American Journal of Therapeutics 0, 000–000 (2014)
Frontline Systemic Therapy With Pemetrexed–Platinum in Nonsquamous Non–Small-Cell Lung Cancer With Asymptomatic Brain Metastases Samer Alsidawi, MD,1 Rekha Chaudhary, MD,2 and Nagla A. Karim, MD, PhD2*
The incidence of brain metastases from nonsquamous non–small-lung cancer is increasing as a result of superior imaging techniques for early detection of distant metastases. Although whole-brain radiation therapy and stereotactic radiosurgery along with systemic chemotherapy have shown to be effective in alleviating symptoms and improving outcomes, the approach to patients with asymptomatic brain metastases remains elusive. We explored the literature for a possible role of frontline systemic chemotherapy in asymptomatic brain metastases from nonsquamous non–small-lung cancer and found promising evidence that upfront systemic therapy with pemetrexed–platinum regimens might be a reasonable option for these patients and would forestall the need for upfront brain radiation therapy. More large-scale phase II and phase III clinical trials are needed to further investigate the frontline use of pemetrexed–platinum regimens in this setting. Keywords: frontline chemotherapy, brain metastases, nonsquamous non–small-cell lung cancer, pemetrexed, platinums
BACKGROUND Metastatic brain lesions are the most frequently occurring intracranial tumors in adults with over 170,000 newly diagnosed patients annually in the United States. This is estimated to be 10 times the incidence of primary brain neoplasms.1,2 The incidence of brain metastases continues to increase as a result of superior imaging techniques and methods for earlier detection of cancers, making it more possible to discover these tumors in the early stage of formation and before
1
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH; and 2Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH. R. Chaudhary is on the advisory board for NovoTTF. The other authors have no conflicts of interest to declare. *Address for correspondence: Vontz Center for Molecular Studies, 3125 Eden Avenue, ML 0562 Cincinnati, OH 45267-0562. Phone: 513-558-2115 Fax: 513-558-2125. E-mail: [email protected] 1075–2765 2014 Lippincott Williams & Wilkins
symptoms arise.3 Studies have shown that the majority of brain metastases originate from the lungs (40%– 50%) followed by breast (15%–25%) and melanoma (5%–20%).4,5 Approximately 40% of all patients with lung cancer develop brain metastases during the course of their disease.6 At the time of diagnosis, brain metastases can be found in approximately 10% of all patients with lung cancer; and in several retrospective series, brain metastases are detected in approximately 50% of patients.7,8 The median survival for patient with brain metastases is approximately 2 months if left untreated, but can be extended to 12–14 months with a multidisciplinary approach that includes neurosurgery, radiosurgery, and chemotherapy.9 However, the negative impact of metastatic brain tumors on patients extends beyond that of poor survival to include the devastating effects on cognition, language, mobility, and emotional well-being of patients and their families. Although the current treatment of patients with brain metastases includes whole-brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery www.americantherapeutics.com
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(SRS), there is actually limited evidence to support these approaches compared with systemic chemotherapy in the treatment of patients with asymptomatic brain metastases. The literature addressing the responsiveness of metastatic brain lesions to systemic chemotherapy is both limited and inconclusive. Studies done on the cellular and tissue levels and in animal models suggest that the brain microenvironment induces genetic changes in the tumor cells increasing their growth potential and rendering them more resistant to chemotherapy agents.10 However, in retrospective studies looking at patients who have not been previously treated with chemotherapy, the response rate of the brain lesions was often comparable with that seen in extracranial disease.11 Most of the studies looking at the effect of systemic chemotherapy on brain metastases had significant hard-to-avoid limitations. Some of these studies included a large variety of tumor histologies with different molecular characteristics. Most of the studies examined the effect of chemotherapy in non-naive patients with extensive chemo-resistant extracranial disease or with previous WBRT or SRS to the brain. These limitations make it difficult to draw conclusions on the preferred course of action in chemo-naive newly diagnosed patients with non– small-cell lung cancer (NSCLC) who are incidentally found to have small, single, or multiple asymptomatic brain lesions—a scenario commonly encountered in clinical practice. In the past, the use of systemic chemotherapy in treating brain metastases remained an unpopular approach due to the presence of the blood–brain barrier (BBB). The BBB is a selective barrier between the systemic circulation and cerebrospinal fluid that is formed by specialized endothelial cells lining the cerebral microvasculature, pericytes, and astrocytic perivascular endfeet.12 An intact BBB limits the passage of large molecules and hydrophilic drugs into normal brain. Large hydrophilic molecules, including many chemotherapeutic and molecular-targeted drugs, cannot penetrate to the central nervous system (CNS) unless actively transported by receptor-mediated transcytosis.13 Other studies also suggest that the BBB can express high levels of the P-glycoprotein/ multidrug resistance proteins, which actively transports out some chemotherapeutic agents from the brain.14 The presence of brain metastases disrupts the normal BBB, and it is wildly accepted now that when a brain lesion grows beyond 1–2 mm, the BBB becomes structurally and functionally compromised.15–17 This is also evidenced by clinical observations of leakage of the contrast material when diagnosing macroscopic brain metastases by conventional imaging modalities.18 American Journal of Therapeutics (2014) 0(0)
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HYPOTHESIS Frontline systemic chemotherapy with a pemetrexed– platinum regimen would be a reasonable option for patients with small asymptomatic brain metastases with nonsquamous NSCLC and would spare patients the need for brain radiation therapy.
METHODOLOGY We conducted a MEDLINE search to identify articles in the English language that address the role of pemetrexed in brain metastases from NSCLC. Search terms included pemetrexed, lung cancer, NSCLC, brain, CNS, metastases, WBRT, SRS, survival, blood, barrier, and response. Search terms were selected on the basis of common key words identified during the initial literature search. The authors reviewed all relevant case reports, original, and review articles published up till January 2014. Reference lists of identified articles were also checked to ensure that all relevant articles had been included in the reviewing process. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.
