Novel strategy of pemetrexed combined with localized therapy: breakthrough impact of long-term maintenance regimen on patient survival—a case report

Abstract

Background

The outcomes of untreated patients with lung adenocarcinoma with brain metastasis are poor; the usual survival period was around weeks to 3 months. While molecularly targeted agents and immune checkpoint inhibitors demonstrate survival benefits in selected populations, significant access barriers persist, particularly among socioeconomically disadvantaged groups. This report details exceptional survival duration in a KRAS p.Q61H/TP53 co-mutant case, exceeding conventional survival estimates and necessitating strategies to overcome system-level care constraints.

Case presentation

A male Asian patient aged 70–80 years presented with bilateral pulmonary lobe lesions (largest: 57 mm in left inferior lobe) and a 14-mm right frontal lobe metastasis. Histopathological and immunohistochemical analysis confirmed stage IV pulmonary adenocarcinoma, with genomic testing revealing co-mutations in KRAS exon 3 c.183A > C (p.Q61H) and TP53 exon 7 c.738G > A (p.R247K). The patient received pemetrexed–cisplatin chemotherapy, radiotherapy, and palliative surgery. Mild adverse events (drug eruption, elevated blood glucose, transient creatinine abnormalities) were resolved with symptomatic management. Patient experienced a confirmed partial response after follow-up for at least 5 years.

Conclusion

This case demonstrates unprecedented long-term survival in a patient with KRAS p.Q61H/TP53 c.G738A-mutant lung adenocarcinoma and brain metastasis treated with pemetrexed-based maintenance therapy combined with local interventions. The regimen showed efficacy, safety, and cost-effectiveness, offering a viable strategy for resource-limited settings.

Introduction

Lung cancer is still one of the most common malignant tumors, comes in at 12% of all malignant tumors, and with its 21% mortality rate, is the main cause of cancer mortality [1]. Advanced non-small cell lung cancer (NSCLC) exhibits particularly grim outcomes, with 5-year relative survival rates rarely exceeding 10% [2–4], a statistic further exacerbated in socioeconomically disadvantaged regions. For NSCLC patients, around 10% developed brain metastases at the time of diagnosis [5], and 40% will develop brain metastases during the course of their disease [6], which shows greatly reduced survival as compared to metastases at other sites.

Molecular subtyping has revolutionized precision oncology, enabling targeted therapies against actionable alterations (for example, EGFR, ALK, ROS1) and immune checkpoint inhibitors [7–10]. Nevertheless, a critical knowledge gap persists: patients lacking these targets, particularly those with KRAS non-G12C or TP53 co-mutations, remain reliant on chemotherapy as first-line treatment [11].

Pemetrexed (PEM), a multi-targeted antifolate agent, suppresses tumor growth by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), thereby disrupting DNA synthesis and repair [12]. Phase III trials (PARAMOUNT, JMEN) established PEM maintenance therapy as a standard-of-care, demonstrating significant improvements in overall survival (OS) and progression-free survival (PFS) [13–16]. Real-world research shows that PEM in combination with platinum chemotherapy is superior for patients with brain metastases in comparison with alternative chemotherapy protocols, yet long-term efficacy beyond 2 years remains undocumented [17].

Three key controversies persist, hindering clinical progress: robust evidence is currently lacking to guide the optimal integration of local interventions (radiotherapy/surgery) with systemic PEM therapy; the tolerance and cost-effectiveness of extended PEM maintenance therapy (> 3 years) require rigorous evaluation; and KRAS/TP53 co-mutant subsets demonstrate limited benefit from conventional chemotherapy. This case report presents an elderly patient with KRAS p.Q61H/TP53 c.G738A-mutant lung adenocarcinoma and synchronous brain metastasis who achieved 5-year survival—an exceptional outcome for this high-risk cohort—following extended PEM maintenance therapy integrated with localized interventions. This study seeks to: first, validate the feasibility and low-toxicity profile of extended PEM therapy; second, assess synergistic efficacy of locoregional-systemic combinations in target-negative NSCLC; third, establish a cost-efficient paradigm for resource-constrained settings.

