A noteworthy treatment of metastatic small‐cell lung cancer with afatinib, followed by subsequent development of rare metastatic lesions in the ascending and sigmoid colon

Abstract

Background

Small‐cell lung cancer (SCLC) represents a group of highly fatal diseases with a tendency toward fast growth, early metastasis, and easy development of chemotherapy resistance. In the past 30 years, few advances have been made in the systemic treatment of SCLC, and cisplatin/etoposide has remained the standard of care for limited‐stage SCLC and, in combination with radiotherapy, extensive‐stage SCLC. The preferred metastatic sites of SCLC include the brain, liver, adrenal glands, bone, and bone marrow. However, bowel metastasis caused by SCLC is extremely rarely proved in patients while they are still alive (although autopsy studies suggest that silent metastases to the bowel are more common), and the standard treatment for bowel metastasis has never been reported. The mean time between the identification of gastrointestinal metastasis and mortality in patients with lung cancer is 100.6 days, with a range of 21–145 days.

Case

We report the case of a patient with extensive SCLC (including brain metastasis), in which exon 19 deletion of epidermal growth factor receptor (EGFR) was detected. She initially refused chemotherapy and cranial radiotherapy and instead only agreed to oral target therapy. The second‐generation EGFR‐tyrosine kinase inhibitor (TKI), afatinib, was administered to the patient, and partial remission, including smaller metastatic brain tumors, was noted. Even though the subsequent development of rare metastatic lesions in the ascending and sigmoid colon was proved by colonoscopic biopsies, the prolonged overall survival (400 days) without standard treatment was marked in this case.

Conclusion

The patient with extensive metastasis of SCLC did not receive standard systemic chemotherapy. Instead, she initially received second‐generation EGFR‐TKI afatinib alone and later on whole brain radiotherapy as well (3 weeks before she expired). The prolonged overall survival of 400 days was marked and is worthy of sharing and further investigation.

1. INTRODUCTION

Lung cancer is a global leading cause of cancer‐related death in both genders. Small‐cell lung cancer (SCLC) is a highly malignant pulmonary neuroendocrine tumor constituting 14‐15% of all lung cancers.1 Around two‐thirds of patients with SCLC are diagnosed with extensive stage, where the metastatic lesions are commonly observed in the contralateral lung, liver, brain, and bones.2 Patients with brain metastasis of SCLC are generally treated with both brain radiotherapy and platinum‐based chemotherapy, which has a limited impact on survival due to its rapid relapses with resistance to further therapies despite high initial objective responses.3, 4 With the recent development of targeted drugs, tumor molecular profile detection allows the selection of appropriate targeted drugs for adjuvant pharmacological treatment of brain metastasis in SCLC patients.5

Afatinib, the second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI), is an irreversible ErbB family blocker reported to provide therapeutic efficacy and a good response rate in the treatment of naive mutant‐EGFR lung adenocarcinoma patients with brain metastases regardless of whether they receive radiotherapy or not.6, 7 However, the efficacy of afatinib in patients with brain metastasis of SCLC still needs to be confirmed.

In this case, we report partial response of afatinib in a patient with extensive SCLC who has attained prolonged survival and unfortunately later developed rare ascending colon (A‐colon) and sigmoid colon (S‐colon) metastasis.

2. CASE REPORT

This 65‐year‐old female patient was sent to our emergency room (ER) on June 28, 2015 for progressive dyspnea for 3‐4 months. Through the biopsy of the left lower lung tumor 4 days after coming to ER and full staging imaging surveillance, she was diagnosed with SCLC (Figure 1) along with liver, adrenal, bone, and brain metastasis (Figures 2 and 3). However, she refused any aggressive treatment at that time, including radiotherapy to the brain, and lost follow‐up. She returned to our hospital and visited the oncology outpatient department (OPD) 3 months later (on September 14, 2015) because of progressive chest discomfort for 1‐2 weeks, and it was noted that there was a progression in the disease with more metastatic sites. Since she still refused systemic chemotherapy and instead only agreed to oral drugs, she started receiving target therapy with afatinib 1 week later (on September 23, 2015) after exon 19 deletion of EGFR was detected in malignant tumor cells. Partial remission, including smaller left lower lung tumor, smaller regional lymph node, smaller metastatic liver tumors, smaller metastatic adrenal tumor (Figure 4), insignificant metastatic bony lesion (Figure 5), and smaller metastatic brain tumors (Figure 6), was noted under image surveillance.

Figure 1.

A, Lung small‐cell carcinoma: tumor cells are densely packed and small, with scanty cytoplasm, finely granular nuclear chromatin, nuclear molding, and absence of nucleoli, ×400. B, Tumor cells show positive staining to pan cytokeratin, ×200 and C, TTF‐1 (nuclear staining), ×200. D, Tumor cells show positive for both cytoplasmic staining to chromogranin A, ×400, E, membranous staining to CD56, ×400, and F, negative to synaptophysin, ×400

Figure 2.

A, PET scan (September 17, 2015): left lower lung tumor with multiple metastatic sites, including left lower lung tumor before afatinib treatment. B, PET scan (September 17, 2015): left lower lung tumor with multiple metastatic sites, including liver metastasis before afatinib treatment. C, PET scan (September 17, 2015): left lower lung tumor with multiple metastatic sites, including right S‐I joint metastasis before afatinib treatment. S‐I, sacroiliac joint

Figure 3.

Brain MRI (June 29, 2015, initial diagnosis): left frontal metastasis

Figure 4.

A, CT (January 18, 2016): smaller left lower lung tumor with afatinib treatment. B, CT (January 18, 2016): smaller metastatic liver tumors with afatinib treatment

Figure 5.