THE UPFRONT USE OF SYSTEMIC THERAPY IN BRAIN METASTASES FROM NSCLC Most major phase III studies have excluded patients with brain metastases from their patient population due to the assumption that the brain is a sanctuary place that chemotherapy cannot get to, and the availability of other treatment modalities such as SRS and WBRT. Although these therapies are known to be effective in relieving neurological symptoms and preventing rapid neurological decline in symptomatic patients, no good quality data exist to suggest that these modalities are superior to chemotherapy in small asymptomatic, single, or multiple brain metastases discovered at the time of initial diagnosis of NSCLC. Given the neurocognitive toxicity associated with brain irradiation and the growing in-depth understanding of the BBB, a few studies tried to investigate the real benefit of early versus delayed CNS radiation treatment with concurrent chemotherapy in newly diagnosed patient with NSCLC and synchronous brain metastases. A phase III trial randomized patients with NSCLC and inoperable brain metastases to chemotherapy with cisplatin and vinorelbine combination with either early or delayed WBRT.19 There was no statistically significant difference in the overall response rate, www.americantherapeutics.com
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Frontline Systemic Chemotherapy in Brain Metastases
cerebral response rate, 6-month survival, or overall survival between the 2 groups. Another study randomized patients with NSCLC and brain metastases to either receive chemotherapy first or WBRT first, and concluded that the response rate of chemotherapy and survival outcomes in the primary chemotherapy arm were not statistically different from those in the WBRT-first arm.20 Interestingly, grade 3 or 4 neutropenia occurred more frequently in the WBRT-first group during chemotherapy and prevented some patients from receiving more chemotherapy because of early death or poor performance status after WBRT. These studies have shown that the upfront use of chemotherapy was a feasible and appropriate option in this setting where neurological symptoms were absent or controlled, and that the timing of radiation therapy (early vs. delayed) did not influence survival of patients with NSCLC and brain metastases treated with chemotherapy. A retrospective study done by Outcome Research Network for Evaluation of Treatment Results in Oncology published their data in 2006 to try address the upfront use of chemotherapy in NSCLC with asymptomatic brain metastases.21 Chemotherapy alone seemed to produce a 27% response rate in the brain, which was not statistically different from the 35% rate obtained in the chemotherapy plus WBRT cohort. The authors concluded that asymptomatic patients who receive frontline chemotherapy may be spared from WBRT and the upfront use of chemotherapy represents an appropriate treatment for asymptomatic patients. The study again confirmed the lack of specific prospective clinical trials to determine the best treatment approach for these patients. Targeted therapy with bevacizumab, a vascular endothelial growth factor inhibitor, or gefitinib/erlotinib, the epithelial growth factor receptor tyrosine kinase inhibitors seems to have a promising role in the treatment of brain metastases from NSCLC. Relatively small studies have used these agents with or without concurrent radiation and demonstrated beneficial effect.22–25 The use of targeted therapy as frontline treatment in selected patients either alone or in combination regimens should be further investigated in larger studies.
RISKS OF CRANIAL IRRADIATION Brain irradiation, either in the form of WBRT or SRS, has been introduced as an effective treatment modality for both primary and secondary brain tumors. Although often perceived as safe, both of these radiation techniques carry a significant number of side effects and a concerning toxicity profile. In most cases of symptomatic patients with metastatic brain lesions, the benefits of www.americantherapeutics.com
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brain irradiation outweigh these risks, and radiation treatment is started promptly to control the symptoms and lessen the, otherwise, very rapid neurologic decline. However, these benefits come into question in patients with small asymptomatic brain metastases from NSCLC where there are no robust data to support the use of brain irradiation along with systemic chemotherapy versus using systemic therapy alone. WBRT has been associated with acute and late reactions that are difficult to overlook. Cerebral edema26 debilitating fatigue,27 alopecia,28 somnolence, and lethargy29 are among the early toxicities with WBRT. It is usually the late effects of WBRT that are more problematic. Radiation necrosis is one late side effect of notable interest because it can be extremely difficult to differentiate from tumor progression and can expose the patient to additional unnecessary and expensive imaging or procedures.30 Other late toxicities of WBRT include nonspecific white matter injury, headaches, and neurocognitive impairment.31,32 Neurocognitive impairment happens at various degrees in almost 90% of patient after brain radiation31 and is not often considered a deleterious side effect when put into the context of patients with significant neurologic symptoms and extremely poor survival. In subsets of asymptomatic patients with good performance status in whom relatively longer survival can be expected, however, the neurocognitive impairment becomes a subject of utmost importance given the limited date on the real value of WBRT in this situation, and the detrimental impact that it can have on the quality of life of these patients. The toxicities of SRS are different from those of WBRT because SRS is limited to a small target field and involves a much higher dose of radiation in a single fraction. Acute reactions of SRS (within 90 days) are uncommon and include neurological deficits, seizures,33–35 and headaches. SRS to brain lesions in the brain stem or thalamus carries higher risk of complications and less favorable outcome.36 Again, radiation necrosis remains a diagnostic dilemma with SRS because it is with WBRT and deciding whether the radiologic changes represent necrosis of the lesion with surrounding edema or progression of the disease can be a frustrating clinical dilemma.37 Radiation necrosis itself can also cause disabling neurological symptoms that affect quality of life.
PEMETREXED IN NONSQUAMOUS NSCLC Pemetrexed is a multitargeted antifolate antimetabolite that has a mechanism of action similar to methotrexate, which is a widely used antineoplastic agent for American Journal of Therapeutics (2014) 0(0)
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hematologic malignancies and solid tumors. Pemetrexed disrupts enzymes involved in both purine and pyrimidine synthesis, including thymidylate synthase, dihydrofolate reductase, and glydinamide ribonucleotide formyl transferase38 (Figure 1). Two large phase III trials demonstrated the efficacy of pemetrexed in nonsquamous NSCLC as a first-line treatment in combination with cisplatin, as maintenance therapy alone, or as second-line treatment.39,40 Pemetrexed is currently FDA approved for this purpose and is widely used as a first-line treatment in combination with platinums. Results from other large trials also supported the use of pemetrexed as a maintenance single agent after induction therapy with pemetrexed–cisplatin, as it significantly prolonged progression-free and overall survival after the initial chemotherapy in patient without disease progression.41,42
PEMETREXED AND THE CNS When pemetrexed emerged as a new multitargeted antifolate agent, some studies tried to look at the penetration of pemetrexed into the CNS to assess its potential role in overcoming methotrexate resistance in CNS lymphoma and other malignancies. The assumption was that inhibition of multiple enzymes by pemetrexed could preclude the development of drug resistance caused by overexpression or mutation of a single enzyme. The initial study43 was done in nonhuman primates, where 4 subjects were injected
FIGURE 1. Mechanism of action of pemetrexed. Pemetrexed inhibits enzymes involved in both purine and pyrimidine synthesis, including thymidylate synthase, dihydrofolate reductase, and glydinamide ribonucleotide formyl transferase leading to disruption of DNA and RNA syntheses and antitumor effect. American Journal of Therapeutics (2014) 0(0)
