Extensive-disease small cell lung cancer, multiple relapses, five lines of therapy and more than 10-year survival

Abstract

Small cell lung cancer (SCLC) accounts for nearly 18% of lung cancer cases. Most of the patients of SCLC are not surgical candidates, due to advanced stage at presentation hence only viable options are chemotherapy and radiotherapy. Long-term survival in SCLC is extremely rare due to relapses and comorbidities. Ten-year survival has never been reported in cases with extensive disease at presentation and history of relapses. Here we are describing a case of extensive disease SCLC who has survived multiple relapses and has received five lines of systemic therapy apart from radiation and palliative care. This case emphasises on the need of active and strict disease surveillance at each follow-up.

Introduction

Small cell lung cancer (SCLC) is the third most common histological subtype of lung cancer accounting for nearly 18% of all cases. Nearly all patients with SCLC are smokers.¹ SCLC shows good response to chemotherapy and radiotherapy but still carries a dismal prognosis with a median overall survival of 10–14 months only, widely depending on the stage of disease. Long-term survival has been reported anecdotally in patients with SCLC but predominantly in limited-stage disease and among patients who have achieved complete remission after the first line of therapy. Relapses and secondary malignancies are the most common causes of poor prognosis among long-term survivors.² Herein we describe a peculiar case of 10-year survival in SCLC with extensive disease (ED) at the time of diagnosis along with multiple relapses following therapy.

Case presentation and investigations

A 65-year-old man with no prior comorbidities, presented with cough and haemoptysis of 2-month duration in May 2009. He was a chronic bidi smoker with a smoking index number (bidis per day multiplied by the number of years smoked) of 170. He was evaluated with chest radiograph followed by CT of thorax, which revealed well-defined heterogeneously enhancing mass lesion in the mediastinum in the prevascular location and moderate pleural effusion on the same side (figure 1). He underwent CT-guided fine needle aspiration cytology (FNAC) from the mediastinal mass along with the cytological evaluation of pleural effusion. Pleural fluid examination revealed exudative, lymphocyte rich effusion with low adenosine deaminase. Cytological examination of the fluid as well as FNAC from the mass was suggestive of SCLC (figure 2). Tumour, node, metastases (TNM) staging at the time of diagnosis was T4N2M1a (eighth TNM staging) stage IVa and ED as per the veterans administration lung study group.³

Figure 1.

Contrast-enhanced CT of (A) thorax showing anterior mediastinal mass (red circle) of 4.0×5.6 cm abutting main pulmonary artery and left pulmonary artery along with left pleural effusion (baseline), (B) abdomen at baseline showing no other site of involvement or metastasis, (C) thorax after four cycles of chemotherapy showing complete response (NO mass seen in the location of previous lesion), (D) thorax showing relapse in the form of re-appearance of the mass (red circle) in anterior mediastinum (NO effusion present), (E) thorax, after chemotherapy and radiotherapy, showing complete response, (F) abdomen showing heterogeneously enhancing mass in the head of pancreas (red arrow) causing biliary obstruction and distension of gall bladder, (G) abdomen after biliary stenting and chemotherapy, showing no mass lesion and NO biliary obstruction stent (opaque structure next to gallbladder) can be seen in situ, (H) abdomen showing 2.5×3.5 cm lesion near the superior pole of left kidney, (I) increase in the size (6.8×7.2 cm) of perinephric mass next to left kidney (red circle) and (J) decrease in size (partial response) of the perinephric mass after six cycles of chemotherapy.

Figure 2.

A panel of micro-photographs. (A) Small-sized tumour cells with high nucleus/cytoplasm ratio and scanty cytoplasm (MGG 20×). (B, C) Cellular smear comprising of loosely cohesive clusters and dispersed population of tumour cells with marked crushing artefacts (H&E 20×). (D) Tumour cells showing nuclear moulding, scanty stripped-off cytoplasm, stippled chromatin and inconspicuous nucleoli (H&E 40×).

