Abstract

A 43-year-old patient with stage T1N2M0 (AJCC-8) non-small cell lung cancer developed a large metastasis in the brain shortly after high dose external beam radiation 60Gy in 30 fractions with concurrent chemotherapy in 2010. She received whole brain irradiation (WBI) 20Gy in five fractions. Her primacy cancer was ALK-positive, so she did well with systemic tyrosine kinase inhibitors (TKI) for three years before she had recurrence in the brain. Craniotomy was performed to remove a large 4 cm mass from the right cerebellum. The remaining nine lesions in the brain received a second course WBI 21Gy after a four-year interval.

Another three years passed, there was progression of a large solitary metastasis in the right brain. She agreed to have hypofractionated stereotactic radiotherapy (HSRT) 20Gy in five fractions. CT scan and MRI showed complete response (CR) after the re-irradiation. We did not observe any neurotoxicity.

Unfortunately, a new symptomatic brain metastasis was found in the left frontal lobe. She refused surgery but accepted a second course HSRT 20Gy in five fractions. Subsequently she developed severe neurotoxicity within ten weeks. Magnetic resonance spectroscopy (MRS) reported borderline low choline to N-acetyl aspartate ratio (Cho/NAA) of 1.78, favoring radionecrosis over progression of brain metastasis.

Eventually, she had a second craniotomy which achieved gross total resection. The pathology confirmed radionecrosis with no viable tumour. She is recovering well after rehab service and recent MRI did not show any residue cancer, new brain metastases, or radionecrosis in the brain. Eleven years after her lung cancer diagnosis, she remained as disease free.

IntroductionLung cancer remains the leading cause accounting for 25.5% of all cancer death in Canada.1Brenner DR Weir HK Demers AA et al.Projected estimates of cancer in Canada in 2020. Non-small cell lung cancer (NSCLC) with symptomatic multiple brain metastases (mbMets) has very limited survival time.2Dawe DE Greenspoon JN Ellis PM Brain metastases in non-small-cell lung cancer. Standard whole brain irradiation (WBI) with or without craniotomy usually can't prolong overall survival (OS) due to high frequency of recurrence. Re-irradiation to the brain can cause severe neurotoxicity and worse quality of life (QoL). There is trend to do stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HSRT) for patients with limited number of brain metastases in order to avoid neurotoxicity.4Kocher M Soffietti R Abacioglu U et al.Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study., 5Soffietti R Kocher M Abacioglu UM et al.A European Organization for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results., 6Andrews DW Scott CB Sperduto PW et al.Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial., 7Aoyama H Shirato H Tago M et al.Stereotactic radio-surgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial., 8Chang EL Wefel JS Hess KR et al.Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomized controlled trial.

Radionecrosis is a concerning neurotoxicity from SRS reported in the literature. However, it is usually difficult to differentiate from tumor progression on computed tomography (CT) or magnetic resonance imaging (MRI) and also difficult to get tissue diagnosis. Without appropriate diagnosis and treatment, it carries very poor prognosis. We present a case of multiple complete response (CR) to two full courses of WBI, two courses of HSRT, and two craniotomies for mbMets from lung cancer over a ten-year period with pathologically confirmed radionecrosis and good recovery.

Case presentationWe previously reported a case of a 43-year-old non-smoker female who was initially diagnosed with stage T1N2M0 lung adenocarcinoma (AJCC-8), positive for Anaplastic Lymphoma Kinase (ALK). She had CR initially after concurrent chemoradiation 60Gy in thirty fractions in 2010. Nine months later, she had biopsy-proven distant metastases. Over a nine-year period, she had multiple recurrent mbMets treated with two WBI 20Gy and 21Gy, in five and seven daily fractions, respectively (four years apart), craniotomy to remove a large 4 cm mass from the right brain (pathology confirmed adenocarcinoma of lung origin), and finally HSRT 20Gy in five fractions every other day to a large solitary metastasis in the right cerebellum. (Figure 1) Every time we achieved CR after radiation and re-irradiation. The right cerebellum lesion completely disappeared on CT and MRI. (Figure 2) We did not observe any neurotoxicity. She was also treated with four different lines of systemic tyrosine kinase inhibitors (TKI), i.e., crizotinib, ceritinib, alectinib, and lorlatinib (switched to another type whenever there was disease progression).

Figure 1First HSRT plan with MRI simulation. HSRT, hypofractionated stereotactic radiotherapy; MRI, magnetic resonance imaging.

Figure 2Brain CT showing CR 9 months after first HSRT. CT, computed tomography; CR, complete response; HSRT, hypofractionated stereotactic radiotherapy.

Ten months after HSRT, she fell and was found to have a new 1.2 cm solitary brain metastasis in the left frontal lobe. MRI did not show any other metastasis. She refused craniotomy, but consented to a second course of HSRT 20Gy in five fractions. (Figure 3) She was able to walk again and do all her housework until about two months later when she had a 10-day deterioration noticed by her family. She completely lost her short memory, fell at home and could no longer walk.