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with pemetrexed intravenously with doses almost similar to the approved dose (400 mg/m2) and serial plasma and cerebrospinal fluid (CSF) samples were assessed to measure the concentrations. The study concluded that pemetrexed had poor penetration to the CNS (less than 2%). The major limitation to the study was that the subjects had an intact BBB, which makes the generalization of these results to patients with brain metastases profoundly limited. In another prospective study,44 the efficacy and CNS penetration of pemetrexed were assessed in patients with brain metastases or leptomeningeal disease. Again, this study showed limited penetration of pemetrexed to the CNS (1%–3%) and failed to demonstrate a significant beneficial role on disease progression. However, this study also had major flaws including the small number of patients (only 3 patients had serial cerebrospinal fluid samples) and wide variety of tumor histologies. Most patients received multiple previous chemotherapy or radiation treatments that have unknown effects on the BBB penetrance and tumor responsiveness. Despite the limitations in the above-mentioned studies, their results raise several questions both at the basic molecular level and in the clinical setting. It is possible that different tumors with different molecular characteristics and oncogenic potential affect the BBB in different ways. Tumors that are known to be rich in metalloproteinases or rich in vascularity due to high expression of the vascular endothelial growth factor45 can alter the BBB more than other tumors with less robust expression, which might make them more responsive to chemotherapy given systemically. The drug concentration in the CSF does not seem to be a surrogate for the efficacy of the drug on the metastatic brain tumor. Other factors related to the biology of the tumor, the integrity of the BBB both histologically and at the molecular level, previous systemic treatments and/or radiation and the specific characteristics of the drug should all be taken into account. For example, there are data to suggest that brain metastases from NSCLC express low levels of p-glycoprotein in their vasculature when compared with gliomas, which might render them susceptible to certain chemotherapy agents used to treat the primary extracranial tumor.46 Furthermore, the coadministration of corticosteroids along with chemotherapy, which is very common in patients with brain metastases, might alter drug penetration into the CNS.47 More studies are needed to assess the pharmacodynamics of pemetrexed in brain metastases from NSCLC and the possibility for manipulating drug penetration on the molecular level, as there are interesting studies that showed a saturable efflux process mediated by www.americantherapeutics.com
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Frontline Systemic Chemotherapy in Brain Metastases
multiple transporters working in tandem to be responsible for the low brain distribution of antifolate drugs.48
ACTIVITY OF PEMETREXED AGAINST BRAIN METASTASES FROM NSCLC Most studies of advanced NSCLC in the previous decade have excluded patients with brain metastases due to concerns of limited activity of systemic chemotherapy on the intracranial disease. However, as mentioned above, the efficacy of a drug on the metastatic tumor is not just a reflection of the drug concentration in the CSF. In the recent years, the literature started emerging to suggest that brain metastases can respond to chemotherapy in a manner that follows systemic response.49 Interestingly, this response was noted to be unrelated to concurrent WBRT.50 When pemetrexed established its role as an effective therapy in advanced nonsquamous NSCLC, the question was raised of whether pemetrexed had any effect on CNS metastases in these patients (Table 1). One of the first articles to address this question was a reported case of a 53-year-old patient with stage IV adenocarcinoma of the lung and multiple brain metastases.51 The CNS disease was progressing despite neurosurgical resection of one of the lesions, WBRT, and multiple chemotherapy treatments. The patient was given pemetrexed 500 mg/m2 for 6 cycles, and repeat magnetic resonance imaging showed regression of the brain metastases and even complete resolution of several lesions. Subsequently, many studies tried to investigate the role of pemetrexed on CNS metastases from NSCLC. One study looked retrospectively at 39 patients with brain metastases from NSCLC who had been treated with pemetrexed as second-line or further-line therapy.52 The study showed overall clinical benefit in 69% of the patients, with stable CNS disease in 30.8% patients and a partial CNS response in 38.4%. Overall median survival was 10 months. Although the study included a heterogeneous sample of patients in regards to previous or current radiation exposure, irradiation-naive patients demonstrated an overall clinical benefit and cerebral benefit in 63% and 68% patients, respectively. In another study looking at newly diagnosed patients with NSCLC and brain metastases, Dinglin et al57 looked at the safety and efficacy of pemetrexed and cisplatin combination with concurrent WBRT. The study showed very promising results with progression free survival of the CNS lesions of 10.6 months and www.americantherapeutics.com
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a median overall survival of 12.6 months. The objective cerebral response rate (complete and partial response) in the intent-to-treat population was 68.3%. These results further prove that in patients with NSCLC and brain metastases, treatment with pemetrexed–platinum combination actually improves survival since, historically, patients with brain metastasis who received WBRT alone had a median survival ranging from 2.4 to 4.8 months.58 More data advocating the efficacy of pemetrexed on brain metastases from NSCLC came from a retrospective study by Ortuzar et al.55 This study looked back at the 2 landmark trials39,40 that established the role of pemetrexed as a cornerstone in the treatment of nonsquamous NSCLC to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence of CNS metastases later in the course of the disease. Patients with known brain metastases at the original study entry were excluded from the data analysis, and investigators recorded the site of progressive disease at the time of disease recurrence. Brain metastases recurrence rates were 3.2% (95% confidence interval [CI], 2.1%– 4.6%) in the pemetrexed-containing arms versus 6.6% (95% CI, 5.0%–8.6%) in the non–pemetrexed-containing arms (P 5 0.002). The odds ratio for CNS recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32–0.76; P 5 0.001). Although this study lacked baseline or periodic brain scans and only looked retrospectively at patients with symptomatic brain lesions, it proved that exposure to pemetrexed as first-line or further-line treatment may reduce the risk of brain metastases as the first site of disease progression. Whether pemetrexed was effective on asymptomatic micrometastases or it acted on the primary tumor to decrease the tendency to seed in the brain remains unclear.
PEMETREXED AS AN UPFRONT TREATMENT IN NONSQUAMOUS NSCLC AND BRAIN METASTASES The first prospective trial to investigate the upfront use of pemetrexed–platinum therapy on NSCLC with asymptomatic brain metastases was done by Barlesi et al.53 The goal of the study was to assess the efficacy of cisplatin plus pemetrexed combination as first-line treatment in the setting of multiple asymptomatic brain metastases from NSCLC. The study included patients with an Eastern Cooperative Oncology Group performance status of 0–2 who were chemo-naive with cytologically or histologically proven NSCLC presenting with asymptomatic brain metastases. Patients with American Journal of Therapeutics (2014) 0(0)
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American Journal of Therapeutics (2014) 0(0)
Study
Type
Omlin et al51 Case report
Sample size n51
Bearz et al52
Retrospective n 5 39
Barlesi et al53
Phase II
n 5 43
Ochi et al54
Case series
n52
Ortuzar et al55
Bailon et al56
Dinglin et al57
Chemotherapy regimen Single-agent pemetrexed
n 5 42
Previous radiation
No
Yes
Single-agent No pemetrexed Pemetrexed + cisplatin No, WBRT after chemotherapy
Pemetrexed + cisplatin or single-agent pemetrexed Retrospective n 5 2296 Pemetrexed vs. docetaxel, pemetrexed + cisplatin vs. gemcitabine + cisplatin Observational n 5 30 Pemetrexed + carboplatin
Single arm phase II
Concurrent radiation
Pemetrexed + cisplatin
RR, response rate; ORR, overall response rate.
Primary end point Radiologic response
Heterogeneous Overall RR and cerebral RR No Overall RR, disease control rate, and cerebral RR
No
Yes
Radiologic response
No
No
Odds ratio for brain metastases with exposure to pemetrexed
No
No
Cerebral RR and event-free survival
Yes
No
Overall RR, disease control rate, and cerebral RR
Results Evidence of disease regression or resolution Overall RR, 68% and cerebral RR, 82% Cerebral RR, 41.9%; global ORR, 34.9%; and disease control rate, 72.1% Successful suppression of brain metastases 0.49 (CI, 0.32–0.76; P 5 0.001)
Cerebral RR, 40% and event-free survival, 31 wk; median overall survival, 39 wk Cerebral RR, 68.3%; extracerebral RR, 34.1%; global ORR and disease control rate, 36.6% and 85.4%, respectively Alsidawi et al
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Table 1. A summary of the published studies that looked at the effect of pemetrexed on brain metastases from NSCLC.
