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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 97-99

Neurological deterioration in a patient with lung cancer and brain metastasis

1 Department of Medical Oncology, Tata Memorial Center, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Homi Bhabha National Institute; Department of Radiation Oncology, Tata Memorial Center, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission30-Dec-2020
Date of Decision12-Jan-2020
Date of Acceptance13-Jan-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Rahul Krishnatry
Department of Radiation Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_108_19

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How to cite this article:
Madala RK, Krishnatry R, Noronha V, Patil V, Joshi A, Menon N, Muthuluri H, Prabhash K. Neurological deterioration in a patient with lung cancer and brain metastasis. Cancer Res Stat Treat 2020;3:97-9

How to cite this URL:
Madala RK, Krishnatry R, Noronha V, Patil V, Joshi A, Menon N, Muthuluri H, Prabhash K. Neurological deterioration in a patient with lung cancer and brain metastasis. Cancer Res Stat Treat [serial online] 2020 [cited 2021 May 9];3:97-9. Available from: https://www.crstonline.com/text.asp?2020/3/1/97/279066

  Case History and Approach Top

A 52-year-old male, known tobacco chewer for 15 years, with no comorbidities was evaluated for complaints of breathlessness on exertion and found to have left lower lobe mass lesion with bilateral pleural effusion and mediastinal and right supraclavicular lymphadenopathy. Pleural fluid cytology and biopsy from the right supraclavicular lymph node revealed adenocarcinoma with epidermal growth factor receptor (EGFR) exon 19 deletion positive. He was diagnosed with cT2N3M1a adenocarcinoma of the lung, Stage IVA as per the American Joint Committee on Cancer, 8th edition. He was treated on a clinical trial and received gefitinib with chemotherapy,[1] consisting of four cycles of 3-weekly pemetrexed and carboplatin, followed by 11 cycles of maintenance pemetrexed with sustained partial response. Post 11 cycles, he developed a headache and was found to have a brain metastasis in the right occipital region [Figure 1]a and [Figure 1]b. He was treated with whole-brain radiotherapy (WBRT) at a dose of 20 Gy in five fractions, 4 Gy per fraction in November 2018. Since he had progressed only in the brain and had stable disease extracranially, he continued on maintenance pemetrexed along with gefitinib, with the last cycle (cycle 21) administered on August 1, 2019.
Figure 1: Preradiotherapy magnetic resonance images with T2 plain axial (a) showing T2 dark hypointense lesion (black arrow) in right parieto-occipital region with disproportionate edema (black star), the same lesion is seen as enhancing hyperintense mass (black arrow) in T1 contrast corresponding sequence (b)

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On August 7, 2019, he presented with complaints of headache, difficulty in walking, and a seizure episode for which he was evaluated with magnetic resonance imaging (MRI) brain which showed a heterogeneously enhancing lesion in the right occipital lobe and surrounding white matter edema with postcontrast enhancement [Figure 2]a and [Figure 2]b. He was started on steroids and antiepileptics, in spite of which he continued to have recurrent seizures.
Figure 2: Postradiotherapy magnetic resonance images with T2 plain axial (a) showing disproportionate edema with posttreatment changes (black arrow) with enhancement locally in the right parieto-occipital region in corresponding image sequence with T1 contrast (black arrow) “cut green pepper appearance” (b)

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What is the diagnosis? Once you have finalized your answer, please read on.

  Discussion Top

Twenty-five percent of patients with advanced non-small cell lung cancer develop brain metastasis, and the incidence continues to rise.[2] Disease progression in the form of brain metastasis occurs in approximately one-third of the patients with EGFR mutation during treatment.[3] Surgery and/or radiotherapy (RT) form the cornerstone of the current management of brain metastasis. RT can be either in the form of WBRT or stereotactic radiosurgery (SRS) or the combination of both. WBRT or SRS leads to a similar overall survival (OS) benefit; WBRT is associated with lower brain progression rates but a higher negative impact on neurocognitive outcomes. WBRT prolongs the OS of patients with brain metastases from 3 to 5 months.[4],[5] Surgical resection followed by WBRT is associated with an improvement in OS to 40 weeks, when compared to patients who undergo biopsy followed by WBRT in whom the median OS is 15 weeks, relative risk of death 2.2, P < 0.01.