Figure 3Second HSRT plan with MRI simulation. HSRT, hypofractionated stereotactic radiotherapy; MRI, magnetic resonance imaging.

MRI showed that the left frontal brain lesion progressed to 2.5 cm in size ten weeks after the second course HSRT. (Figure 4) There was marked increased vasogenic edema, mild mass effect and midline shift to the right side for about 0.3 cm. No other suspicious lesions were seen in the brain. Magnetic resonance spectroscopy (MRS) reported borderline low choline to N-acetyl aspartate ratio (Cho/NAA) of 1.78 which is slightly lower than the cut-off value of 1.8 in the literature, favoring radionecrosis over progression of brain metastasis.10Anbarloui MR Ghodsi SM Khoshnevisan A et al.Accuracy of magnetic resonance spectroscopy in distinction between radiation necrosis and recurrence of brain tumors. (Figure 5)

Figure 4Brain MRI showing left frontal lesion 2 weeks before (left) versus 10 weeks after second HSRT (right) MRI, magnetic resonance imaging; HSRT, hypofractionated stereotactic radiotherapy.

Figure 5Brain MRS 2 months after second HSRT showing radionecrosis with pathological confirmation. MRS, magnetic resonance spectroscopy; HSRT, hypofractionated stereotactic radiotherapy.

Ultimately, she had a second craniotomy which achieved gross total resection. The pathology confirmed radionecrosis with no viable tumour in the brain. Unfortunately, she had further deterioration of her neurological symptoms after the surgery for about four weeks. She could not stand up. She could not remember anything that happened within the last several minutes. Nevertheless, she was started on oral dexamethasone 4 mg twice per day and her symptoms improved dramatically. MRI two months and six months post-surgery did not show any residue cancer, new brain metastases, or radionecrosis in the brain. (Figure 6)

Figure 6Brain MRI showing CR 2 months after (left) versus 10 days before second craniotomy surgery (right). MRI, magnetic resonance imaging; CR, complete response.

We tried to wean off her steroids temporarily, but now she remained on low dose oral dexamethasone 2 mg once per day. On the last follow up, she was able to stand up without assistance. She could even walk without a walker. She no longer needed Foley catheters or a commode beside her bed. She had no further falls. Her short-term memory had partial recovery.

Eleven years after her lung cancer diagnosis, she remained as disease free.

