizer that has been employed for decades as an resonance imaging (MRI) scans were eligible for this prospec- antimalarial agent. Its clinical use has a well-established safety tive study. Metastatic lesions were required to be less than profile. CQ and its derivatives have gained interest in recent 5 cm in diameter, and radiographic findings could not be years due to their ability to modulate inflammation, immune consistent with leptomeningeal metastases. Patients were only response, and sensitivity to cancer therapy. Most CQ-related eligible to receive CQ after clearance from their physician that studies have focused on its ability to block autophagy, a the drug should not pose a medical problem to the patient.
cellular process that sustains cancer cell survival under thera- Patients were excluded from the study if they had received peutic stress. CQ has also been found to activate the p53 prior radiotherapy to the brain, were pregnant or nursing, or pathway and induce apoptosis in glioma cells [Of partic- had a history of hypotension, cardiomyopathy, epilepsy or ular interest, a prospective, randomized, clinical trial evaluat- seizure disorder, impaired renal function, psoriasis, porphyria, ing low-dose CQ in the treatment of high-grade gliomas or known hypersensitivity to 4-aminoquinoline compounds.
reported enhanced treatment response and improved overall Patients were also excluded if, during the CQ treatment, they survival (OS) with the addition of CQ to external beam complained of any visual or auditory disturbances or suffered radiotherapy and chemotherapy[, To date, CQ therapy from severe acute gastrointestinal problems like vomiting, has not been evaluated in patients receiving radiotherapy for IDO2 is a tryptophan catabolic enzyme implicated in sup- Radiotherapy WBRT was delivered with 6 to 10 MV photons pressing T cell immunity in the tumor microenvironment to a total dose of 37.5 Gy in 2.5 Gy once daily fractions over a where its pharmacologic inhibition may potentiate cancer course of 3 weeks. Each patient was treated in the supine chemotherapy [-]. IDO2 is a relative of the better- position while wearing a head immobilization mask to ensure known enzyme IDO that is widely implicated in cancer pro- that daily positioning was reproducible. Target volumes in- gression through an ability to block T cell-mediated immune cluded the entire cranial contents, with flashing beyond skin surveillance by supporting the expansion of T regulatory cells and a minimum margin of 0.75 cm on the skull-base as and myeloid-derived suppressor cells []. While less visualized on the simulator or portal films to account for beam widely expressed than IDO, it is evident that IDO2 is penumbra and day-to-day set-up variation. The ocular lens expressed in brain ]. Remarkably, there is a wide variation was shielded from the direct beam at all times using collima- in IDO2 function in human populations based on the broad tors. SRS boost after WBRT has been validated by random- distribution of two single-nucleotide polymorphisms (SNPs) ized trials to improve local control in patients with 1-4 brain in the coding region of the human IDO2 gene that reduce or metastases and to improve survival in patients with a single abolish its enzyme activity []. The broad distribution of brain metastasis Patients were permitted to receive SRS boost if posttreatment imaging revealed residual disease of target lesions, taking as reference the baseline sum diame- or if this therapy was recommended at the discretion of the ters. Complete response (CR) was defined as complete reso- lution or disappearance of target lesions. Stable disease (SD)occurred when the size of persistent lesions remained Chloroquine therapy Chloroquine branded as Aralen (Sanofi- unchanged, while progressive disease (PD) occurred when Aventis U.S., Bridgewater, NJ) was used in this study. CQ there was unequivocal progression of existing lesions or ap- therapy began 1 week prior to initiation of WBRT and was administered daily (250 mg/day) for a total of 5 weeks.