Case presentation

In this case report, we present a male Asian patient aged 70–80 years. He had a long history of heavy smoking, with around 280 pack-years for 50 years, who was admitted to the hospital on 2019-Q4, with a chief complaint of recurrent cough and sputum production lasting 5 months. During the course of the disease, the patient exhibited no evidence of hemoptysis, cachexia, neurological deficits (dizziness, headache, limb mobility impairment), or gastrointestinal symptoms (nausea, vomiting). On physical examination, lung auscultation revealed decreased breath sounds in the left lower lobe. Immediately after the blood draw, the blood tumor marker indicators were tested, the serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and carbohydrate antigen 242 (CA242) were elevated. Chest contrast computed tomography (CT) examination was performed, and a mass in the lower lobe of the left lung was confirmed, the tumor was 45 mm × 40 mm × 57 mm in size. In addition, multiple scattered cotton ball-like nodules of varying sizes were observed in both lungs, with lymphadenopathy in the bilateral subclavian regions and mediastinum by chest CT (Fig. 1A). The cranial MRI showed a round-like nodular lesion (14 mm × 10 mm) observed in the subcortical region of the right frontal lobe, accompanied by patchy areas of cerebral edema in the surrounding tissue (Fig. 2A). We performed a diagnostic needle biopsy of the pulmonary mass; the histopathologic examination (HE) analysis of the biopsy showed adenocarcinoma cells (Fig. 3). Tumor staging was classified as cT3N2M1 (stage IV), lung cancer staging relied on the TNM system designed by the American Joint Committee on Cancer (AJCC) eighth edition. Genetic testing is necessary for patients diagnosed with advanced lung adenocarcinoma who are not candidates for surgery. The results of our hospital's 24-gene panel testing for lung cancer indicated KRAS exon3 p.Q61H and TP53 exon7 c. G738A mutation in patient’s tumor DNA samples.

Fig. 1.

Comparison of chest computed tomography (CT) scans for patient’s baseline images and after chemotherapy. A The CT scan revealed a mass in the left lower lobe of the lung measuring approximately 45 mm × 40 mm × 57 mm, with heterogeneous density on non-contrast imaging and heterogeneous enhancement after contrast administration. B A follow-up CT scan after chemotherapy showed that the left lower lobe mass had decreased in size to 16 mm × 13 mm, with multiple speculations at the lesion margins and adhesion/traction of the adjacent pleura. C At 52 months of treatment, a repeat CT scan demonstrated enlargement of the left lower lobe mass to 24 mm × 18 mm, with adhesion to nearby pulmonary blood vessels and bronchi. D At 61 months of treatment, a follow-up CT scan showed no signs of tumor progression

Fig. 2.

Comparison of brain magnetic resonance imaging (MRI) and CT scans for patient’s baseline images and after treatment. A The MRI demonstrated a round-like nodular lesion in the subcortical region of the right frontal lobe, measuring approximately 14 mm × 10 mm, with relatively well-defined borders. On non-contrast imaging, it exhibited slightly prolonged T1 and T2 signals, with marked enhancement after contrast administration. B Follow-up MRI after radiotherapy revealed a reduction in the right frontal lobe lesion to 10 mm × 7 mm. C Subsequent CT imaging showed enlargement of a right frontal lobe nodule (20 mm × 21 mm) with increased surrounding edema. D Further CT scans indicated progressive growth of the right frontal lobe lesion (39 mm × 32 mm). E Postoperative MRI identified postoperative changes in the right frontal region, including residual cavity formation and surrounding cerebral edema. F At 61 months of treatment, follow-up CT showed no signs of intracranial tumor recurrence or metastasis

Fig. 3.

