Pemetrexed long-term maintenance therapy for advanced severe lung cancer with long-term progression-free survival: a case report

Abstract

It is relatively rare to achieve a median progression-free survival (PFS) of 40 months with pemetrexed monotherapy maintenance, especially in patients with advanced and severe lung cancer. Here, we reported a case of advanced severe lung adenocarcinoma treated with pemetrexed monotherapy maintenance achieving long survival with a median PFS of 46 months. A 52-year-old female diagnosed with stage IV lung adenocarcinoma was tested for no targeted drug benefit in the driver gene. The patient was financially disadvantaged and could not afford and refused immune checkpoint inhibitor drugs but was in the favor of platinum-based double-drug chemotherapy. After six cycles of effective administration of cisplatin in combination with pemetrexed, pemetrexed monotherapy was given for long-term maintenance treatment to date, with a median PFS of 46 months, with a treatment effect close to complete response and tolerable side effects.

Introduction

At present, immune checkpoint inhibitors (ICIs) alone or in combination have become the standard treatment for advanced non-small cell lung cancer (NSCLC) without driver genes [1–3]. The use of ICIs has been constrained, nonetheless, by their steep cost and contraindications. Platinum-based chemotherapy remains a key treatment option for economically disadvantaged populations. For the first-line treatment of patients with advanced NSCLC, combination chemotherapy with pemetrexed or two other platinum-containing agents is recommended. For patients with advanced lung adenocarcinoma that have not progressed after first-line chemotherapy, continuous maintenance chemotherapy can be considered if the general condition is good [4].

Pemetrexed maintenance therapy is well tolerated in patients with advanced NSCLC and can improve progression-free survival (PFS) and overall survival [5-7]. However, pemetrexed monotherapy maintenance with a median PFS of 40 months is relatively uncommon, especially in patients with advanced and severe lung cancer. Here, we reported a case of long-term survival using pemetrexed monotherapy as maintenance therapy for advanced, severe, driver-negative lung adenocarcinoma with a median PFS of nearly 46 months.

Case report

A 52-year-old Chinese female with no smoking history was admitted to the hospital in September 2018, due to chest tightness, shortness of breath and worsening cough. Physical examination: semi-sitting position with 30 breaths/min. A lymph node of 1 × 0.5 cm with a firm texture and poor mobility was palpable on the right side of the neck. The breath sounds of both lungs were low, and no obvious dry or wet rales and pleural friction rubs were heard. Heart rate: 100 beats/min, regular rhythm, distant heart sounds, and no pathological murmurs were heard in each valve auscultation area. The lower extremities showed no edema. Chest computed tomography (CT): an irregular nodule with a size of about 24.5 × 26.8 mm in the right middle lung, a large number of liquid density shadows in the pericardial cavity, multiple enlarged lymph node shadows in the right hilum and mediastinum and fluid in the left bilateral pleural cavity density shadow (Fig. 1a). Bedside echocardiography: apical four-chamber view scan, pericardial wall separation, lateral pericardial cavity systolic/diastolic separation approximately 4.0 cm/3.5 cm, apical pericardial cavity systolic/diastolic separation around 5.0 cm/ 4.6 cm.

Fig. 1.

Computed tomography (CT) images of the patient’s primary pulmonary tumor lesion (a) before chemotherapy (September 2018), (b) resistance after six cycles of chemotherapy (April 2019), (c) maintenance pemetrexed alone for 46 cycles (June 2022). (d) PET-CT revealed a right middle lobe nodule with no abnormal radioactive uptake. The red arrows indicate the pulmonary lesions.

After admission, pericardial effusion puncture and drainage were performed, and the patient could lie supine. The drainage fluid was sent to pathology and adenocarcinoma cells were seen. CT-guided percutaneous lung biopsy was conducted and revealed pathological lung adenocarcinoma (Fig. 2 ). Gene testing for anaplasticlymphomakinase (ALK) missense mutation was sent and was negative for epidermal growth factor receptor (EGFR), c-ros oncogene 1 (ROS1), Kirsten Rat Sarcoma Viral Oncogene Homolog, mesenchymal-epithelial transition factor, v-raf murine sarcoma viral oncogene homolog B1, RET proto-oncogene, human epidermal growth factor receptor 2 (HER2), and there was no benefit of targeted drugs in the tested genes. The enhanced MRI scan of the brain showed a punctate mildly enhancement signal in the right frontal cortex, approximately 3 mm in diameter, with no clear signs of abnormal enhancement in the rest of the brain or meninges. No metastases were found in the chest, abdomen and pelvis. Based on these data, a diagnosis of lung adenocarcinoma stage IV (cT1cN3M1b) lung cancer with multiple lymph node metastases, pericardial metastases and craniocerebral metastases was considered. The performance status was 3 points at admission and 2 points after drainage of pericardial effusion.

