Salvage pemetrexed for brain metastases from ALK-positive lung cancer after Gamma Knife radiosurgery: illustrative case

Abstract

BACKGROUND

Systemic therapy for cancer treatment has improved, and therapeutic options for intracranial lesions are increasing. Combinations of treatment modalities are required in certain difficult cases. Gamma Knife radiosurgery (GKS) is effective for the treatment of brain metastases, especially for lesions that are inoperable because of their anatomical or functional location.

OBSERVATIONS

The authors report a case of brain metastases in anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma initially treated with GKS followed by the combination of repeat GKS and ALK tyrosine kinase inhibitors (ALK-TKIs) for tumor recurrence. During the clinical course, acquired resistance to ALK-TKIs due to the long exposure period was suspected. After a great deal of thought and discussion with the oncologist responsible for the treatment of the pulmonary lesions, the authors successfully controlled the lesion for the next 17 months by salvage pemetrexed administration.

LESSONS

This is the first report on the effectiveness of pemetrexed for recurrent brain metastasis from ALK-positive lung adenocarcinoma resistant to both radiosurgery and ALK inhibitors. Salvage pemetrexed showed a favorable therapeutic effect in this specific case.

Recently, a paradigm shift in systemic therapy¹ has changed the standard treatment for cancer, and life expectancy has been prolonged. Accordingly, the incidence of brain metastases is estimated to increase; therefore, tailored multimodal treatment strategies are essential. Treatment options for brain metastasis have improved outcomes; however, management has concurrently become more complicated. Thus, the interdisciplinary treatment of brain metastases requires the collaboration of specialists from several fields, such as medical oncology, neurosurgery, and radiation oncology.

In this report, we present a case of anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma with a brain metastasis that showed an insufficient response to Gamma Knife radiosurgery (GKS) and repeated recurrence due to acquired resistance to ALK tyrosine kinase inhibitors (ALK-TKIs). On the basis of evidence and consultation with thoracic oncologists, the patient was successfully treated with salvage pemetrexed.

Illustrative Case

A 63-year-old man with a medical history of ALK-positive lung adenocarcinoma was diagnosed 5 years earlier (cT1aN3M0, stage 3B). After conventional treatment with cytotoxic chemotherapy (cisplatin with tegafur, gimeracil oteracil, and otastat potassium) and concurrent radiotherapy, the patient experienced a recurrence of the pulmonary lesion. Alectinib 600 mg/day was started as a second-line treatment. One year later, magnetic resonance imaging (MRI) revealed multiple brain metastases, including one lesion on the left side of the pons (asymptomatic). The patient underwent GKS for all lesions. The prescribed dose for the pons lesion was 18 Gy (0.3 mL, maximum dose 27.7 Gy; Fig. 1A). The dose for the other tumor was 20 Gy (0.01–0.04 mL, maximum dose 29.4–30.8 Gy). In 15 months, most of the tumors remained under control, except for the lesion on the pons, which regrew and was accompanied by a few new lesions (Fig. 1B and C). The regrowth was diagnosed as a tumor recurrence, and alectinib was switched to lorlatinib 100 mg/day, with successful control for the next 9 months until the lesion showed another regrowth (Fig. 1D–F). ¹¹C-methionine positron emission tomography (MET-PET) demonstrated increased uptake (Fig. 1G), and the lesion was diagnosed as a second recurrence, followed by repeat GKS (1.0 mL, prescribed dose 35.1 Gy in 13 fractions, maximum dose 41.8 Gy; Fig. 1H). The lesion showed a transient response (Fig. 1I) to the treatment. However, a third recurrence diagnosed on the basis of MET-PET was detected at 10 months (Fig. 1J and K). Considering the risks of reirradiation and the difficulty of surgical removal, systemic therapy was chosen, and lorlatinib was switched to brigatinib 180 mg/day. Nevertheless, the recurrent lesion grew gradually, with another metastasis appearing in the pituitary gland (Fig. 1L and M). Eventually, trigeminal neuralgia resulted from direct invasion of the cranial nerve (Fig. 1N). Brigatinib was replaced with four courses of pemetrexed (150 mg/m²) with carboplatin (320 mg/m²), followed by pemetrexed maintenance (150 mg/m²), based on the association between ALK-positive lung adenocarcinoma and durable responses to pemetrexed. The recurrent tumor and pituitary metastasis showed an immediate response to cytotoxic chemotherapy and were kept under control for the next 17 months (Fig. 2). The pulmonary lesion did not show any aggravation of its status, and no other extracranial metastases were detected during the clinical course.