Pathological findings of the biopsy specimen

The patient subsequently received six cycles of palliative dual-agent chemotherapy (every 21 days). The chemotherapy regimen used PEM combined with cisplatin (PEM: 800 mg D1; cisplatin: 30 mg D1, 40 mg D2–3); the efficacy of partial response (PR) evaluation (the pulmonary tumor lesion has decreased in size to 16 mm × 13 mm, (Fig. 1B). Subsequently, the patient began long-term regular PEM (PEM: 800 mg D1) single-agent maintenance chemotherapy (every 21–28 days). The patient experienced grade 1 bone marrow suppression and grade 2 gastrointestinal reaction, the symptoms were relieved after drug treatment.

After 3 months of chemotherapy, the patient’s blood glucose increased to 7.31 mmol/L from the baseline value of 6.53 mmol/L, a difference of 0.78 mmol/L (CTCAE v5.0: Grade 1). Following this change in diet, blood glucose measurements decreased to the normal range. However, at the 58-month treatment mark, the patient exhibited elevated blood glucose levels (fasting: 10 mmol/L, 2-h postprandial: 18 mmol/L, CTCAE v5.0: Grade 3). Upon recommendation by the endocrinology team, dual oral hypoglycemic agents (acarbose + glimepiride) were initiated. Subsequent glycemic monitoring demonstrated restoration of blood glucose parameters to physiologic ranges.

After 6 months of chemotherapy, the patient developed scattered erythematous rashes on the scalp, anterior chest, and interscapular region, with localized presence of pustules (CTCAE v5.0: Grade 2), the rash resolved gradually with topical therapy. After 1 year of chemotherapy, patient’s serum creatinine increased to 111 μmol/L from the baseline value of 97 μmol/L, a difference of 14 μmol/L (CTCAE v5.0: Grade 1); following intensive hydration and diuretic therapy, the serum creatinine level returned to normal.

After 40 months of chemotherapy, due to recurrent rashes, the patient requested adjustment of the PEM regimen to a tri-monthly schedule until now. During the treatment course, at the 52-month mark, the pulmonary tumor lesion increased in size to 24 mm × 18 mm (Fig. 1C). Through structured multidisciplinary case review and therapeutic optimization, the original therapeutic regimen was maintained. Subsequent imaging re-evaluation at the 54-month interval demonstrated stabilization of the lesion with no further progression (Fig. 1D).

The patient received coplanar stereotactic brain radiotherapy for two metastatic lesions in the right frontal lobe and right occipital lobe 1 month following the lung cancer diagnosis. The prescribed doses were 39 Gy in 3 fractions to the gross tumor volume (GTV) and 30 Gy in 3 fractions to the planning target volume (PTV). Imaging surveillance at the two-cycle interval demonstrated stable intracranial lesions, while the four-cycle follow-up revealed regression of the intracranial tumor lesion to 10 mm × 7 mm (Fig. 2B). At the 15-month mark of treatment, progressive enlargement of the intracranial tumor lesion was observed (20 mm × 21 mm, Fig. 2C), regular reviews were scheduled. Subsequent imaging surveillance at the 21-month interval revealed continued tumor progression (39 mm × 32 mm, Fig. 2D), prompting surgical resection of the lesion as advised by the neurosurgery team in Beijing, the postoperative pathological findings indicated extensive necrotic areas with adjacent reactive gliosis, a few dispersed atypical cells exhibiting nuclear enlargement and pleomorphism were identified, suggesting the potential presence of neoplastic cells; however, radiation necrosis could also induce cellular atypia. Regular follow-up evaluations since then have shown no evidence of residual or recurrent intracranial tumor (Fig. 2E, F). The full treatment pathway appears in Fig. 4. And diagnostic/therapeutic measures followed written consent procedures.

Fig. 4.

Schematic diagram of patient treatment timeline. The patient was diagnosed with lung adenocarcinoma via transbronchial lung biopsy. Genetic testing revealed mutations in KRAS (exon 3: p.Q61H) and TP53 (exon 7: c.G738A). Subsequently, the patient underwent six cycles of chemotherapy, radiotherapy, surgical intervention, and long-term regular maintenance chemotherapy. The diagnosis was designated as Month 0

Serum tumor markers were monitored continuously over the course of treatment (CEA, CA199, and CA242). In our patient, 3 weeks after treatment initiation, all tumor markers demonstrated a downward trend. By the fifth treatment month, the aforementioned tumor markers had normalized to reference ranges (Fig. 5).

