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| LETTER TO EDITOR |
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| Year : 2020 | Volume
: 3
| Issue : 2 | Page : 417-418 |
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Authors' reply to Gaikwad et al., Munshi, and Pandey et al.
Rahul Krishnatry1, Ravi Krishna Madala2
1 Department of Radiation Oncology; Tata Memorial Center, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Tata Memorial Center; Department of Medical Oncology, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| Date of Submission | 01-Apr-2020 |
| Date of Decision | 02-Apr-2020 |
| Date of Acceptance | 12-Apr-2020 |
| Date of Web Publication | 19-Jun-2020 |
Correspondence Address:
Rahul Krishnatry
Homi Bhabha National Institute; Department of Radiation Oncology, Tata Memorial Center, Tata Memorial Hospital, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/CRST.CRST_107_20
How to cite this article:
Krishnatry R, Madala RK. Authors' reply to Gaikwad et al., Munshi, and Pandey et al. Cancer Res Stat Treat 2020;3:417-8 |
We thank Jalali and Gaikwad,[1] Pandey,[2] and Munshi [3] for their valuable comments on our article titled, “Neurological deterioration in a patient with lung cancer and brain metastasis.”[4] Their thoughts have added value to the discussion on multiple aspects of the complicated issue of radionecrosis in brain metastasis.
Before we take this discussion further and contemplate the drug efficacy in brain metastasis, we must absolve some of the important molecular clues. Recently, several groups have been working to understand whether the clone in the brain metastasis retains the same mutational load as the primary tumor of the patient that was targeted by therapy. It is suggested that metastatic tumor cells undergo reprogramming in the brain microenvironment to gain the characteristics of neuronal cells.[5] Although clonally related to the primary tumor, the metastatic site has a distinct evolution pattern. Clinically, relevant mutations have been found in brain metastases that were not detected in the primary tumors. Moreover, the metastatic tumor may not share the driver mutations of the primary tumor. In non-small cell lung cancer (NSCLC), both the primary tumor and brain metastases have shown EGFR and KRAS gene amplifications. However, alterations in the AKT1, ALK, ERBB2, MET, FGFR1, and PDGFRA genes were not observed in brain metastases. Moreover, deletions in the PTEN and TP53 genes observed in the primary tumor were not identified in brain metastases; instead, new deletion in the LKB1 gene was identified.[6]
If we delve into the details, which are still very preliminary, the topic of brain metastasis and its management is full of controversies, as is the subset of radiation necrosis with concurrent use of modern era systemic therapy. In this context, we concur with Munshi,[3] but we will restrict further discussion to NSCLC brain metastases treated with gefitinib and whole-brain radiotherapy (WBRT). This is even more challenging because of the limited data of retrospective nature that are subject to several biases, especially regarding the patient selection and physician preference. There are more questions than real answers regarding the combination of radiotherapy with systemic agents, but we must raise them so that in future, we are better informed.
First, it is still not clear whether the use of gefitinib increases the incidence of brain metastasis, and if it does, is it by prolonging survival and its own limited penetration through the blood–brain barrier or are there more reasons for it? Second, is it best to add radiotherapy to gefitinib, and how? Several single- and multi-institutional retrospective studies have suggested best outcomes with concurrent treatments with higher doses of radiotherapy, such as stereotactic radiotherapy, followed by whole-brain radiation and worse with gefitinib alone.[7],[8] However, this is still widely debated and challenged due to the lack of prospective unbiased data.
Third, radiotherapy is one of the oldest methods believed to alter the blood–brain barrier, both for the normal brain as well as in the brain metastases. Despite the in vivo data, clinical evidence is still controversial. In a study of 30 patients, with 64 analyzed metastatic lesions, who received WBRT or stereotactic radiosurgery, radiotherapy improved the permeability of the initially low leaky tumors at 2 weeks and 1-month post-therapy.[9] However, there was little or decreased permeability in the initially leaky metastases. Two other studies of small groups of patients of NSCLC treated with WBRT and concurrent gefitinib showed equally conflicting results. One showed increased drug penetration with escalating WBRT doses, while the other did not.[10],[11]
Hence, combining and sequencing targeted systemic therapy and brain radiotherapy has many puzzling aspects, right from the molecular to the clinical level, and we are still in the hypothesis phase. Nevertheless, such discussions are pertinent as they provide an opportunity to introspect deeply and the motivation to record clinical observations systematically. Such intriguing discussions help us ask clear prospective questions to guide future practice in a more informed way.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Gaikwad U, Jalali R. Differentiating radiation necrosis vis-a-vis recurrence in brain metastasis. Cancer Res Stat Treat 2020;3:414-5.  [Full text] |
| 2. | Pandey P, Ullas VA. Distinguishing radiation necrosis from tumor recurrence. Cancer Res Stat Treat 2020;3:416-7. [Full text] |
| 3. | Munshi A. Brain radionecrosis in the present multiagent systemic therapy era: Time to redefine brain radiotherapy tolerance? Cancer Res Stat Treat 2020;3:413-4. [Full text] |
| 4. | Madala RK, Krishnatry R, Noronha V, Patil V, Joshi A, Menon N, et al. Neurological deterioration in a patient with lung cancer and brain metastasis. Cancer Res Stat Treat 2020;3:97-9. [Full text] |
| 5. | Park ES, Kim SJ, Kim SW, Yoon SL, Leem SH, Kim SB, et al. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis. Proc Natl Acad Sci U S A 2011;108:17456-61. |
| 6. | Achrol AS, Rennert RC, Anders C, Soffietti R, Ahluwalia MS, Nayak L, et al. Brain metastases. Nat Rev Dis Primers 2019;5:5. |
| 7. | Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, et al. Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol 2017;35:1070-7. |
| 8. | Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53. [Full text] |
| 9. | Teng F, Tsien CI, Lawrence TS, Cao Y. Blood-tumor barrier opening changes in brain metastases from pre to one-month post radiation therapy. Radiother Oncol 2017;125:89-93. |
| 10. | Zeng YD, Liao H, Qin T, Zhang L, Wei WD, Liang JZ, et al. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget 2015;6:8366-76. |
| 11. | Fang L, Sun X, Song Y, Zhang Y, Li F, Xu Y, et al. Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non-small cell lung cancer: A self-controlled, pilot study. Cancer Chemother Pharmacol 2015;76:873-7. |
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