FIG. 1.

Chronological MRI scans of the left pons lesion before the introduction of pemetrexed. A: The first GKS was performed for the lesion in the left pons (0.3 mL in volume; 18 Gy, maximum dose 27.7 Gy). The treatment was performed under the use of alectinib. B: Seven months (m) after GKS, the treated lesion showed a complete response. C: The lesion showed regrowth 15 months after the first GKS. The systemic treatment was changed from alectinib to lorlatinib. D: Three months later (18 months after the first GKS), the lesion showed a partial response to systemic therapy change. E: Five months later (20 months after the first GKS), the lesion showed a complete response to systemic therapy change. F: The lesion showed a second regrowth 2 years (y) after the first GKS. G: MET-PET image confirms the recurrence. The maximum standardized uptake value (SUVmax) was 5.01, and the tumor/normal tissue standardized uptake value ratio (TNR) was 4.04. H: The second GKS was applied to the recurrent lesion (1.0 mL; 35.1 Gy, maximum dose 41.8 Gy). I: The lesion showed a decrease in volume (0.6 mL) at 7 months after the second GKS. J: The lesion showed a third regrowth (1.2 mL) at 10 months after the second GKS. K: MET-PET confirmed the recurrence (SUVmax = 4.32, TNR = 3.76). The systemic treatment was changed from lorlatinib to brigatinib. L: Two months after the change in systemic therapy (1 year after the second GKS), the lesion showed a slight increase (1.6 mL). The image revealed a new metastatic lesion on the pituitary gland (arrowhead; 0.6 mL). M: Both lesions did not improve 3 months after the change in systemic therapy (13 months after the second GKS; the recurrent lesion 1.6 mL and the pituitary lesion 0.6 mL). N: Four months after the change in systemic therapy (14 months after the second GKS), the two lesions increased further (the recurrent lesion 2.3 mL and the pituitary lesion 0.7 mL), causing trigeminal neuralgia.

FIG. 2.

Chronological MRI of the left pons lesion after the introduction of pemetrexed. The recurrent lesions showed significant regression in volume. The pituitary lesion showed a complete response to treatment in 3 months (arrowhead; 0.05 mL). Trigeminal neuralgia improved within 6 months. Both lesions were controlled over the next 17 months with pemetrexed maintenance therapy. CBDCA = carboplatin; PEM = pemetrexed.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

ALK-TKI is a TKI that acts on non–small cell lung cancer (NSCLC) with ALK mutations, such as EML4-ALK translocation. ALK-TKIs function by binding to the ATP pocket of the abnormal ALK protein, blocking the abnormal growth of tumor cells.² It is known that ALK-TKIs are likely to cross the blood–brain barrier easier than conventional chemotherapy, especially for second-generation ALK-TKIs and their successors.³ In fact, it has been reported that intracranial lesions respond well to ALK-TKIs^4,5 and that the objective intracranial response rates of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are 16%–71%, 73%, 86%–94%, 78%, and 82%, respectively.⁶ In the present case, GKS was selected as the initial treatment for multiple metastases because the extracranial lesions showed no signs of progression under alectinib. The treatment was effective for most lesions, except for the one in the pons. Both GKS and TKI switching showed transitional local tumor control but failed to maintain long-term tumor control. This can be explained by the acquisition of resistance toward TKI.⁷ One difficulty in molecularly targeted drug therapy is the acquisition of drug resistance caused by additional gene mutations during treatment. Drug resistance can be overcome by changing the ALK-TKI,⁸ and lorlatinib is the most sensitive drug for several ALK variants.^9–11 However, the sequential use of ALK-TKIs can cause multiple gene mutations, resulting in high resistance to all ALK-TKIs.^9,12