Secondary endpoints included toxicity scored according to the National Cancer Institute Common Toxic Criteria for IDO2 genotyping One week prior to WBRT, 5 mL of blood was Adverse Events (CTCAE), cause of death, overall survival, collected from each patient and stored for subsequent IDO2 interval to intracranial progression, and to correlate survival genotyping. Standard methods were used to isolate genomic times with IDO2 genotypes. Overall survival and interval to DNA from blood cells, perform PCR, and define the DNA intracranial progression were determined using the Kaplan- sequence of the IDO2 SNPs as described The coding Meier method. Intention-to-treat analysis was performed to region SNP in exon 8 is rs10109853 (C/T encoding R248W change) which attenuates the IDO2 enzyme activity ∼90 %in vitro ]. The coding region SNP in exon 10 is rs4503083(T/A encoding Y359Stop change) which truncates the IDO2enzyme, completely abolishing its catalytic activity Patient monitoring Baseline clinical assessments were Patient evaluation Twenty patients were enrolled in the study performed for each patient prior to the start of WBRT and between January 2009 and November 2011. The 20 evaluable CQ combination therapy. Assessments included medical his- patients consisted of 11 women and 9 men with a median age tory, complete physical exam including neurologic examina- of 64 years (range, 47-81). The patient and tumor character- tion and mental status exam, complete blood count, and istics are summarized in Table The median duration of contrast-enhanced imaging of the brain. Most patients re- WBRT treatment was 20 days (range, 19-23). The median ceived contrast-enhanced MRI imaging of the brain, the pre- clinical follow-up of all patients was 5 (range, 0.5-31)months ferred imaging method; however, contrast-enhanced CT scans were permitted for evaluation of metastatic disease in patients Nineteen patients completed WBRT. One patient withdrew who could not tolerate MRI or in whom MRI was contraindi- after receiving 27.5 Gy of the 37.5 Gy prescribed due to cated. Patients were assessed for toxicity and clinical response intrathoracic disease progression of non-small cell lung cancer by the radiation oncologist (A.D.) at weeks 1-3 of WBRT and (NSCLC) and clinical deterioration. This patient did not ex- at the 1- and 3-month follow-up and then every 3 months perience a treatment-related adverse event. The remaining 19 thereafter until death. Brain imaging was also performed at 1- patients did complete radiotherapy, and no patient suffered and 3-month follow-up and then every 3 months thereafter treatment interruption due to adverse effect or toxicity. Two until death. Overall survival was calculated from the time of patients received a stereotactic radiosurgery boost to a single randomization into the study until death or April 1, 2013, intracranial lesion following WBRT. No patient had neurosur- whichever occurred first. Patients who were still alive were gical resection of a metastasis prior to enrollment, and no patient received cytotoxic chemotherapy during the courseof WBRT. Four patients did not receive any posttreatment Endpoints and statistical analysis The primary endpoint was brain imaging due to clinical demise or death and were not intracranial radiologic response to treatment as determined by included in radiologic response analysis.
brain metastases profile on contrast-enhance CT and MRI scans.
Intracranial tumor response to treatment was not assessed Radiographic response and patient survival Contrast-en- using the Response Evaluation Criteria in Solid Tumors hanced brain MRI was performed after concurrent CQ and (RECIST), which requires measurable target lesions to have WBRT in 16 patients. The objective intracranial response rate a minimum diameter of 10 mm ]. RECIST criteria was 3 months after WBRT included CR in 2 patients, PR in 13 inappropriate for the patient population recruited for this stud- patients, and stable disease in 1 patient. This response rate y, as many patients with BM have multiple, clinically signif- corresponded to an objective clinical response of 93 % at icant lesions that measure less than 10 mm in diameter. There- 3 months. Intracranial disease control rate was 100, 83, and fore, target lesions acceptable for inclusion in this study had a 55 % at 3, 6, and 12 months, respectively. Among the two diameter of ≥4 mm. Partial response (PR) to therapy was patients with CR, one patient had a single lesion while the defined as 20 % or greater decrease in the sum of the diameters other had three lesions and neither patient received an SRS Table 1 Patient and cancer characteristics two patients, bowel perforation in two patients, pulmonaryembolism in one patient, cardiac event in one patient, and due to a second primary malignancy (pancreatic) in one patient.
Three patients died in hospice of unspecified causes, and eight Treatment toxicity No patient suffered from observed CQ toxicity or radiotherapy treatment interruptions. There were no documented grade 3 or greater toxicities observed during the course of WBRT treatment nor was there any evidence of increased radiation skin reaction or CNS injury due to con- current administration of CQ as noted in two case studies in the literature []. Grade 1 radiation dermatitis was ob- served in four patients (20 %), and grade 2 alopecia was observed in eight patients (40 %). There were no detectable neurocognitive defects or radiation necrosis. One serious ad- verse event interpreted as unrelated to study treatment oc- Recursive partitioning analysis (RPA) class curred in a patient who developed respiratory failure due to lung cancer progression and pulmonary infection.
IDO2 host genotype and correlation with clinical outcomes Host IDO2 genotype for the SNPs in coding exons 8 and 10 were determined from blood-derived genomic DNA prepared from patients Briefly, homozygosity or hetero- zygosity of enzymatically ablative SNPs at each site were detected in 14/20 patients recruited to the study, where the IDO2 genotype implied reduced IDO2 activity in this cohort.
Conversely, 6/20 patients displayed wild-type alleles at each SNP site, where the IDO2 genotype implied full IDO2 activ- ity in this cohort. This relative proportion of allelic distribu- tions approximately paralleled that seen in a larger disease- free population that had been characterized previously ].
Median and mean OS for all patients was 5.7 and 8.9 months (range, 0.8-31 months), respectively, from the time of enroll- ment. A trend toward improved OS was observed for patients with wild-type IDO2 (n =6) compared to patients with enzy- matically ablative SNPs in either exon 8 or 10 (n =16) (10.4 vs.
4.1 months; p =0.07). Due to the high rates of radiologic response, there was no appreciable difference in response be-tween patients with wild-type IDO2 compared with enzymat-ically ablative SNPs. Table summarizes the patient and tumor boost. Among the 12 patients with a PR to combined therapy, characteristics associated with SNP patterns. Due to small there were 39 brain lesions total with the following responses: patient numbers in this pilot trial, some prognostic factors were 11 lesions CR, 27 lesions PR, and 1 stable lesion. One patient dissimilar among the two genotype groups.
with initial PR was able to achieve a CR following SRS boost.