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previous WBRT were not included in the study. The patients received 4–6 cycles of chemotherapy, and received WBRT only at disease progression, unacceptable toxicity from chemotherapy, or after finishing the chemotherapy. This phase II trial showed high activity of this chemoregimen on CNS disease with a cerebral response rate of 41.9% and cerebral disease control rate of 83.7% with a good safety profile. These data suggest that a pemetrexed–cisplatin regimen might substitute frontline radiation therapy in asymptomatic brain metastases from NSCLC, and that a study comparing platinum–pemetrexed regimen with concurrent WBRT versus delaying WBRT until progression only with continuous neurocognitive assessment would be of great value. Unfortunately, the trial did not address the specific question of whether these patients can be spared the need for brain irradiation until there was evidence of disease progression in the form of either neurologic symptoms or radiologic findings. An observational study by Bailon et al56 tried to address this uncertainty in patients with adenocarcinoma of the lung and brain metastases. Thirty patients with histologically confirmed nonsquamous NSCLC and newly diagnosed brain metastases not amenable to surgery or radiation treatment were included. Patients did not have previous chemotherapy or radiation therapy and were treated with pemetrexed plus carboplatin combination therapy. At the end of the study, the overall cerebral response rate was 40% in the intent-to-treat population. Two patients who had lesions less than 1 cm had a complete response. Despite the small number of patients, the results seen (cerebral response rates) were comparable with other studies that used almost the same regimen either as an upfront regimen or at recurrence after radiation therapy. The results, again, advocates the possible role of upfront pemetrexed–platinum regimens in the management of asymptomatic brain metastases from NSCLC and delaying surgery or radiation treatment until the time of cerebral progression.
PLATINUMS IN ADVANCED NSCLC Platinums are one of the earliest drugs used in the management of NSCLC with positive trials dating back to the 1970s. Almost all of the chemotherapy agents used today as first-line treatment for advanced NSCLC have been studied as a combination with cisplatin versus cisplatin alone or with a different agent. Carboplatin was introduced in the late 1980s and gained popularity in clinical practice due to a better toxicity profile.59 In their most recently published guidelines, the American Society of Clinical Oncology www.americantherapeutics.com
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recommends that a platinum-based regimen be used for stage IV NSCLC.60
PLATINUMS AGAINST BRAIN METASTASES FROM NSCLC There are very limited data on the effect of platinum agents on brain metastases from NSCLC. Most of the clinical studies used platinums in combination regimens when studying the effect of systemic chemotherapy on metastatic brain lesions. Although it is difficult to draw conclusions from these studies on the actual effect of these agents on CNS disease, their use in different combination regimens have shown to be effective in obtaining disease control.53,56,57,61–63 The use of platinums as single agents against brain metastases from NSCLC does not seem to affect the course of the disease even when combined with radiation64; however, including these agents in combination regimens might increase the response rate of the CNS lesions. As for now, there is limited clinical evidence to support this hypothesis, and more prospective studies are needed to address this question. Since platinums have been proven to be effective on the primary tumor and are recommended to be included in first-line regimens, their use in upfront treatment of asymptomatic brain metastases from NSCLC seems a reasonable and inevitable option given their well-proven effect on the extracranial disease.
CONCLUSIONS Brain metastases are a common complication of lung cancer that carries a very poor prognosis. The new advances in imaging modalities have allowed the detection of brain metastases very early in the course of the disease or as a synchronous finding with the initial diagnosis and before neurological symptoms arise. Despite the lack of enough evidence in comparison with chemotherapy alone, most of these patients are referred to SRS or WBRT before systemic therapy. These treatment modalities, which have proven effective in improving outcomes, alleviating neurological symptoms and preventing the rapid functional decline in symptomatic patients, carry obvious risks and toxicities and have not been well validated in the setting of asymptomatic brain metastases from NSCLC, not only in terms of cerebral response rates but also regarding their effect on progression-free and overall survival.65 Pemetrexed has established its role as an effective therapy in nonsquamous NSCLC and became one of the standard first-line treatments when American Journal of Therapeutics (2014) 0(0)
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combined with platinums. We have explored the literature for the possible upfront effect of pemetrexed on brain metastases from NSCLC and found promising evidence advocating a potential role for pemetrexedplatinum regimens on CNS disease. Although most of the currently available studies are small size and often included a heterogeneous patient population, there is appealing evidence to support the use of pemetrexed– platinum regimens in patients with asymptomatic brain metastases from nonsquamous NSCLC as an upfront modality while delaying radiation treatment until disease progression or symptoms occurrence. With close neurological monitoring and periodic imaging, these patients might be spared the risks and toxicities of brain irradiation without affecting their CNS disease response rate or overall survival. More largescale well-designed phase II and phase III clinical trials are needed to further investigate the role of frontline pemetrexed–platinum regimens on asymptomatic brain metastases from nonsquamous NSCLC in terms of CNS response rate, CNS progression-free survival, overall survival, and quality of life in an attempt to forestall the need for upfront brain radiation.
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Frontline Systemic Chemotherapy in Brain Metastases 26. DeAngelis LM, Posner JB. Neurologic Complications of Cancer. 2nd ed. Oxford University Press, Inc. 2008:163. 27. Powell C, Guerrero D, Sardell S, et al. Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: a prospective study. Radiother Oncol. 2011;100:131. 28. Lawenda BD, Gagne HM, Gierga DP, et al. Permanent alopecia after cranial irradiation: dose-response relationship. Int J Radiat Oncol Biol Phys. 2004;60:879. 29. Ryan J. Radiation somnolence syndrome. J Pediatr Oncol Nurs. 2000;17:50. 30. Wara WM, Bauman GS, Sneed PK, et al. Brain, brain stem and cerebellum. In: Perez E, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1997:799. 31. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 2004;22:157. 32. Li J, Bentzen SM, Renschler M, et al. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25:1260. 33. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000; 47:291. 34. Chin LS, Lazio BE, Biggins T, et al. Acute complications following gamma knife radiosurgery are rare. Surg Neurol. 2000;53:498. 35. Gelblum DY, Lee H, Bilsky M, et al. Radiographic findings and morbidity in patients treated with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 1998;42:391. 36. Sherman JD, Kager CD, Ward J, et al. Stereotactic radiosurgery for brainstem and thalamic metastases. J Radiosurgery. 2000;3:133–138. 37. Petrovich Z, Yu C, Giannotta SL, et al. Survival and pattern of failure in brain metastasis treated with stereotactic gamma knife radiosurgery. J Neurosurg. 2002;97:499. 38. Adjei AA. Pemetrexed: a multitargeted antifolate agent with promising activity in solid tumors. Ann Oncol. 2000; 11:1335–1341. 39. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–1597. 40. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551. 41. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care afterinduction therapy with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer (PARAMOUNT): www.americantherapeutics.com
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Alsidawi et al III pemetrexed trials in advanced non-small-cell lung cancer. Clin Lung Cancer. 2012;13:24–30. Bailon O, Chouahnia K, Augier A, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol. 2012;14:491–495. Dinglin XX, Huang Y, Liu H, et al. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J Neurooncol. 2013;112:461–466. Khuntia D, Brown P, Li J, et al. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol. 2006;24:1295–1304. Wheate NJ, Walker S, Craig GE, et al. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans. 2010;39:8113–8127. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27:6251.