One of the feared complications of brain RT is the development of radiation necrosis. It is more commonly described associated with SRS than conventional WBRT, with variable incidences in reports ranging from 5% to 24% depending on various factors.[6] These factors include dose–volume relation, prior RT treatment, the use of concurrent chemotherapy or targeted agents, location, volume of normal brain irradiated as clinical target volume or planning target volume, intrinsic radiosensitivity of a patient, and the criteria for diagnosis to name a few.[7] The exact etiology of radiation necrosis is poorly understood and is believed to be due to either direct vascular injury or glial injury; both mechanisms finally lead to the upregulation of local inflammatory response, ischemia, and expression of vascular epidermal growth factor (VEGF) causing increased leakage and accumulation of fluid into the extracellular space resulting in cerebral edema.[8],[9]

It is of paramount importance to differentiate radiation necrosis from progressive or recurrent disease. Although histology is considered the gold standard for diagnosis, this is rarely obtained due to the risk of complications. The critical diagnosis depends on noninvasive diagnostic modalities. The most common radiological investigation used is used is MRI demonstrating some degree of contrast enhancement and perilesional edema. However, these classical features considerably overlap with tumor progression. At times, the clinical picture is also overlapping. The dogma of temporal changes (i.e., increase in size over time) is again not specific to either entity.[10],[11] There are certain enhancement patterns described in the literature as 'Swiss cheese,' 'soap bubble,' or 'cut green pepper' [Figure 2]b, initially thought to favor radiation necrosis, but these have only a 25% positive predictive value.[12] The MRI of our patient showed successful use of conventional MR for diagnosing and treating radiation necrosis that developed in the background of a large metastasis treated with WBRT and concurrent systemic agents. It showed a contrast-enhanced lesion in the right parieto-occipital lobe [Figure 2]b with surrounding white matter edema [Figure 2]a, showing decreased, ill-defined gyriform postcontrast enhancement which represented post-RT necrosis rather than recurrence.

Other modern modalities which are useful in differentiating radiation necrosis from tumor progression are perfusion- weighted imaging and MR spectroscopy. The percentage of signal recovery more than 76% in perfusion-weighted imaging is a highly sensitive (95%) and specific (100%) finding of radiation necrosis.[13] In MR spectroscopy, tumor progression shows a choline (Cho) peak which corresponds to a higher rate of metabolism in proliferative tissues, whereas RT-induced damage with cellular debris containing lactate and fatty acids contributes to lipid or lactate peak in postradiation necrosis.[14],[15] When compared to radiation necrosis, progressive disease shows higher Cho–creatine ratio and Cho–N-acetylaspartate ratio in MR spectroscopy.[16] The sensitivity and specificity for identifying tumors using MR spectroscopy imaging are 89% and 83%, respectively.[17] Recently, methionine, fluoro-l-thymidine, and fluoroethyltyrosine (FET) have been used with promising results. Of these, the FET–positron emission tomography has convincing adjunct value with a sensitivity of 100% and a specificity of 93%, comparable to some MRS results.[18]

The management of radiation necrosis primarily depends on the presence of symptoms such as headache, nausea, cognitive impairment, seizures, or focal deficits relating to the location of the lesion. An oral corticosteroid-like dexamethasone at a dose of 4–8 mg/m2/day is the preferred first line. As many patients may need steroids for a long duration, care must be taken to address associated toxicity, such as myopathy, iatrogenic Cushing's syndrome, and gastric ulcers.[19] Caution is advised in the dose of mannitol or other osmotic diuretics during the acute phase because there are risks of increasing intratumoral bleed and electrolyte imbalances. Nowadays, bevacizumab (anti-VEGF) is commonly used either upfront or in steroid-dependent patients with good success. A pooled analysis involving 71 patients showed that the use of bevacizumab led to a radiographic response rate of 97% and a clinical improvement rate of 79% with a mean decrease in dexamethasone of 6 mg.[20],[21] Other agents such as heparin, local surgery with resection of the nidus of necrosis, and hyperbaric oxygen therapy have also been tried with very little evidence of utility.[21]

