Neoadjuvant Capecitabine Plus Temozolomide in Atypical Lung NETs

Abstract

Neoadjuvant and adjuvant treatment in lung neuroendocrine tumors (NETs) is a field that has not been explored in-depth, with little information on the impact on disease-free survival. This case study highlights the effectiveness of neoadjuvant treatment with capecitabine plus temozolomide (CAPTEM) in a woman with well-differentiated atypical carcinoid. The patient was asymptomatic at diagnosis and was referred to the outpatient NET clinic at Sotiria Hospital in Athens, following an incidental finding on a chest x-ray. ¹⁸F-fluorodeoxyglucose (FDG) PET/CT and ⁶⁸Ga-Dotatoc PET/CT revealed another mass in the pancreas, with avidity in both imaging studies. The patient underwent treatment for 6 months with CAPTEM with a response in the lung NET and mediastinal lymph nodes. However, the mass in the pancreas slightly increased and was removed with a central pancreatectomy. The patient continued treatment with CAPTEM for 6 more months. There was further response according to RECIST 1.1 criteria (partial response in the mediastinal lymph nodes and a 21% regression in the primary tumor size). Pathology report after lobectomy with lymph node dissection showed a pathologic complete response in the mediastinal lymph nodes. Twenty-four months after surgery, the patient remains disease-free and has a good quality of life. Although large clinical trials are needed, this case study underlines the value of preoperative chemotherapy in atypical carcinoids.

Background

Lung neuroendocrine tumors (NETs) are rare malignancies, accounting for 1% to 2% of all lung cancers.¹ They are sporadic tumors with an unclear association with smoking, and a minority are related to MEN1 pathogenic variants.² There is a paucity of evidence for managing different clinical scenarios in patients diagnosed with these tumors, including the indications for adjuvant and neoadjuvant treatment. Surgery is the recommended approach in the local/locally advanced stage without generally accepted criteria defining what constitutes a resectable disease. In this case report, a woman with MEN1 pathogenic variant, an atypical lung NET in the lower lobe of her left lung with confirmed metastases to mediastinal lymph nodes with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy, and a synchronous primary grade 2 NET in the body of the pancreas underwent treatment with capecitabine plus temozolomide (CAPTEM). After 6 months of treatment, the pancreatic NET (panNET) was removed with a central pancreatectomy. The patient continued treatment with CAPTEM for another 6 months and underwent lobectomy with lymph node dissection (including stations 12, 11, 10, 9, 8, and 7); there was complete pathologic remission in the mediastinal lymph nodes, with a primary tumor shrinkage of approximately 21%.

Case Presentation

A 62-year-old White woman with a known history of hypercalcemia treated with parathyroidectomy 8 years ago presented with fever and productive cough to her general practitioner (GP). She was a never-smoker and had a history of dyslipidemia on treatment with a statin. Her GP ordered a chest x-ray, revealing a mass in the left lower lobe. The GP prescribed antibiotics and referred the patient to the outpatient NET clinic of Sotiria General Hospital of Thoracic Diseases in Athens, Greece, to manage the lung mass. There was no family history of cancer; her older son received a diagnosis of hypercalcemia at age 30 years. At the outpatient clinic, the patient appeared in good general health; symptoms from the recent infection had subsided, and she was anxious about the mass in the chest x-ray. There was no stridor on auscultation, and respiratory sounds were normal in both lungs. She reported no changes in her ability to manage everyday tasks or weight loss over the past year. She had no breathlessness, pain, or other symptoms over the previous year besides coughing and fever in the first days of the infection, which had resolved.

Imaging and Laboratory Results

• A chest CT scan showed a mass of 3.8 x 3.2 cm in
  the left lower lobe and enlarged subcarinal lymph nodes (2.4 x 1.9 cm). Bronchoscopic biopsy of the mass revealed atypical bronchial NET.
• Ki-67 of 20%
• Thyroid transcription factor-1 negative
• Orthopedia homeobox protein (OTP) negative
  Somatostatin receptor subtype 2 + 3 (Figure 1)
• EBUS-TBNA confirmed metastasis of the NET to
  lymph nodes in station 7.

FIGURE 1. SSTR2 staining of surgical biopsy tissue 40x[50].

FIGURE 2. ¹⁸FDG PET-CT showing avidity of the primary tumor in the left lower lobe (standard uptake value 24.1).