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61. Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85:1599. 62. Fujita A, Fukuoka S, Takabatake H, et al. Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology. 2000;59:291. 63. Cortes J, Rodriguez J, Aramendia JM, et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology. 2003;64:28. 64. Guerrieri M, Wong K, Ryan G, et al. A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung Cancer. 2004;46:107. 65. Kim KH, Lee J, Lee JI, et al. Can upfront systemic chemotherapy replace stereotactic radiosurgery or whole brain radiotherapy in the treatment of non-small cell lung cancer patients with asymptomatic brain metastases? Lung Cancer. 2010;68:258–263.
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Frontline Systemic Therapy With Pemetrexed–Platinum in Nonsquamous Non–Small-Cell Lung Cancer With Asymptomatic Brain Metastases Samer Alsidawi, MD,1 Rekha Chaudhary, MD,2 and Nagla A. Karim, MD, PhD2*
The incidence of brain metastases from nonsquamous non–small-lung cancer is increasing as a result of superior imaging techniques for early detection of distant metastases. Although whole-brain radiation therapy and stereotactic radiosurgery along with systemic chemotherapy have shown to be effective in alleviating symptoms and improving outcomes, the approach to patients with asymptomatic brain metastases remains elusive. We explored the literature for a possible role of frontline systemic chemotherapy in asymptomatic brain metastases from nonsquamous non–small-lung cancer and found promising evidence that upfront systemic therapy with pemetrexed–platinum regimens might be a reasonable option for these patients and would forestall the need for upfront brain radiation therapy. More large-scale phase II and phase III clinical trials are needed to further investigate the frontline use of pemetrexed–platinum regimens in this setting. Keywords: frontline chemotherapy, brain metastases, nonsquamous non–small-cell lung cancer, pemetrexed, platinums
BACKGROUND Metastatic brain lesions are the most frequently occurring intracranial tumors in adults with over 170,000 newly diagnosed patients annually in the United States. This is estimated to be 10 times the incidence of primary brain neoplasms.1,2 The incidence of brain metastases continues to increase as a result of superior imaging techniques and methods for earlier detection of cancers, making it more possible to discover these tumors in the early stage of formation and before
1
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH; and 2Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH. R. Chaudhary is on the advisory board for NovoTTF. The other authors have no conflicts of interest to declare. *Address for correspondence: Vontz Center for Molecular Studies, 3125 Eden Avenue, ML 0562 Cincinnati, OH 45267-0562. Phone: 513-558-2115 Fax: 513-558-2125. E-mail: [email protected] 1075–2765 2014 Lippincott Williams & Wilkins
symptoms arise.3 Studies have shown that the majority of brain metastases originate from the lungs (40%– 50%) followed by breast (15%–25%) and melanoma (5%–20%).4,5 Approximately 40% of all patients with lung cancer develop brain metastases during the course of their disease.6 At the time of diagnosis, brain metastases can be found in approximately 10% of all patients with lung cancer; and in several retrospective series, brain metastases are detected in approximately 50% of patients.7,8 The median survival for patient with brain metastases is approximately 2 months if left untreated, but can be extended to 12–14 months with a multidisciplinary approach that includes neurosurgery, radiosurgery, and chemotherapy.9 However, the negative impact of metastatic brain tumors on patients extends beyond that of poor survival to include the devastating effects on cognition, language, mobility, and emotional well-being of patients and their families. Although the current treatment of patients with brain metastases includes whole-brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery www.americantherapeutics.com
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(SRS), there is actually limited evidence to support these approaches compared with systemic chemotherapy in the treatment of patients with asymptomatic brain metastases. The literature addressing the responsiveness of metastatic brain lesions to systemic chemotherapy is both limited and inconclusive. Studies done on the cellular and tissue levels and in animal models suggest that the brain microenvironment induces genetic changes in the tumor cells increasing their growth potential and rendering them more resistant to chemotherapy agents.10 However, in retrospective studies looking at patients who have not been previously treated with chemotherapy, the response rate of the brain lesions was often comparable with that seen in extracranial disease.11 Most of the studies looking at the effect of systemic chemotherapy on brain metastases had significant hard-to-avoid limitations. Some of these studies included a large variety of tumor histologies with different molecular characteristics. Most of the studies examined the effect of chemotherapy in non-naive patients with extensive chemo-resistant extracranial disease or with previous WBRT or SRS to the brain. These limitations make it difficult to draw conclusions on the preferred course of action in chemo-naive newly diagnosed patients with non– small-cell lung cancer (NSCLC) who are incidentally found to have small, single, or multiple asymptomatic brain lesions—a scenario commonly encountered in clinical practice. In the past, the use of systemic chemotherapy in treating brain metastases remained an unpopular approach due to the presence of the blood–brain barrier (BBB). The BBB is a selective barrier between the systemic circulation and cerebrospinal fluid that is formed by specialized endothelial cells lining the cerebral microvasculature, pericytes, and astrocytic perivascular endfeet.12 An intact BBB limits the passage of large molecules and hydrophilic drugs into normal brain. Large hydrophilic molecules, including many chemotherapeutic and molecular-targeted drugs, cannot penetrate to the central nervous system (CNS) unless actively transported by receptor-mediated transcytosis.13 Other studies also suggest that the BBB can express high levels of the P-glycoprotein/ multidrug resistance proteins, which actively transports out some chemotherapeutic agents from the brain.14 The presence of brain metastases disrupts the normal BBB, and it is wildly accepted now that when a brain lesion grows beyond 1–2 mm, the BBB becomes structurally and functionally compromised.15–17 This is also evidenced by clinical observations of leakage of the contrast material when diagnosing macroscopic brain metastases by conventional imaging modalities.18 American Journal of Therapeutics (2014) 0(0)
Alsidawi et al
HYPOTHESIS Frontline systemic chemotherapy with a pemetrexed– platinum regimen would be a reasonable option for patients with small asymptomatic brain metastases with nonsquamous NSCLC and would spare patients the need for brain radiation therapy.