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  References Top

Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol 2020;38:124-36.  Back to cited text no. 1
Sørensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: Frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474-80.  Back to cited text no. 2
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.  Back to cited text no. 3
  [Full text]  
Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastases. Ann Neurol 1980;7:529-41.  Back to cited text no. 4
Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, et al. The palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1-9.  Back to cited text no. 5
Marks JE, Baglan RJ, Prassad SC, Blank WF. Cerebral radionecrosis: Incidence and risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 1981;7:243-52.  Back to cited text no. 6
Sneed PK, Mendez J, Vemer-van den Hoek JG, Seymour ZA, Ma L, Molinaro AM, et al. Adverse radiation effect after stereotactic radiosurgery for brain metastases: Incidence, time course, and risk factors. J Neurosurg 2015;123:373-86.  Back to cited text no. 7
Li YQ, Ballinger JR, Nordal RA, Su ZF, Wong CS. Hypoxia in radiation-induced blood-spinal cord barrier breakdown. Cancer Res 2001;61:3348-54.  Back to cited text no. 8
van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999;104:1613-20.  Back to cited text no. 9
Peterson AM, Meltzer CC, Evanson EJ, Flickinger JC, Kondziolka D. MR imaging response of brain metastases after gamma knife stereotactic radiosurgery. Radiology 1999;211:807-14.  Back to cited text no. 10
Huber PE, Hawighorst H, Fuss M, van Kaick G, Wannenmacher MF, Debus J. Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2001;49:1339-49.  Back to cited text no. 11
Dequesada IM, Quisling RG, Yachnis A, Friedman WA. Can standard magnetic resonance imaging reliably distinguish recurrent tumor from radiation necrosis after radiosurgery for brain metastases? A radiographic-pathological study. Neurosurgery 2008;63:898-903.  Back to cited text no. 12
Barajas RF, Chang JS, Sneed PK, Segal MR, McDermott MW, Cha S. Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 2009;30:367-72.  Back to cited text no. 13
Kamada K, Houkin K, Abe H, Sawamura Y, Kashiwaba T. Differentiation of cerebral radiation necrosis from tumor recurrence by proton magnetic resonance spectroscopy. Neurol Med Chir (Tokyo) 1997;37:250-6.  Back to cited text no. 14
Schlemmer HP, Bachert P, Herfarth KK, Zuna I, Debus J, van Kaick G. Proton MR spectroscopic evaluation of suspicious brain lesions after stereotactic radiotherapy. AJNR Am J Neuroradiol 2001;22:1316-24.  Back to cited text no. 15
Chuang MT, Liu YS, Tsai YS, Chen YC, Wang CK. Differentiating radiation-induced necrosis from recurrent brain tumor using MR perfusion and spectroscopy: A meta-analysis. PLoS One 2016;11:e0141438.  Back to cited text no. 16
Plotkin M, Eisenacher J, Bruhn H, Wurm R, Michel R, Stockhammer F, et al. 123I-IMT SPECT and 1H MR-spectroscopy at 3.0 T in the differential diagnosis of recurrent or residual gliomas: A comparative study. J Neurooncol 2004;70:49-58.  Back to cited text no. 17
Rachinger W, Goetz C, Pöpperl G, Gildehaus FJ, Kreth FW, Holtmannspötter M, et al. Positron emission tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus magnetic resonance imaging in the diagnosis of recurrent gliomas. Neurosurgery 2005;57:505-11.  Back to cited text no. 18
Shaw PJ, Bates D. Conservative treatment of delayed cerebral radiation necrosis. J Neurol Neurosurg Psychiatry 1984;47:1338-41.  Back to cited text no. 19
Sharpton SR, Oermann EK, Moore DT, Schreiber E, Hoffman R, Morris DE, et al. The volumetric response of brain metastases after stereotactic radiosurgery and its post-treatment implications. Neurosurgery 2014;74:9-15.  Back to cited text no. 20
Kim WH, Kim DG, Han JH, Paek SH, Chung HT, Park CK, et al. Early significant tumor volume reduction after radiosurgery in brain metastases from renal cell carcinoma results in long-term survival. Int J Radiat Oncol Biol Phys 2012;82:1749-55.  Back to cited text no. 21


  [Figure 1], [Figure 2]


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