Intracranial progression was confirmed on follow-up imagingin two patients at a median of 7 months following completionof WBRT.
Kaplan-Meier estimates reveal a median overall survival of 5.7 (range, 0.8-31)months. At the time of analysis, two patients This is the first prospective trial to report a combination of were alive, one of whom had a survival time exceeding WBRT and concurrent CQ for the treatment of brain metasta- 30 months. For each patient who died, an attempt was made ses. The results demonstrated that this combination was well- to determine the cause of death, which was respiratory failure in tolerated with no observed treatment interruptions due to Table 2 Patient stratification of prognostic factors to IDO2 genotype endpoints of overall survival and cause of death propose aCQ treatment benefit since neurologic death secondary to brain metastases was not observed. Additionally, the present series demonstrated a median overall survival of 5.7 months which compares slightly favorably to the RTOG recursive partitioning analysis (RPA), which estimates a median surviv- al of 4.2 months for patients in class II ]. This data also compares favorably with the predicted median survival of 3.8 and 2.6 months for patients with scores of 1.5-2.5 or 0-1, respectively, on the Graded Prognostic Index (GPI)-scores Recursive partitioning analysis (RPA) class that are representative of most patients in the current series [ Larger, randomized studies would be required to confirm the ventured survival benefit from the addition of CQ to standardWBRT, but this data is encouraging. Additionally, it is impor- tant to note that a primary goal of WBRT remains the im- provement of local tumor control to provide palliation of neurologic problems and prevent progression of symptoms.
Thus, improvement in survival may not be the only measure of benefit of a local therapy like WBRT, as overall survival is determined by extracranial disease and comorbid conditions in addition to the presence of brain metastases Future trials with CQ and WBRT should consider endpoints to mea- +/+, wild-type configuration at exon 8 and exon 10 SNPs in the IDO2 sure quality of life, symptom relief, or neurologic progression.
gene derived from the patient host; +/p or p/p, heterozygosity or homo- A variety of dose and radiation fractionation schedules zygosity in either the exon 8 or the exon 10 SNPs in the IDO2 gene have been tested in prospective, randomized trials in patients derived from the patient host, both of which ablate the enzymatic activityof the IDO2 enzyme 10-fold or greater [] with multiple brain metastases, but none have improved effi-cacy or survival, to date -]. Since survival outcomeshave not been improved by dose escalation (including doses in treatment-related toxicity. Two case studies have reported an excess of 50 Gy), there has been interest in radiation sensi- intensification of skin reactions with bullous eruptions and tizers to potentiate the efficacy of WBRT. However, a variety moist desquamation after concurrent treatment with CQ and of agents have been tested with little, if any, effect on survival.
external beam radiotherapy but we did not observe Some trials have even reported serious adverse effects these toxicities in our trial. In contrast, the toxicity experi- This situation may be changing with more recent enced in this study was in agreement with that reported promising reports of motexafin gadolinium and efaproxiral as previously by Sotelo and colleagues from their prospective radiosensitizers that can improve quality of life and survival in trial of combined CQ and external beam radiotherapy for breast cancer patients with brain metastases ]. Our glioblastoma multiforme, where they reported no signs or findings suggest CQ as another agent that might find use in symptoms of retinopathy related to CQ toxicity nor any radi- leveraging the efficacy of WBRT to some patients with lung ation treatment breaks due to toxicity. These investigators cancer or other cancers where brain metastases frequently reported an increase in the incidence of seizure during treat- ment or the clinical follow-up period in glioblastoma patients CQ is an antimalarial agent that has been used safely in a who received the combined therapy ]; however, we did variety of clinical settings for decades. CQ exerts complex not document any similar occurrence in any of the brain pleiotropic effects that may enhance radiotherapy, for exam- ple, by inhibiting DNA repair or blocking autophagic re- Up to half of patients with brain metastases who receive sponses that promote cancer cell survival under stress condi- WBRT will die due to intracranial disease. In our study, tions However, it is also clear that CQ exerts immu- intracranial control rates were excellent-100 % at 3 months nomodulatory effects that have been used for years to treat with 93 % radiologic response. In addition, only two patients certain autoimmune diseases, such as arthritis and systemic developed intracranial progression at a median of 7 months lupus erythematosus, and, more recently, to treat an increasing which is clinically meaningful in a patient population with number of other diseases including cancer In evaluating the ability of CQ to improve outcomes in brain metastases In addition to the excellent local control provided by com- patients receiving WBRT, our work employed a relatively low bined CQ and WBRT therapy, the data for the secondary dose of CQ not expected to affect DNA repair or autophagy, based on existing information [], but consistent with im- mune modifier effects known to yield beneficial effects inautoimmune disease patients.
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