METHODOLOGY We conducted a MEDLINE search to identify articles in the English language that address the role of pemetrexed in brain metastases from NSCLC. Search terms included pemetrexed, lung cancer, NSCLC, brain, CNS, metastases, WBRT, SRS, survival, blood, barrier, and response. Search terms were selected on the basis of common key words identified during the initial literature search. The authors reviewed all relevant case reports, original, and review articles published up till January 2014. Reference lists of identified articles were also checked to ensure that all relevant articles had been included in the reviewing process. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.
THE UPFRONT USE OF SYSTEMIC THERAPY IN BRAIN METASTASES FROM NSCLC Most major phase III studies have excluded patients with brain metastases from their patient population due to the assumption that the brain is a sanctuary place that chemotherapy cannot get to, and the availability of other treatment modalities such as SRS and WBRT. Although these therapies are known to be effective in relieving neurological symptoms and preventing rapid neurological decline in symptomatic patients, no good quality data exist to suggest that these modalities are superior to chemotherapy in small asymptomatic, single, or multiple brain metastases discovered at the time of initial diagnosis of NSCLC. Given the neurocognitive toxicity associated with brain irradiation and the growing in-depth understanding of the BBB, a few studies tried to investigate the real benefit of early versus delayed CNS radiation treatment with concurrent chemotherapy in newly diagnosed patient with NSCLC and synchronous brain metastases. A phase III trial randomized patients with NSCLC and inoperable brain metastases to chemotherapy with cisplatin and vinorelbine combination with either early or delayed WBRT.19 There was no statistically significant difference in the overall response rate, www.americantherapeutics.com
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Frontline Systemic Chemotherapy in Brain Metastases
cerebral response rate, 6-month survival, or overall survival between the 2 groups. Another study randomized patients with NSCLC and brain metastases to either receive chemotherapy first or WBRT first, and concluded that the response rate of chemotherapy and survival outcomes in the primary chemotherapy arm were not statistically different from those in the WBRT-first arm.20 Interestingly, grade 3 or 4 neutropenia occurred more frequently in the WBRT-first group during chemotherapy and prevented some patients from receiving more chemotherapy because of early death or poor performance status after WBRT. These studies have shown that the upfront use of chemotherapy was a feasible and appropriate option in this setting where neurological symptoms were absent or controlled, and that the timing of radiation therapy (early vs. delayed) did not influence survival of patients with NSCLC and brain metastases treated with chemotherapy. A retrospective study done by Outcome Research Network for Evaluation of Treatment Results in Oncology published their data in 2006 to try address the upfront use of chemotherapy in NSCLC with asymptomatic brain metastases.21 Chemotherapy alone seemed to produce a 27% response rate in the brain, which was not statistically different from the 35% rate obtained in the chemotherapy plus WBRT cohort. The authors concluded that asymptomatic patients who receive frontline chemotherapy may be spared from WBRT and the upfront use of chemotherapy represents an appropriate treatment for asymptomatic patients. The study again confirmed the lack of specific prospective clinical trials to determine the best treatment approach for these patients. Targeted therapy with bevacizumab, a vascular endothelial growth factor inhibitor, or gefitinib/erlotinib, the epithelial growth factor receptor tyrosine kinase inhibitors seems to have a promising role in the treatment of brain metastases from NSCLC. Relatively small studies have used these agents with or without concurrent radiation and demonstrated beneficial effect.22–25 The use of targeted therapy as frontline treatment in selected patients either alone or in combination regimens should be further investigated in larger studies.
RISKS OF CRANIAL IRRADIATION Brain irradiation, either in the form of WBRT or SRS, has been introduced as an effective treatment modality for both primary and secondary brain tumors. Although often perceived as safe, both of these radiation techniques carry a significant number of side effects and a concerning toxicity profile. In most cases of symptomatic patients with metastatic brain lesions, the benefits of www.americantherapeutics.com
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brain irradiation outweigh these risks, and radiation treatment is started promptly to control the symptoms and lessen the, otherwise, very rapid neurologic decline. However, these benefits come into question in patients with small asymptomatic brain metastases from NSCLC where there are no robust data to support the use of brain irradiation along with systemic chemotherapy versus using systemic therapy alone. WBRT has been associated with acute and late reactions that are difficult to overlook. Cerebral edema26 debilitating fatigue,27 alopecia,28 somnolence, and lethargy29 are among the early toxicities with WBRT. It is usually the late effects of WBRT that are more problematic. Radiation necrosis is one late side effect of notable interest because it can be extremely difficult to differentiate from tumor progression and can expose the patient to additional unnecessary and expensive imaging or procedures.30 Other late toxicities of WBRT include nonspecific white matter injury, headaches, and neurocognitive impairment.31,32 Neurocognitive impairment happens at various degrees in almost 90% of patient after brain radiation31 and is not often considered a deleterious side effect when put into the context of patients with significant neurologic symptoms and extremely poor survival. In subsets of asymptomatic patients with good performance status in whom relatively longer survival can be expected, however, the neurocognitive impairment becomes a subject of utmost importance given the limited date on the real value of WBRT in this situation, and the detrimental impact that it can have on the quality of life of these patients. The toxicities of SRS are different from those of WBRT because SRS is limited to a small target field and involves a much higher dose of radiation in a single fraction. Acute reactions of SRS (within 90 days) are uncommon and include neurological deficits, seizures,33–35 and headaches. SRS to brain lesions in the brain stem or thalamus carries higher risk of complications and less favorable outcome.36 Again, radiation necrosis remains a diagnostic dilemma with SRS because it is with WBRT and deciding whether the radiologic changes represent necrosis of the lesion with surrounding edema or progression of the disease can be a frustrating clinical dilemma.37 Radiation necrosis itself can also cause disabling neurological symptoms that affect quality of life.