FIGURE 3. ¹⁸FDG PET-CT showing avidity in mediastinal lymph nodes (station 7; standard uptake value 25.1).

An ¹⁸F-fluorodeoxyglucose (FDG) PET/CT scan confirmed the findings and, in addition, showed an FDG-avid mass in the body of the pancreas, 1.2x1 cm (Figures 2 and 3). The cytology from the endoscopic ultrasound–guided fine-needle aspiration biopsy of the pancreatic mass showed a NET. However, because of inadequate material, there was no further characterization of the tumor’s primary origin and grade. A ⁶⁸Ga-PET/CT scan revealed avidity in the mass of the left lower lobe, subcarinal lymph nodes, and pancreatic mass (Figures 4 and 5).

FIGURE 4. Dotatoc PET-CT showing avidity of the primary tumor in the left lower lobe (standard uptake value 15.9).

FIGURE 5. Dotatoc PET-CT showing avidity in mediastinal lymph nodes (station 7; standard uptake value 8.8).

Treatment

The patient was referred to a geneticist due to a family history of hypercalcemia and NET diagnosis. The genetic assessment revealed 4 members in the genealogic tree with early-onset hyperparathyroidism, and genetic testing in the patient confirmed a pathologic variant in MEN1 gene c.959C>G (p.Pro320Arg) in exon 7 (Figure 6). Consequently, members of her family tree were informed and screened for the same variant, although some refused to undergo the test. Her older son, was also a carrier of the pathogenic variant, and further investigations revealed no signs of MEN1 syndrome manifestations. Even though surgical treatment was an option for both lung and pancreatic lesions at this point, a stepwise approach was considered more appropriate. The investigators decided to start treatment with CAPTEM and observe the responsiveness of the disease and its biological behavior. If there was disease progression following 3 to 6 months of treatment with CAPTEM, the risk-benefit ratio of surgical resection of both the lung and the pancreatic lesions would be of dubious value for the patient based on data extrapolated from other neoplasms such as oligometastatic non–small cell lung cancer (NSCLC) and colon cancer liver metastases.^3,4

FIGURE 6. Patients’ genealogic tree. The patient’s older son was diagnosed with hypercalcemia at 30 years old. Both he and the patient are carriers of the pathologic variant in MEN1 gene c.959CG (p.Pro320Arg) in exon 7.

On the contrary, disease control or tumor shrinkage with CAPTEM would render surgical resection a more favorable option with possibly better chances for prolonged disease-free survival. The patient tolerated CAPTEM well, with main complaints of nausea and exhaustion on the days the 2 drugs were taken together. There was also grade 1 leukopenia and anemia that did not require medical intervention. Following 6 months of treatment, there was a minor volume reduction of the mass in the left lower lobe from 3.8 x 3.2 cm to 3.7 x 3.0 cm and subcarinal lymph node from 2.4 x 1.9 cm to 2.2 x 1.8 cm but an increase in the size of the pancreatic mass from 1.2 x 1 cm to 1.4 x 1 cm. Treatment with CAPTEM was discontinued for 1 month, and the mass was excised with a central pancreatectomy. Pathology reported a grade 2 panNET, islet cell antibody positive, 2 to 3 mitoses per mm2, Ki-67 of 3%, without lymph node metastases. The patient recovered without complications and continued treatment with CAPTEM for 6 weeks after the operation. After another 6 months of treatment with CAPTEM, a further reduction was observed in the mass size in left lower lobe from 3.7 x 3.0 cm to 3.1 x 3.0 cm and in the subcarinal lymph node from 2.2 x 1.8 cm to 2.0 x 1.6 cm. Because of the response to treatment, the patient underwent left lower lobe resection with hilar and mediastinal lymph node excision. The pathology report confirmed the initial diagnosis of atypical carcinoid, Ki-67 of 20%, OTP negative, 4 mitoses per 2 mm², and no cancer cells identified in the subcarinal lymph nodes.