DiscussionWBI can cause severe neurotoxicity. The current trend is to do SRS or HSRT whenever possible for cancer patients who had limited number of brain metastases due to equivalent OS with reduced toxicity most notably involving neurocognition.4Kocher M Soffietti R Abacioglu U et al.Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study., 5Soffietti R Kocher M Abacioglu UM et al.A European Organization for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results., 6Andrews DW Scott CB Sperduto PW et al.Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial., 7Aoyama H Shirato H Tago M et al.Stereotactic radio-surgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial., 8Chang EL Wefel JS Hess KR et al.Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomized controlled trial.,11Sahgal A Aoyama H Kocher M et al.Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis., 12Greenspoon JN Ellis PM Pond G Caetano S Broomfield J Swaminath A Comparative survival in patients with brain metastases from non-small-cell lung cancer treated before and after implementation of radiosurgery., 13Rodrigues G Yartsev S Roberge D et al.A phase II multi-institutional clinical trial assessing fractionated simultaneous in-field boost radiotherapy for brain oligometastases., 14Minniti G Clarke E Lanzetta G et al.Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis., 15Sneed PK Mendez J Vemer-van den Hoek JG et al.Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors., 16Brown PD Jaeckle K Ballman KV et al.Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial., 17Brown PD Ballman KV Cerhan JH et al.Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC•3): a multicentre, randomised, controlled, phase 3 trial., 18Yamamoto M Serizawa T Shuto T et al.Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. However, even though well tolerated, SRS does have side effects including most concerning radionecrosis (low rate).14Minniti G Clarke E Lanzetta G et al.Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. There are questions whether current low radionecrosis rates apply to metastatic patients who are living longer due to improvements in systemic therapy, as in the past these patients would have passed away before developing late neurotoxicity. As such, there is occasional hesitation to consider reirradiation to mbMets.Sneed et al. found previous WBI or SRS can increase the radionecrosis risk and long interval between re-irradiation can reduce that risk, about 20% at one year after SRS to the same lesion.15Sneed PK Mendez J Vemer-van den Hoek JG et al.Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. McKay et al. also reported repeat SRS as re-irradiation for local failure after previous SRS can have durable local control (LC) but high rates of radionecrosis, i.e., 11 of 46 brain metastases (24%) had symptomatic radionecrosis. The volume of a lesion receiving 40 Gy (V40Gy) was statistically significant to predict radionecrosis (p = 0.003).19McKay WH McTyre ER Okoukoni C et al.Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. Rae et al. suggested that re-irradiation with both SRS and WBI to recurrent brain metastases after initial SRS was associated with the highest radionecrosis rate (6/28, 21.42%), while no patient had radionecrosis if the salvage treatment was SRS alone (0/31), WBI alone (0/58), craniotomy alone (0/7), or craniotomy followed by radiation (0/8). It should be noted that most radionecrosis in their study had no pathological confirmation.20Rae A Gorovets D Rava P et al.Management approach for recurrent brain metastases following upfront radiosurgery may affect risk of subsequent radiation necrosis.Comparing to gamma knife (GK), Linear accelerator (LINAC)-based SRS is easy to use and has lower cost.21Marcrom SR McDonald AM Thompson JW et al.Fractionated stereotactic radiation therapy for intact brain metastases., 22Sebastian NT Glenn C Hughes R et al.Linear accelerator-based radiosurgery is associated with lower incidence of radionecrosis compared with gamma knife for treatment of multiple brain metastases., 23Park HS Wang EH Rutter CE et al.Changing practice patterns of gamma knife versus linear accelerator-based stereotactic radiosurgery for brain metastases in the US. Subgroup analyses of RTOG 9508 found similar OS comparing GK and LINAC SRS.6Andrews DW Scott CB Sperduto PW et al.Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial. Sebastian et al. reported LINAC SRS has less radionecrosis than GK for treatment of mbMets. However, their definition of radionecrosis was vague without pathological confirmation.22Sebastian NT Glenn C Hughes R et al.Linear accelerator-based radiosurgery is associated with lower incidence of radionecrosis compared with gamma knife for treatment of multiple brain metastases. Meta-analysis of 1887 brain metastases from 24 trials by Lehrer et al. also suggested that multifraction SRS or HSRT to large brain metastasis might reduce the risk of radionecrosis (7.3% versus 23.1%, p = 0.003), while maintaining or improving 1-year LC (92.9% versus 77.6%, p = 0.18) compared with single-fraction SRS.24Lehrer EJ Peterson JL Zaorsky NG et al.Single versus multifraction stereotactic radiosurgery for large brain metastases: An international meta-analysis of 24 trials.Our institution does not have SRS and is located remotely from GK center. We use a very conservative LINAC-based HSRT protocol similar to Marcrom et al.21Marcrom SR McDonald AM Thompson JW et al.Fractionated stereotactic radiation therapy for intact brain metastases. We only treat small number of brain oligometastases (1-4) to 25-30 Gy in 5 fractions every other day. Salvage re-irradiation with HSRT (for up to four recurrent mbMets) or with WBI 21Gy in 7 daily fractions (if there are more lesions) after upfront WBI 20Gy is allowed when there is long interval. To our surprise, this patient had excellent response to four TKI and two WBI without neurotoxicity. She preferred HSRT over craniotomy after developing further symptomatic oligometastases in the brain. To reduce the risk of neurotoxicity, we didn't use standard dose HSRT for the second and third re-irradiation. We also used prophylactic steroids during treatment.Obviously, the rule of V40Gy thresholds doesn't apply as the entire brain received 41 Gy prior to the two HSRT.19McKay WH McTyre ER Okoukoni C et al.Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. It is interesting to see the larger lesion in right cerebellum had CR and no radionecrosis, while the smaller lesion in left frontal lobe developed radionecrosis in just 10 weeks. MRS showed Cho/NAA ratio of 1.78 which is at the borderline of the cut-off value of 1.8 in the literature.10Anbarloui MR Ghodsi SM Khoshnevisan A et al.Accuracy of magnetic resonance spectroscopy in distinction between radiation necrosis and recurrence of brain tumors. But we favored radionecrosis as it was unlikely to have such rapid tumor progression after the last HSRT. Fortunately, her second craniotomy confirmed the tissue diagnosis and she received prompt proper treatment. It also confirmed CR in the brain.

It is possible that the risk of radionecrosis has been reduced by offering re-irradiation with HSRT instead of WBI or single fraction SRS, reducing the total dose of HSRT, treating every other day instead of daily, and especially with super long interval of several years. However, we suspect that we have reached the limit and can no longer offer her more radiation to the brain, either by WBI, SRS or HSRT. She has received a combined biologically effective dose (BED) of 135.34 Gy and equivalent dose for 2 Gy per fraction (EQD2) of 81.2 Gy, using α/β ratio of 3 for late-responding normal brain tissue.

Although rare, there has been report of long-term CR and cure after WBI 20Gy. But to our knowledge, this is the first case of multiple CR to two courses of WBI, two courses of HSRT, and two craniotomies for mbMets from lung cancer over a ten-year period with pathologically confirmed radionecrosis and good recovery ever reported in the literature.