PEMETREXED IN NONSQUAMOUS NSCLC Pemetrexed is a multitargeted antifolate antimetabolite that has a mechanism of action similar to methotrexate, which is a widely used antineoplastic agent for American Journal of Therapeutics (2014) 0(0)
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hematologic malignancies and solid tumors. Pemetrexed disrupts enzymes involved in both purine and pyrimidine synthesis, including thymidylate synthase, dihydrofolate reductase, and glydinamide ribonucleotide formyl transferase38 (Figure 1). Two large phase III trials demonstrated the efficacy of pemetrexed in nonsquamous NSCLC as a first-line treatment in combination with cisplatin, as maintenance therapy alone, or as second-line treatment.39,40 Pemetrexed is currently FDA approved for this purpose and is widely used as a first-line treatment in combination with platinums. Results from other large trials also supported the use of pemetrexed as a maintenance single agent after induction therapy with pemetrexed–cisplatin, as it significantly prolonged progression-free and overall survival after the initial chemotherapy in patient without disease progression.41,42
PEMETREXED AND THE CNS When pemetrexed emerged as a new multitargeted antifolate agent, some studies tried to look at the penetration of pemetrexed into the CNS to assess its potential role in overcoming methotrexate resistance in CNS lymphoma and other malignancies. The assumption was that inhibition of multiple enzymes by pemetrexed could preclude the development of drug resistance caused by overexpression or mutation of a single enzyme. The initial study43 was done in nonhuman primates, where 4 subjects were injected
FIGURE 1. Mechanism of action of pemetrexed. Pemetrexed inhibits enzymes involved in both purine and pyrimidine synthesis, including thymidylate synthase, dihydrofolate reductase, and glydinamide ribonucleotide formyl transferase leading to disruption of DNA and RNA syntheses and antitumor effect. American Journal of Therapeutics (2014) 0(0)
Alsidawi et al
with pemetrexed intravenously with doses almost similar to the approved dose (400 mg/m2) and serial plasma and cerebrospinal fluid (CSF) samples were assessed to measure the concentrations. The study concluded that pemetrexed had poor penetration to the CNS (less than 2%). The major limitation to the study was that the subjects had an intact BBB, which makes the generalization of these results to patients with brain metastases profoundly limited. In another prospective study,44 the efficacy and CNS penetration of pemetrexed were assessed in patients with brain metastases or leptomeningeal disease. Again, this study showed limited penetration of pemetrexed to the CNS (1%–3%) and failed to demonstrate a significant beneficial role on disease progression. However, this study also had major flaws including the small number of patients (only 3 patients had serial cerebrospinal fluid samples) and wide variety of tumor histologies. Most patients received multiple previous chemotherapy or radiation treatments that have unknown effects on the BBB penetrance and tumor responsiveness. Despite the limitations in the above-mentioned studies, their results raise several questions both at the basic molecular level and in the clinical setting. It is possible that different tumors with different molecular characteristics and oncogenic potential affect the BBB in different ways. Tumors that are known to be rich in metalloproteinases or rich in vascularity due to high expression of the vascular endothelial growth factor45 can alter the BBB more than other tumors with less robust expression, which might make them more responsive to chemotherapy given systemically. The drug concentration in the CSF does not seem to be a surrogate for the efficacy of the drug on the metastatic brain tumor. Other factors related to the biology of the tumor, the integrity of the BBB both histologically and at the molecular level, previous systemic treatments and/or radiation and the specific characteristics of the drug should all be taken into account. For example, there are data to suggest that brain metastases from NSCLC express low levels of p-glycoprotein in their vasculature when compared with gliomas, which might render them susceptible to certain chemotherapy agents used to treat the primary extracranial tumor.46 Furthermore, the coadministration of corticosteroids along with chemotherapy, which is very common in patients with brain metastases, might alter drug penetration into the CNS.47 More studies are needed to assess the pharmacodynamics of pemetrexed in brain metastases from NSCLC and the possibility for manipulating drug penetration on the molecular level, as there are interesting studies that showed a saturable efflux process mediated by www.americantherapeutics.com
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Frontline Systemic Chemotherapy in Brain Metastases
multiple transporters working in tandem to be responsible for the low brain distribution of antifolate drugs.48
ACTIVITY OF PEMETREXED AGAINST BRAIN METASTASES FROM NSCLC Most studies of advanced NSCLC in the previous decade have excluded patients with brain metastases due to concerns of limited activity of systemic chemotherapy on the intracranial disease. However, as mentioned above, the efficacy of a drug on the metastatic tumor is not just a reflection of the drug concentration in the CSF. In the recent years, the literature started emerging to suggest that brain metastases can respond to chemotherapy in a manner that follows systemic response.49 Interestingly, this response was noted to be unrelated to concurrent WBRT.50 When pemetrexed established its role as an effective therapy in advanced nonsquamous NSCLC, the question was raised of whether pemetrexed had any effect on CNS metastases in these patients (Table 1). One of the first articles to address this question was a reported case of a 53-year-old patient with stage IV adenocarcinoma of the lung and multiple brain metastases.51 The CNS disease was progressing despite neurosurgical resection of one of the lesions, WBRT, and multiple chemotherapy treatments. The patient was given pemetrexed 500 mg/m2 for 6 cycles, and repeat magnetic resonance imaging showed regression of the brain metastases and even complete resolution of several lesions. Subsequently, many studies tried to investigate the role of pemetrexed on CNS metastases from NSCLC. One study looked retrospectively at 39 patients with brain metastases from NSCLC who had been treated with pemetrexed as second-line or further-line therapy.52 The study showed overall clinical benefit in 69% of the patients, with stable CNS disease in 30.8% patients and a partial CNS response in 38.4%. Overall median survival was 10 months. Although the study included a heterogeneous sample of patients in regards to previous or current radiation exposure, irradiation-naive patients demonstrated an overall clinical benefit and cerebral benefit in 63% and 68% patients, respectively. In another study looking at newly diagnosed patients with NSCLC and brain metastases, Dinglin et al57 looked at the safety and efficacy of pemetrexed and cisplatin combination with concurrent WBRT. The study showed very promising results with progression free survival of the CNS lesions of 10.6 months and www.americantherapeutics.com
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a median overall survival of 12.6 months. The objective cerebral response rate (complete and partial response) in the intent-to-treat population was 68.3%. These results further prove that in patients with NSCLC and brain metastases, treatment with pemetrexed–platinum combination actually improves survival since, historically, patients with brain metastasis who received WBRT alone had a median survival ranging from 2.4 to 4.8 months.58 More data advocating the efficacy of pemetrexed on brain metastases from NSCLC came from a retrospective study by Ortuzar et al.55 This study looked back at the 2 landmark trials39,40 that established the role of pemetrexed as a cornerstone in the treatment of nonsquamous NSCLC to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence of CNS metastases later in the course of the disease. Patients with known brain metastases at the original study entry were excluded from the data analysis, and investigators recorded the site of progressive disease at the time of disease recurrence. Brain metastases recurrence rates were 3.2% (95% confidence interval [CI], 2.1%– 4.6%) in the pemetrexed-containing arms versus 6.6% (95% CI, 5.0%–8.6%) in the non–pemetrexed-containing arms (P 5 0.002). The odds ratio for CNS recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32–0.76; P 5 0.001). Although this study lacked baseline or periodic brain scans and only looked retrospectively at patients with symptomatic brain lesions, it proved that exposure to pemetrexed as first-line or further-line treatment may reduce the risk of brain metastases as the first site of disease progression. Whether pemetrexed was effective on asymptomatic micrometastases or it acted on the primary tumor to decrease the tendency to seed in the brain remains unclear.