Fig. 2.

Pathological diagnosis and Immunohistochemical analysis. (a) Percutaneous lung biopsy indicating poorly-differentiated adenocarcinoma, hematoxylin, and eosin, ×40. (b) Immunohistochemical analysis, ×40. (c) Pericardial effusion pathology indicating adenocarcinoma, hematoxylin, and eosin, ×40.

ICI medications might be added to the conventional first-line treatment for driver gene-negative NSCLC, but they are expensive, the patient’s financial situation is precarious, and immunological drug therapy is declined in favor of platinum-based double-drug chemotherapy. The patient initially received pemetrexed in combination with cisplatin as first-line chemotherapy (pemetrexed 500 mg/m² + cisplatin 75 mg/m² on day 1, every 21 days). After six cycles of chemotherapy, treatment response was assessed with reference to response evaluation criteria in solid tumors (RECIST) version 1.1, and follow-up CT scans showed primary lesions (24.5 × 26. 8 mm to 12 × 13 mm) with partial remission (PR) response (Fig. 1b). Thereafter, pemetrexed single-agent maintenance therapy was started for 46 cycles to date. During the PET-CT examination on 18 January 2022, irregular nodules were observed in the right middle lobe, measuring approximately 1.5 × 0.8 cm; PET showed no abnormal radioactive uptake. The lymph nodes with enhanced metabolic activity in the mediastinum were similar in size to the previous ones, and no significant high radiation uptake lesions were found in the cervical and axillary lymph nodes. Recently, in June 2022, the chest enhanced CT showed a smaller primary lesion than before, measuring approximately 12 × 5 mm and the brain MRI showed no metastases. The patient’s pericardial effusion disappeared, and no enlarged lymph nodes were palpated in the neck. The curative effect was PR.

During the treatment period, the patient was well tolerated with only first-degree myelosuppression and mild gastrointestinal reactions, and the symptoms improved with symptomatic treatment without serious adverse reactions. As of June 2022, the patient was in good general condition with a performance status score of 0 and had achieved long-term PFS.

Discussion

Pemetrexed, a third-generation multi-targeted antifolate drug, prevents DNA and RNA biosynthesis by inhibiting the activity of numerous enzymes involved in the folate-dependent metabolic pathway. As a result, tumor cell proliferation is inhibited in the S phase, allowing for the control of tumor cell growth [8–10]. Before the era of immunotherapy, first-line platinum-based chemotherapy and maintenance therapy with pemetrexed were the standard of care for patients with advanced non-squamous NSCLC (NS-NSCLC) [11]. In the era of immunotherapy, although most patients are now receiving chemotherapy plus immunotherapy in the first line, some are not. Many regions of the world lack easy access to checkpoint inhibitors, some people have medical conditions that make their usage contraindicated, and some have negligible or no benefits [12]. For these patients, first-line chemotherapy remains the option.

For advanced NS-NSCLC patients without progression after induction with pemetrexed-cisplatin, single-agent maintenance chemotherapy with pemetrexed is well tolerated and effective, and can significantly prolong PFS. The mean number of maintenance cycles with pemetrexed has been reported to be 7.9 (range 1–44) [13], but only very few cases of the advanced severe disease reported a long PFS with pemetrexed single-agent maintenance. In our study, the patient achieved a PFS of 46 months, with a treatment effect close to complete response and tolerable side effects.

In this case, stage IV lung adenocarcinoma was diagnosed by histopathological immunohistochemistry on percutaneous lung biopsy, and next-generation sequencing showed negativity for EGFR, ALK, ROS1, and other driver genes. The patient had a difficult economic condition to afford and then refuses to use ICI drugs. Long-term maintenance therapy with pemetrexed achieved a long PFS after six cycles of effective cisplatin in combination with pemetrexed. Therefore, pemetrexed maintenance therapy was well tolerated for advanced NS-NSCLC patients in good status who have not progressed during pemetrexed-cisplatin induction therapy.

Acknowledgements

We thank Dr Li kang for his assistance in the English revision of this article.

Conflicts of interest

There are no conflicts of interest.