Pemetrexed is a multitargeted antifolate that inhibits three or more enzymes involved in folate metabolism and purine and pyrimidine synthesis.¹³ The pharmaceutical mechanism is different from that of ALK-TKI. It has been widely used to treat NSCLC. Although it is not clear whether pemetrexed crosses the blood–brain barrier, the efficacy of pemetrexed-based chemotherapy for brain metastases from NSCLC with a previous history of whole-brain radiation therapy has been reported to be 41.9%,¹⁴ and the response rate for brain metastases without previous central nervous system irradiation has been reported to be 40.0%–68.0%.^15–17 Although carboplatin was used along with pemetrexed in our case, the continued decrease in the lesion during pemetrexed maintenance therapy proves that pemetrexed contributed to the outcome. It has also been suggested that pemetrexed is effective in ALK-positive lung adenocarcinoma,^18–21 including in cases with acquired resistance to ALK-TKIs.^21–23 However, few studies have reported its effects on brain metastases,^24,25 and only one study has reported its effectiveness for brain metastases refractory to ALK-TKI.²⁶ However, all these reports used first-generation ALK-TKIs. Of note, in this case, the focal radiation via two GKS sessions to the tumor could have disrupted the microenvironment of the blood–brain barrier surrounding the lesion, facilitating the infiltration of pemetrexed. In general, the efficacy of chemotherapeutic agents is hampered by the blood–brain barrier; however, radiation exposure augments the permeability of the blood–brain barrier by breaking down its microenvironment,²⁷ thereby enhancing the pharmacological effects of pemetrexed against brain metastasis.

The neurosurgical team also carefully considered the option of surgical treatment. However, resecting the tumor was deemed impractical because of its anatomical location. Theoretically, in suitable patients with appropriate indications, repeat biopsy could assist in guiding systemic therapy, and although this approach is currently uncommon in clinical practice, tissue diagnosis may contribute to identifying targetable molecular lesions and their drug resistance profile.²⁸ Unfortunately, our case was not suitable for biopsy because of the invasiveness in terms of the tumor location.

One of the limitations of this study is that there are currently no means of confirming acquired resistance to ALK-TKIs. However, our meticulous MRI follow-up served as circumstantial evidence for the diagnosis and enabled us to establish the necessary treatment. Second, this is a report of a single case; consequently, the findings cannot be generalized. However, the insights gained from this case could contribute to assisting physicians who are dealing with challenging brain metastases, whose treatment necessitates a multimodal approach.

Lessons

This report provides the first evidence on the effectiveness of pemetrexed for ALK-positive adenocarcinoma brain metastasis refractory to ALK-TKIs across generations. A multimodal treatment approach for brain metastases required collaboration with the respiratory oncology team in this case. After considerable discussion with the oncologist, salvage pemetrexed treatment showed a dramatic response. Experience and knowledge in the field of neurosurgery or radiosurgery alone could not have led to this decision, and an oncologist would not have sufficient knowledge regarding the boundaries of surgery or extended indications for radiosurgery. Accordingly, collaboration between oncologists and neurosurgeons provided the necessary expertise to arrive at the best solution for the patient.

In conclusion, this report describes an informative case on the interdisciplinary management of a complicated instance of brain metastasis. In the current era of systemic therapy for brain metastasis, treatment options and their combinations must be managed on a case-by-case basis by physicians and surgeons in each field.

Author Contributions

Conception and design: Noda. Acquisition of data: Noda. Analysis and interpretation of data: Noda. Drafting the article: Noda. Critically revising the article: Kawashima, Inoue. Reviewed submitted version of manuscript: Noda, Akabane, Kawashima, Segawa, Tsunoda. Approved the final version of the manuscript on behalf of all authors: Noda. Study supervision: Akabane, Inoue.