Fig. 5.

Serial combined monitoring of serum tumor markers, CEA, CA242 and CA199. The diagnosis date was designated as Month 0

To date, the patient has been followed up for over 60 months, with clinical physical examinations, tumor marker assays, and CT/MRI surveillance scans performed at 2–4 cycle intervals. No evidence of tumor progression has been observed in current evaluation.

Discussion

This report details a patient aged 70–80 years with chronic heavy smoking history and stage IV lung adenocarcinoma harboring KRAS Q61H and TP53 G738A mutations. Following six cycles of first-line PEM/cisplatin chemotherapy achieving partial response, maintenance pemetrexed monotherapy was initiated. Due to recurrent rashes during treatment, the PEM regimen was adjusted from every 3–4 weeks to every 3 months. Despite exhibiting radiographic progression of pulmonary lesions (mean diameter increase: 2.7 mm/month) at 52 months of treatment, sustained maintenance PEM therapy achieved disease control (RECIST v1.1 criteria) following 7-month treatment continuation, with subsequent serial CT surveillance demonstrating stabilization. This case uniquely achieved sustained remission beyond 5 years in advanced adenocarcinoma by modifying traditional 3-week chemotherapy cycles, demonstrating the potential of tailored chronic disease management in selected populations.

This case presents a unique therapeutic trajectory in managing advanced driver mutation-negative lung adenocarcinoma, characterized by the absence of actionable genetic alterations and constraints on standard immunotherapies. While current guidelines recommend bevacizumab chemotherapy or immune checkpoint inhibitor (ICI)-based regimens as first-line options for such patients, this case diverged significantly: first, omission of pembrolizumab due to financial barriers, despite its status as a Category 1 recommendation for PD-L1—high (≥ 50%) or even PD-L1—low (< 50%) non-squamous NSCLC in the 2019 NCCN guidelines [18]; second, avoidance of bevacizumab owing to concerns about intracranial hemorrhage risk in metastatic brain lesions; and third, adoption of cisplatin–pemetrexed chemotherapy combined with localized radiotherapy as the primary strategy. This tripartite divergence, including economic, safety-driven, and therapeutic, distinguishes our case from conventional approaches and underscores the complex decision-making in resource-limited settings.

Studies demonstrate that in patients with advanced driver gene-negative lung adenocarcinoma, the pemetrexed–cisplatin combination achieves an objective response rate (ORR) of 30.6%, though with a relatively short median survival time (12.6 months) [19]. Following 4–6 cycles of first-line platinum-based chemotherapy with pemetrexed, patients without disease progression and preserved performance status may transition to pemetrexed monotherapy maintenance until disease progression or intolerable toxicity. This regimen extends median OS to 15.5 months [20, 21]. In elderly populations, this approach yields a disease control rate (DCR) of 64% and a median PFS of 3.3 months [22]. The mechanism underlying prolonged maintenance therapy may relate to pemetrexed’s interference with tumor folate metabolism, suppression of DNA replication and cellular proliferation, and potential delay in the emergence of drug-resistant clones [12].

The defining feature of this case is the presentation of driver gene-negative advanced lung adenocarcinoma accompanied by significantly elevated levels of multiple serum tumor markers (CEA, CA199, CA242, NSE) at diagnosis. Crucially, these markers demonstrated highly synchronized, progressive decline culminating in complete normalization during systemic therapy. This multi-marker co-elevation and coordinated dynamic pattern holds particular significance. While isolated CEA elevation is relatively common in lung adenocarcinoma, its diagnostic sensitivity and specificity are limited [23]. The observed tightly correlated trajectory of CEA, CA199, and CA242 in this patient, aligning precisely with the radiologically confirmed PR, suggests this specific biomarker combination may constitute a more sensitive and reliable serum biomarker profile for assessing treatment response in such patients.