Treatment

He was started on chemotherapy with irinotecan (65 mg/m² on day 1 and day 8) and cisplatin (30 mg/m² on day 1 and day 8). After six cycles of the chemotherapy, repeat imaging showed complete response (figure 1) as per response evaluation criteria in solid tumours version 1.1.⁴ He was kept under follow-up.

Follow-up and relapses

Subsequently, in November 2010 (9 months later), he relapsed in the form of re-appearance of mediastinal mass (figure 1). He was again treated with six cycles of irinotecan (65 mg/m² on day 1 and day 8) and carboplatin (area under curve or AUC 5), and achieved partial response (figure 1) as the relapse was after more than 6 months of previous therapy. Radiation (30 Gy) to thorax was also done, as in this relapse there was no pleural effusion contra-indicating radiotherapy, along with prophylactic cranial irradiation. Subsequently he was kept under follow-up.

In February 2013 (20 months later), he presented with jaundice and pruritus. Liver function tests revealed conjugated hyperbilirubinemia. Contrast-enhanced CT (CECT) of the abdomen was done, which showed a well defined heterogeneously enhancing mass lesion in the head of pancreas (figure 1). CT-guided FNAC from pancreatic mass showed metastatic small cell lung carcinoma. He underwent endoscopic retrograde cholangio-pancreatography, which showed obstruction at mid-common bile duct, stenting was done in the same setting and symptoms of obstructive jaundice improved. He was again started on chemotherapy (irinotecan and carboplatin—six cycles). Repeat imaging showed a partial response (figure 1). He was kept under follow-up. Repeat imaging did not show any interval change. Symptomatically as well, there was no relapse of hyperbilirubinemia.

In April 2016 (30 months later), he presented with non-colicky abdominal pain in left lower quadrant, for which ultrasound abdomen was advised. It showed presence of a left renal hypoechoic lesion and the possibility of metastasis was kept. No other site was found involved in CECT thorax and abdomen. He was prescribed oral topotecan (fourth line of therapy) in April 2016. He took this medicine for 1 month but then discontinued it due to gastrointestinal toxicity. Later he lost to follow-up till June 2018.

When he came for follow-up after 2 years of the previous visit, he was clinically asymptomatic, a repeat imaging (CECT of the chest and abdomen) was done to look for disease activity status which showed an increase in the size of the perinephric mass (figure 1) (from 2.5×3.5 cm to 6.8×7.2 cm). At the same time, gallium-68 DOTATATE positron emission technology/CT was also done which showed the presence of somatostatin receptor in perinephric mass apart from other sites (figure 3). CT-guided FNAC (third time) from perinephric mass showed metastatic small cell lung carcinoma. Given the favourable response to previous irinotecan-based therapy, he was restarted on fifth line of treatment—irinotecan and carboplatin.

Figure 3.

68-Gallium DOTATATE scan showing (A) somatostatin receptor expressing lesion in left perinephric location (~1.9×1.8 cm; maximum standardized uptake value (SUVmax) 4.8) (white arrow) and (B, C) somatostatin receptor expressing mediastinal (subcarinal ~1.8×1.3 cm; SUVmax 3.8) and right supraclavicular lymph nodes (SUVmax 3.8).

Outcome

Imaging was done after four cycles, which showed partial response (renal lesions decreased in size) (figure 1). He completed six cycles and has been kept in follow-up. The last visit was on 5 August 2019, and he is doing fine (figure 4).

Figure 4.

Timeline of the case, from diagnosis until, showing relapses, responses, chemotherapy (CT) durations and follow-ups.

Discussion

SCLC is the third most common type of lung cancer, subclassified under neuroendocrine tumours as per 2015 WHO histological classification of lung tumours.⁵ In contrast to the progress made in the management of lung adenocarcinoma and squamous cell lung cancer, management of SCLC has remained nearly the same without any new developments except role of immunotherapy.