PEMETREXED AS AN UPFRONT TREATMENT IN NONSQUAMOUS NSCLC AND BRAIN METASTASES The first prospective trial to investigate the upfront use of pemetrexed–platinum therapy on NSCLC with asymptomatic brain metastases was done by Barlesi et al.53 The goal of the study was to assess the efficacy of cisplatin plus pemetrexed combination as first-line treatment in the setting of multiple asymptomatic brain metastases from NSCLC. The study included patients with an Eastern Cooperative Oncology Group performance status of 0–2 who were chemo-naive with cytologically or histologically proven NSCLC presenting with asymptomatic brain metastases. Patients with American Journal of Therapeutics (2014) 0(0)
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American Journal of Therapeutics (2014) 0(0)
Study
Type
Omlin et al51 Case report
Sample size n51
Bearz et al52
Retrospective n 5 39
Barlesi et al53
Phase II
n 5 43
Ochi et al54
Case series
n52
Ortuzar et al55
Bailon et al56
Dinglin et al57
Chemotherapy regimen Single-agent pemetrexed
n 5 42
Previous radiation
No
Yes
Single-agent No pemetrexed Pemetrexed + cisplatin No, WBRT after chemotherapy
Pemetrexed + cisplatin or single-agent pemetrexed Retrospective n 5 2296 Pemetrexed vs. docetaxel, pemetrexed + cisplatin vs. gemcitabine + cisplatin Observational n 5 30 Pemetrexed + carboplatin
Single arm phase II
Concurrent radiation
Pemetrexed + cisplatin
RR, response rate; ORR, overall response rate.
Primary end point Radiologic response
Heterogeneous Overall RR and cerebral RR No Overall RR, disease control rate, and cerebral RR
No
Yes
Radiologic response
No
No
Odds ratio for brain metastases with exposure to pemetrexed
No
No
Cerebral RR and event-free survival
Yes
No
Overall RR, disease control rate, and cerebral RR
Results Evidence of disease regression or resolution Overall RR, 68% and cerebral RR, 82% Cerebral RR, 41.9%; global ORR, 34.9%; and disease control rate, 72.1% Successful suppression of brain metastases 0.49 (CI, 0.32–0.76; P 5 0.001)
Cerebral RR, 40% and event-free survival, 31 wk; median overall survival, 39 wk Cerebral RR, 68.3%; extracerebral RR, 34.1%; global ORR and disease control rate, 36.6% and 85.4%, respectively Alsidawi et al
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Table 1. A summary of the published studies that looked at the effect of pemetrexed on brain metastases from NSCLC.
Frontline Systemic Chemotherapy in Brain Metastases
previous WBRT were not included in the study. The patients received 4–6 cycles of chemotherapy, and received WBRT only at disease progression, unacceptable toxicity from chemotherapy, or after finishing the chemotherapy. This phase II trial showed high activity of this chemoregimen on CNS disease with a cerebral response rate of 41.9% and cerebral disease control rate of 83.7% with a good safety profile. These data suggest that a pemetrexed–cisplatin regimen might substitute frontline radiation therapy in asymptomatic brain metastases from NSCLC, and that a study comparing platinum–pemetrexed regimen with concurrent WBRT versus delaying WBRT until progression only with continuous neurocognitive assessment would be of great value. Unfortunately, the trial did not address the specific question of whether these patients can be spared the need for brain irradiation until there was evidence of disease progression in the form of either neurologic symptoms or radiologic findings. An observational study by Bailon et al56 tried to address this uncertainty in patients with adenocarcinoma of the lung and brain metastases. Thirty patients with histologically confirmed nonsquamous NSCLC and newly diagnosed brain metastases not amenable to surgery or radiation treatment were included. Patients did not have previous chemotherapy or radiation therapy and were treated with pemetrexed plus carboplatin combination therapy. At the end of the study, the overall cerebral response rate was 40% in the intent-to-treat population. Two patients who had lesions less than 1 cm had a complete response. Despite the small number of patients, the results seen (cerebral response rates) were comparable with other studies that used almost the same regimen either as an upfront regimen or at recurrence after radiation therapy. The results, again, advocates the possible role of upfront pemetrexed–platinum regimens in the management of asymptomatic brain metastases from NSCLC and delaying surgery or radiation treatment until the time of cerebral progression.
PLATINUMS IN ADVANCED NSCLC Platinums are one of the earliest drugs used in the management of NSCLC with positive trials dating back to the 1970s. Almost all of the chemotherapy agents used today as first-line treatment for advanced NSCLC have been studied as a combination with cisplatin versus cisplatin alone or with a different agent. Carboplatin was introduced in the late 1980s and gained popularity in clinical practice due to a better toxicity profile.59 In their most recently published guidelines, the American Society of Clinical Oncology www.americantherapeutics.com
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recommends that a platinum-based regimen be used for stage IV NSCLC.60
PLATINUMS AGAINST BRAIN METASTASES FROM NSCLC There are very limited data on the effect of platinum agents on brain metastases from NSCLC. Most of the clinical studies used platinums in combination regimens when studying the effect of systemic chemotherapy on metastatic brain lesions. Although it is difficult to draw conclusions from these studies on the actual effect of these agents on CNS disease, their use in different combination regimens have shown to be effective in obtaining disease control.53,56,57,61–63 The use of platinums as single agents against brain metastases from NSCLC does not seem to affect the course of the disease even when combined with radiation64; however, including these agents in combination regimens might increase the response rate of the CNS lesions. As for now, there is limited clinical evidence to support this hypothesis, and more prospective studies are needed to address this question. Since platinums have been proven to be effective on the primary tumor and are recommended to be included in first-line regimens, their use in upfront treatment of asymptomatic brain metastases from NSCLC seems a reasonable and inevitable option given their well-proven effect on the extracranial disease.
CONCLUSIONS Brain metastases are a common complication of lung cancer that carries a very poor prognosis. The new advances in imaging modalities have allowed the detection of brain metastases very early in the course of the disease or as a synchronous finding with the initial diagnosis and before neurological symptoms arise. Despite the lack of enough evidence in comparison with chemotherapy alone, most of these patients are referred to SRS or WBRT before systemic therapy. These treatment modalities, which have proven effective in improving outcomes, alleviating neurological symptoms and preventing the rapid functional decline in symptomatic patients, carry obvious risks and toxicities and have not been well validated in the setting of asymptomatic brain metastases from NSCLC, not only in terms of cerebral response rates but also regarding their effect on progression-free and overall survival.65 Pemetrexed has established its role as an effective therapy in nonsquamous NSCLC and became one of the standard first-line treatments when American Journal of Therapeutics (2014) 0(0)
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combined with platinums. We have explored the literature for the possible upfront effect of pemetrexed on brain metastases from NSCLC and found promising evidence advocating a potential role for pemetrexedplatinum regimens on CNS disease. Although most of the currently available studies are small size and often included a heterogeneous patient population, there is appealing evidence to support the use of pemetrexed– platinum regimens in patients with asymptomatic brain metastases from nonsquamous NSCLC as an upfront modality while delaying radiation treatment until disease progression or symptoms occurrence. With close neurological monitoring and periodic imaging, these patients might be spared the risks and toxicities of brain irradiation without affecting their CNS disease response rate or overall survival. More largescale well-designed phase II and phase III clinical trials are needed to further investigate the role of frontline pemetrexed–platinum regimens on asymptomatic brain metastases from nonsquamous NSCLC in terms of CNS response rate, CNS progression-free survival, overall survival, and quality of life in an attempt to forestall the need for upfront brain radiation.
Alsidawi et al
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