Outcomes and Follow-Up

The patient recovered with no significant complications. However, returning to her usual activities took 5 to 6 months. She lost 7% of her weight in the first 4 months and has been stable ever since. FDG PET/CT and ⁶⁸Ga PET/CT scans post surgery showed no avid lesions. The patient is on follow-up with CT scans every 6 months with no signs of recurrence 24 months following the lobectomy. The patient reports occasional pain in the area around the surgical wound, which she correlates with weather changes. Regarding her older son, an MRI of the pituitary gland showed an enlarged gland (1.8x1.5x1.7 cm) with no definite indications of a lesion with a mild shift of the stalk of the gland. He remains asymptomatic and has regular follow-ups according to published guidelines by the neurosurgeon and in the NET clinic.⁵

Discussion

The case study highlights the efficacy of neoadjuvant treatment in a patient with atypical carcinoid, which can significantly affect the management of these tumors. There are limited prospective data for the effectiveness of neoadjuvant or adjuvant treatment for these rare tumors, and therefore clinical management relies on consensus guidelines and published case series. In addition, MEN1 pathogenic variants are rare findings in patients with atypical carcinoids, and this report contributes to a better understanding of the biological behavior of these rare cases.

In the study by Daddi et al, a retrospective analysis of 247 patients with atypical carcinoids, only 1 patient had the MEN1 pathogenic variant (0.4%), indicating that these tumors are mostly sporadic.⁶ Neoadjuvant chemotherapy was chosen as a treatment plan in 6 of 247 patients (2.8%), reflecting the clinicians’ lack of confidence in the effectiveness of neoadjuvant treatment. On the contrary, adjuvant therapy with either chemotherapy, radiotherapy, or both was chosen in 27% of patients, with nodal metastasis being the main selection criterion. This analysis illustrates the bias in decision-making for managing these tumors mostly from practices used in NSCLC or SCLC.

Neoadjuvant chemotherapy has been evaluated in retrospective studies, mostly locally advanced and oligometastatic gastroenteropancreatic NETs (GEP-NETs). In 662 patients with GEP-NETs treated in European and Asian centers, chemotherapy was administered in the neoadjuvant setting in 1.4% of the patients,6 while in another series, this percentage was 4%.^7,8 Different regimens were tested in the preoperative setting with no head-to-head comparison of their effectiveness. Results of a study by Dumont et al showed improved rates of R0 resection and higher rates of tumor downstaging following neoadjuvant treatment, which led to surgical resection in low to intermediate panNETs.⁹ Contrary to these results, other studies showed no significant downstaging in localized panNETs with preoperative treatment when different regimens were used.^10,11 Besides tumor shrinkage, a recent study by Xie et al investigated the use of neoadjuvant therapy in the largest group of patients with pancreatic neuroendocrine neoplasms (pNENs).¹² The study included 4892 patients who underwent surgery with the intent of curing their cancer. The researchers found no significant improvement in overall survival, even in patients with grade 1 and 2 pNENs. These findings suggest that neoadjuvant therapy should be used with caution in patients with pNENs, as there is a lack of conclusive evidence to support its use.

Limited evidence exists on the effectiveness of preoperative chemotherapy in lung NETs. In a series of 45 patients with typical and atypical carcinoids, 2 patients underwent neoadjuvant treatment with fluorouracil, cisplatin, and streptozocin, and both patients had good response and tumor downstaging.13 Peptide receptor radionuclide therapy (PRRT) has also been evaluated in the preoperative setting in patients with midgut and lung NETs with moderate response rates.^14-16 In a meta-analysis of 468 patients with pNENs, both PRRT and chemotherapy showed efficacy in tumor shrinkage, with PRRT having a significant advantage over chemotherapy regarding overall response rate.¹⁷ In patients with lung NETs, tumor shrinkage was significantly less than in those with panNETs.

CAPTEM is a chemotherapy regimen with a moderate toxicity profile and response rates ranging from 21% to 44%.^18-20 It is effective both in typical and atypical carcinoids as well as GEP-NETs and can be used in first or later lines of treatment.²¹ In a study where CAPTEM was used in the preoperative setting in patients with panNETs, 43% of patients had a partial response and 54% had stable disease.²² These patients had a median progression-free survival of ^28.2 months and 5-year overall survival of 63%.

The results of most studies show that adjuvant chemotherapy has no clear benefit in typical and atypical carcinoids, even in confirmed nodal metastasis.^23,24 These results should be interpreted cautiously because of their retrospective nature and considering that many variables could affect the findings, such as staging with both FDG PET/CT and [⁶⁸Ga]- PET/CT, type of chemotherapy administered, criteria for patient selection, and type of surgical resection. These variables can vary significantly between studies, considerably influencing the results.