Bone scan (January 18, 2016): insignificant right S‐I joint uptake with afatinib treatment. S‐I, sacroiliac joint

Figure 6.

Brain MRI (October 14, 2015): smaller left frontal metastatic tumors with afatinib treatment

Unfortunately, progression of the disease, including new metastatic brain tumor, was noted through whole body CT on April 6, 2016 (Figures 7 and 8A). She stopped taking afatinib and still refused any other treatment. She received colonoscopy on May 18, 2016 for lower abdominal pain and was noted to have metastatic small‐cell carcinoma in A‐colon and S‐colon, according to biopsy of polyp‐like lesions of the two sites (Figure 9). EGFR mutations in metastatic colon specimens were not tested because the patient had very low desire for further therapy. Thereafter, she only agreed to brain radiotherapy (3000 cGy/10fxs; July 11‐22, 2016) after progressive brain metastasis was reevaluated on June 29, 2016 by brain MRI (Figure 8B‐D), which was arranged due to progressive headache for 2 weeks. Sadly, she passed away due to respiratory failure on August 1, 2016.

Figure 7.

A, CT (April 6, 2016): bigger left lower lung tumor, showing progressive disease. B, CT (April 6, 2016): bigger metastatic liver tumors, showing progressive disease

Figure 8.

A, Brain CT (April 6, 2016): progressive brain metastasis with new right temporal metastatic tumor. B, Brain MRI (June 29, 2016): progressive brain metastasis with new right temporal metastatic tumor. C, Brain MRI (June 29, 2016): progressive brain metastasis with bigger left frontal metastatic tumor. D, Brain MRI (June 29, 2016): progressive brain metastasis with bigger right cerebellum metastatic tumor

Figure 9.

A, A‐colon tumor (×200) and B, S‐colon tumor (×200) show similar tumor morphology to the lung small‐cell carcinoma. Metastatic tumor cells show positive staining to, C, cytokeratin 7 (×200), D, TTF‐1 (×200), and E, negative to cytokeratin 20 (×200), and F, CDX2 (×200). The IHC stain indicates malignant cells in A‐colon and S‐colon are originated from lung, compatible with lung cancer with colon metastases. The colon tumor cells show similar neuroendocrine markers to the primary small‐cell lung cancer, positive for both, G, cytoplasmic staining to chromogranin A (×200) and H, membranous staining to CD56 (×200), I, negative to synaptophysin (×200), indicating metastatic SCLC in colon. SCLC, small‐cell lung cancer

3. DISCUSSION

Small‐cell lung cancer is the most aggressive form of neuroendocrine tumor of the lung, and novel and more effective treatment strategies are urgently needed due to the rapidly growing resistance to chemotherapy and dismal relapse of SCLC.1, 8, 9

Although numerous characterizations of the genomic landscape of SCLC have been made for the development of rational and promising targeted agents, the advance in tumor genomics and targeted therapy for this aggressive cancer is still sluggish since SCLC is usually diagnosed by small biopsies or cytology specimens and is always at unresectable stages at diagnosis.10, 11 Despite a large number of clinical trials, results remain disappointing and there are still no approved targeted drugs for SCLC.8 Therefore, platinum‐based chemotherapy remains as the backbone to treat the disease.

The median survival of lung cancer patients with brain metastasis is only 3‐6 months. In the past 30 years, the only advances in the management of SCLC have been in the field of radiotherapy, where chest and prophylactic cranial irradiation have been demonstrated to significantly increase survival.4, 12, 13 Patients with brain metastasis of SCLC are generally treated with local or whole brain radiotherapy (WBRT). However, standard treatment for brain metastasis may be intolerable to some cases because of severe adverse reaction.

Because it is not common and often asymptomatic, gastrointestinal metastasis (stomach, small intestine, and large intestine) from lung cancer in living patients is rare and is usually discovered during autopsy as a result.14

With an incidence between 0.2 and 4.0%, SCLC combined with EGFR mutations is rare. Most of these mutations are deletions in exon 19.15, 16, 17 Since bowel metastatic SCLC found in living patients is extremely rare, the odds of having EGFR mutations in bowel metastatic SCLC in living patients are next to none.18, 19, 20, 21

The second‐generation EGFR‐TKIs, including afatinb, dacomitinib, and neratinib, are clinically selected to treat some patients with epidermal growth factor receptor mutations.22

In our case, the patient was initially diagnosed with SCLC and metastasis in the liver, adrenal, bone, and brain, and she had progression‐free survival of 195 days and overall survival of 400 days with the second‐generation EGFR‐TKI afatinib alone.

We hope that by sharing our experience, we may provide a promising research in the treatment of extensive‐stage SCLC, especially with brain metastasis.

EGFR‐TKI, for metastatic SCLC.

4. ETHICAL STATEMENT

Permission to publish this article was given by the patient's family (her son's signature) and approved by the ethical committee of our institute.

CONFLICT OF INTEREST

The authors have no conflict of interest to be disclosed related to this article.

AUTHOR CONTRIBUTIONS

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, S.C.H.; Investigation, S.C.H.; Resources, S.C.H., Y‐H.C., C‐C.L., and C‐I.L.; Writing ‐ Original Draft, S.C.H.; Writing ‐ Review & Editing, S.C.H.; Visualization, S.C.H.; Supervision, S.C.H.

Hsiao S‐C, Chen Y‐H, Lo C‐C, Lin C‐I. A noteworthy treatment of metastatic small‐cell lung cancer with afatinib, followed by subsequent development of rare metastatic lesions in the ascending and sigmoid colon. Cancer Reports. 2020;3:e1243. 10.1002/cnr2.1243

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.