Regarding safety profiles, prior clinical studies reported grade ≥ 3 hematologic toxicities (30%) and gastrointestinal reactions (21.7%), with non-hematologic toxicities including fatigue (67%), hepatic dysfunction (22%), and mucositis (18%) being frequently observed. Additional documented adverse events encompassed elevated serum creatinine and pulmonary fibrosis. In this case, the patient developed grade ≥ 3 hyperglycemia during treatment, which was successfully managed with dietary modifications and pharmacological intervention. Although the optimal duration of pemetrexed maintenance therapy remains undefined, this case demonstrates two critical clinical insights: firs, the patient exhibited a notable clinical response to pemetrexed alongside a manageable toxicity profile, suggesting that extended pemetrexed maintenance therapy (beyond 5 years) may confer survival benefits in selected populations. Second, Longitudinal monitoring revealed sustained PFS and OS, aligning with emerging evidence from the Mark et al. analysis [24].

Intracranial lesions in this patient demonstrated radiological stability for 15 months following helical tomotherapy (TOMO). Subsequent contrast-enhanced CT surveillance revealed progressive enlargement of both the tumor mass (volume increase: 100%) and peri-lesional edema. Initial enlargement was clinically interpreted as radiation-induced pseudoprogression, warranting close observation with 2-month intervals neuroimaging follow-up. Persistent volumetric progression (> 95% increase over 3 consecutive scans) ultimately prompted neurosurgical intervention. Although the postoperative pathological report only described microscopic findings (atypical cells with nuclear enlargement and pleomorphism), the absence of tumor recurrence on imaging follow-up for more than 60 months post-surgery supported the clinical inference that the resected lesion represented radiation necrosis without viable tumor cells, further confirming the diagnosis of pseudoprogression following radiotherapy. For patients receiving intracranial radiotherapy, research has shown that radiation necrosis typically occurs 3 months to several years post-radiation, with incidence rates correlating with factors such as radiation dose and fractionation [25]. Radiologically, radiation necrosis often manifests as brain swelling within the irradiated field, which can be mistaken for tumor progression. Differentiation between radiation necrosis and pseudoprogression can be aided by contrast-enhanced MRI or PET/MRI. For cases with indeterminate imaging findings, surgical resection or stereotactic biopsy is warranted. Subsequent follow-up protocols will implement an intensified schedule of contrast-enhanced brain MRI surveillance with serial dynamic contrast-enhanced (DCE) sequences performed at 12-week intervals. This enhanced imaging regimen is designed to facilitate early discrimination between tumor recurrence and radiation-induced pseudoprogression through multiparametric analysis. Our case underscores the ongoing difficulty in distinguishing tumor pseudoprogression from actual recurrence, despite utilizing all currently available diagnostic modalities. Structured follow-up with enhanced surveillance modalities is essential for early recurrence detection in these cases.

Brain metastases (encompassing parenchymal and leptomeningeal involvement) constitute a major determinant of poor survival outcomes in advanced lung cancer populations. Current evidence remains inconclusive regarding pemetrexed's blood–brain barrier (BBB) penetration capacity, with no pharmacokinetic studies demonstrating conclusive CNS penetration. Notably, pooled analysis of Scagliotti and Hanna et al. studies demonstrated a prophylactic effect against symptomatic CNS progression in non-squamous NSCLC (3.0% versus 7.3%) with maintenance pemetrexed regimens [19, 26]. Intracranial lesion responsiveness to pemetrexed-based regimens appears superior to systemic responses in asymptomatic NSCLC brain metastases (42% versus 35% confirmed ORR) [27, 28]. Mechanistic insight from our case, the durable PR observed following chemoradiation synergy likely reflects radiation-enhanced BBB permeability, potentially enhancing pemetrexed penetration.