A case report published in 2021 underlies the effectiveness of CAPTEM in a patient with unresectable atypical carcinoid tumor of the mediastinum.²⁵ The patient underwent treatment for 6 months before the tumor was considered resectable. Although the authors report that the tumor was primarily mediastinal and not a lung carcinoid, this case shows successful tumor shrinkage due to neoadjuvant chemotherapy. Downstaging was achieved following 6 months of treatment, indicating that results appear after prolonged preoperative treatment administration, as in the patient with the atypical carcinoid we present, and not after 3 months, as, for example, in patients with NSCLC. Although there are no accepted protocols for response reevaluation in lung NETs on treatment with chemotherapy, reevaluation should be performed every 6 months along with a resectability assessment of the disease, given that the treatment is well tolerated during this period.

The possibility of disagreement between preoperative biopsy diagnosis and the final surgical specimen adds to the difficulty in decision-making for patients with advanced lung NETs. It is estimated that discordance can be as frequent as 57% of patients with resectable disease, and thus bronchoscopic biopsies should be interpreted cautiously when forming treatment plans.²⁶ Considering the findings from both FDG PET/CT and [⁶⁸Ga]- PET/CT helps to increase accuracy in the staging of the disease and alleviate, to some degree, the bronchoscopic biopsy shortcomings.²⁷ The decision for neoadjuvant treatment in lung NETs should employ FDG PET/CT and [⁶⁸Ga]- PET/CT and not rely entirely on the pathology report of the bronchoscopic biopsy and CT scans.

The preferred treatment for lung NETs is lobectomy with systematic nodal dissection in both typical and atypical carcinoids, although parenchyma-sparing approaches might be considered for the former. A common challenge in clinical practice is the extent of lung parenchyma removal when these tumors are centrally located. A bronchoplasty is often employed, and when this procedure is not indicated, a sleeve resection can be performed to avoid pneumonectomy.²⁸ Tumor downstaging may offer fewer ablative surgical excisions in these tumors and possibly improve survival and R0 resections, although clinical trials will answer these questions.

Another issue that must be addressed in lung NETs is the resectability criteria. Clinicians might be prejudiced by the recommended practice in NSCLC, where N2 disease is often considered a relative resection contraindication unless neoadjuvant treatment leads to tumor downstaging. In 2019, Yoon et al published their paper on the prognostic significance of TNM staging in lung NETs.²⁹ Prognosis in the advanced T or N stages is considerably better in lung NETS than in NSCLC Based on these findings, resectability criteria should be broader in typical and atypical carcinoids, and clinicians should not follow the paradigm of NSCLC management.

The limitation of this case study is the fact that this is not a sporadic atypical carcinoid case since the patient is a carrier of a known pathologic variance in the MEN1 gene. In addition, there are no guidelines to describe the pathology findings of neoadjuvant treatment in these tumors, and only imaging criteria are presented for response in the primary tumor. With these limitations, it is a case study showing that preoperative treatment can benefit selected patients with lung carcinoids when tumor burden reduction is the primary goal.

In conclusion, typical and atypical carcinoids can often be very challenging to manage because the prognosis is considerably better than either NSCLC or SCLC, and the impact of medical interventions must be weighed carefully against the immediate or late adverse effects. There are limited data for managing different clinical scenarios, and clinicians often base their decisions on extrapolating evidence from either NSCLC or SCLC and GEP-NETs. A typical scenario is a need for downstaging when tumors are centrally located and lobectomy is not an option, or when adjacent structures are invaded. Neoadjuvant treatment with CAPTEM with reevaluation every 6 months can be proposed in such a scenario, as in our case study. There might also be a benefit in survival, although large clinical trials will answer this question.

Patient’s Perspective

The patient’s primary concern during the treatment was whether the benefit/risk ratio would be favorable for her in the long run, despite the initial discomfort and recovery period. She tolerated treatment with CAPTEM well without significant adverse effects (grade 3/4) and did not have to change her daily activities. She describes that her mood changes during the treatment oscillated between hope and fear that the treatment might not be sufficient or might have adverse effects. Twenty-four months following the lobectomy, she finds that the fear of recurrence affects her daily life, particularly when experiencing occasional pain in any area of her body. She is under periodic surveillance by a clinic psychiatrist and is not taking any medication for anxiety or depression. She is also concerned about the possibility of her older son developing MEN1-related diseases and how this will affect the rest of his life. She is satisfied that both operations did not affect her quality of life in the long term and that she is 2 years disease-free.

Funding Statement

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Patient Consent

Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.

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