The traditional classification of SCLC is a two-stage division based on the radio-therapeutic feasibility of the extent of the disease. Limited stage SCLC can be encompassed into one field and does not have effusions. This stage is associated with less tumour burden and significantly better survival, whereas ED is considered when the diseased area is beyond the scope of one radiation field. It is usually due to metastasis or effusions. In comparison with limited stage SCLC, ED has poor outcomes.³

Current treatment options of SCLC depend on the TNM stage and extent of disease. Three main pillars of therapy include surgery, radiotherapy and chemotherapy. Most of the patients of SCLC present in an advanced/metastatic stage where surgery is not feasible. Chemotherapy with or without radiotherapy remains the mainstay of management of SCLC. Immunotherapy is upcoming and has recently been incorporated in treatment armamentarium of SCLC.⁶ Our patient presented with a lung mass at the time of presentation along with pleural effusion on the same side, thus making it an ED. The first line of therapy recommended in such a setting is irinotecan with platinum compound or platinum-based doublet with etoposide. The index case had multiple relapses at various sites over 10 years of follow-up, but every time the temporal gap between two relapses was more than 1 year (figure 4). It has been recommended in NCCN guidelines that if relapse is after more than 6 months of previous therapy than the same regimen should be used again. Four out of five times he was managed with irinotecan-based doublet, and repose rates were either complete remission (CR) or partial remission (PR).⁶

Long-term (5 or 10 years) survival in advanced/metastatic lung cancer has been described in adenocarcinoma and that too, especially in malignancies carrying targetable gene alteration, especially anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations.^7–10 Long-term survival in SCLC is uncommon due to high relapse rates, high propensity to metastasise, toxicity of chemotherapy and comorbidities. Survivals up to 10 years have been rarely reported in patients who had complete remission after the first line of therapy and had limited disease, to begin with.¹¹ Until, all the reported cases of SCLC with long-term survival had complete remission after the first line of therapy.¹² No ED case until has been reported with more than 10-year survival with active disease. One exceptional case that requires attention was reported by Gressner et al, a 52-year-old man, case of limited disease (LD)-SCLC managed with nearly nine lines of chemotherapy, in addition to radiotherapy and hematopoietic stem cell transplant, surviving for more than 10 years. This case, like ours, highlights the importance of surveillance and picking up relapses at an early stage before the deterioration in performance status or organ dysfunction/limitation.¹³

Long-term survival of the subjects of SCLC included in nine major trials was analysed by Lassen et al and it was estimated that 10-year survival of up to 1.2% could be achieved by strict surveillance and follow-up. Among the negative prognostic factors for long-term survival for SCLC are ED, elevated lactate dehydrogenase, alkaline phosphatase, liver and bone marrow metastasis and performance status more than 2.² This study along with our case emphasises on the importance of frequent follow-up and surveillance.

Given such good response to therapy at each stage, a possibility of alternate diagnosis was entertained. But the presence of chromogranin on immunocytochemistry and multiple crushing artefacts reconfirmed the diagnosis.¹⁴ On the other hand, the positivity of somatostatin receptors on 68-gallium DOTATATE scan can be seen in up to 20% of the patients with SCLC.¹⁵ At the same time, the expression of somatostatin receptor has not been found helpful in predicting prognosis/response, nor it can be used for any change in therapy like octreotide.¹⁶

In conclusion, this patient has been under our follow-up for more than a decade and has been a survivor of ED SCLC along with four relapses and five lines of chemotherapy. This success story is the outcome of strict surveillance and his committed follow-up even during asymptomatic periods of remission.

Patient’s perspective.

Over past more than 10 years. I have visited this hospital and have met several doctors who studied here. Doctors tell me that I am a lucky man to have survived this horrible disease for so long, but it has not been easy. Even in my good times, I am not able to carry out all my activities which I used to do before. Chemotherapy has been harsh on me. But, fortunately, I have seen my fellow patients dying while I survived. I could tell that my cancer is back even before my doctor could advise me to get a CT scan. And also I knew that there is nothing wrong inside me when they advised me to get CT done, to look for disease status. May god bless these junior doctors who are helping patients like me.

Learning points.

• Small cell lung cancer has good response to chemotherapy and radiotherapy but is associated with frequent relapses.

• Strict surveillance and follow-up can help in picking up relapses early before deterioration in general condition.

• If the relapse is after more than 6 months of previous therapy, then same regimen can be used to replicate the response.