The genetic testing in this case revealed KRAS exon3: p.Q61H and TP53 exon7: c.G738A mutations. The KRAS Q61H mutation represents a common activating mutation in KRAS, for which no direct targeted therapies are currently available. TP53 mutations are present in approximately 30–50% of lung adenocarcinoma patients [29], frequently co-occurring with driver mutations such as EGFR and KRAS. Current evidence indicates that concurrent TP53 and KRAS mutations exacerbate tumor heterogeneity, thereby elevating the risk of distant metastases (for example, brain, bone, and adrenal) and fostering therapeutic resistance [30–33], and have demonstrated a negative correlation with OS and PFS [32, 34]. Our findings exhibit a notable divergence from the established conclusions in the literature. We hypothesize that distinct KRAS/TP53 mutational subtypes may reprogram the tumor microenvironment, potentially counteracting the detrimental effects typically associated with these mutations, particularly the oncogenic impact of KRAS activation. Further validation in larger cohorts with integrated genomic/clinical data is warranted to identify predictive biomarkers for risk stratification. Notably, accumulating preclinical and clinical data indicates that concurrent KRAS/TP53 mutations may potentiate therapeutic responses to ICIs [35]. Our team faces the following dilemma: If disease progression occurs subsequently, we first recommend repeating comprehensive genetic testing. Should the results still indicate KRAS and TP53 co-mutations, although domestically produced immune checkpoint inhibitors (ICIs) have undergone widespread price reductions and are now covered by national health insurance (thereby alleviating financial burdens), the patient's age exceeding 75 years raises uncertainty regarding potential clinical benefits from ICI therapy.

Despite the encouraging clinical outcome, several limitations warrant consideration. As a single-case report, the findings inherently lack the statistical robustness derived from larger clinical cohorts, potentially influencing the generalizability of the efficacy observations. Furthermore, the absence of comprehensive molecular profiling (genomic or epigenomic) precludes definitive mechanistic insights into the sustained response to pemetrexed and the extended survival period. Validating these observations necessitates future investigation in larger, multicenter cohort studies. Ultimately, refining therapeutic strategies for similar patients will require comprehensive molecular characterization integrating genomic, transcriptomic, and radiomic analyses to inform precise, individualized treatment approaches.

Conclusion

Pemetrexed maintenance combined with localized treatments achieves sustained disease control in driver mutation-negative advanced lung adenocarcinoma with brain metastases. Balancing efficacy and tolerability, this combination allows for prolonged therapy administration and enhanced clinical benefit. This case proposes a novel management paradigm for advanced adenocarcinoma, moving beyond the extension of conventional approaches. It suggests that, with tumor histology-directed agents administered via adaptive dosing regimens anchored in tumor biology, this malignancy may be potentially re-conceptualized as a chronic, dynamically controllable condition. This observation calls for a paradigm shift from fixed-cycle chemotherapy toward chronicity models guided by therapeutic response.

Abbreviations

AJCC

American Joint Committee on Cancer

BBB

Blood–brain barrier

CA199

Carbohydrate antigen 199

CA242

Carbohydrate antigen 242

CEA

Carcinoembryonic antigen

CT

Computed tomography

DCE

Dynamic contrast-enhanced

DCR

Disease control rate

DHFR

Dihydrofolate reductase

GARFT

Glycinamide ribonucleotide formyltransferase

GTV

Gross tumor volume

HE

Histopathologic examination

ICI

Immune checkpoint inhibitor

NSCLC

Non-small cell lung cancer

ORR

Objective response rate

OS

Overall survival

PEM

Pemetrexed

PFS

Progression-free survival

PR

Partial response

PTV

Planning target volume

TOMO

Tomotherapy

TS

Thymidylate synthase

Author contributions

L.L. and D.L. wrote the main manuscript text. X.M., C.G., Q.H., and Y.D. prepared Figs. 1, 2, 3, 4 and 5. All authors reviewed and approved the final manuscript.

Funding

The work was financially supported by Beijing Science and Technology Innovation Medical Development Foundation (Grant No. KC2023-JX-0288-PM94).

Data availability

The data generated or analyzed during this study are included in this article, or if absent are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declared no conflict of interest financial or otherwise.