Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report

Jermaine I.G.Coward, Nicola-Louise Ding, Roger Feakins, Hermant Kocher, Sanjay Popat & Piotr W.Szlosarek
Medical Oncology ISSN 1357-0560 Med Oncol DOI 10.1007/s12032-011-0150-3

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Med Oncol DOI 10.1007/s12032-011-0150-3

SHORT COMMUNICATION

Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report

Jermaine I. G. Coward Nicola-Louise Ding Roger Feakins Hermant Kocher Sanjay Popat Piotr W. Szlosarek

Received: 13 December 2011 / Accepted: 20 December 2011 Springer Science+Business Media, LLC 2011

Abstract This case report focuses on an elderly gentleman with extensive stage small cell lung cancer (SCLC) who experienced episodes of bowel obstruction shortly after commencing rst-line chemotherapy with cisplatin and etoposide. The patient had no radiological or pathological evidence of intra-abdominal carcinomatosis or paraneoplastic bowel disease secondary to SCLC. Although neurotoxicity is commonly associated with platinum agents, the effect is predominantly peripheral as opposed to autonomic. The authors conclude that the observations documented in this case were secondary to etoposide; a podophyllotoxin that can bind microtubules and inhibit fast axonal transport. Although paralytic ileus is well recognised with podophyllotoxin poisoning, to our knowledge, this is the rst report to associate bowel obstruction with standard doses of etoposide and highlights the need for physicians to be aware of such deleterious effects in patients treated with this cytotoxic agent.

Keywords Small cell lung cancer Bowel obstruction Etoposide Podophyllotoxin Neurotoxicity Paraneoplastic AXR

Introduction The treatment of small cell lung cancer (SCLC) with platinum-based chemotherapy still remains the standard of rstline care, with a doublet containing the podophyllotoxin, etoposide, being the most widely adopted regime [1]. SCLC is often associated with a spectrum of paraneoplastic conditions that can manifest as aberrant hormone secretion (e.g. vasopressin (ADH) and adrenocorticotrophic hormone (AC TH)), neurological syndromes (Lambert-Eaton syndrome) or intestinal pseudo-obstruction. The inherent chemosensitivity of SCLC is exemplied by the fact that these presentations can respond in up to 80% of cases treated with platinum-etoposide in the rst instance [2]. Despite this, most patients succumb within either 1520 months for limited stage or 813 months for extensive stage disease [24]. This case report documents the observation of bowel obstruction induced by carboplatin and etoposide in a patient with extensive stage SCLC.

J. I. G. Coward (&) S. Popat Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK e-mail: jim.coward@gmail.com J. I. G. Coward H. Kocher P. W. Szlosarek Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK N.-L. Ding H. Kocher P. W. Szlosarek St Bartholomews Hospital, West Smitheld, London EC1A 7BE, UK R. Feakins The Royal London Hospital, 80 Newark Street, Whitechapel, London E1 2ES, UK S. Popat Molecular Genetics Group, Imperial College London, Dovehouse Street, London, UK

Case history In December 2005, a 62-year-old gentleman with an 80-pack year smoking history was diagnosed with extensive stage small cell lung cancer by transbronchial biopsy following an acute presentation of dyspnoea. Baseline computer tomography (CT) staging revealed a left hilar mass arising from the lower lobe bronchus associated with pretracheal and

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Fig. 1 Abdominal X-rays illustrating the development of small bowel obstruction shortly after rst exposure to carboplatin and etoposide (a), that resolved with surgical management (b). Following re-exposure to carboplatin and etoposide, gross small bowel dilatation recurred (c)

subcarinal lymphadenopathy. There was no evidence of any extrathoracic visceral metastases. Within a few days of diagnosis, the patient commenced chemotherapy with carboplatin AUC 5 i.v. day 1 and etoposide 200 mg/m2 i.v. day 1 and 100 mg/m2 p.o. b.d. day 2 and 3. On day 8, sudden onset left upper quadrant pain ensued which was associated with vomiting. Although generalised abdominal tenderness was elicited on palpation, bowel sounds were normal in character, and no guarding was evident. A subsequent abdominal X-ray (AXR) conrmed faecal loading in the ascending colon in addition to gas in the rectosigmoid and proximal bowel loop. CT imaging had indicated some interval response in the left hemithorax disease, but there were no signicant ndings within the abdomen. Although symptoms initially settled with analgesia, after a further week, increasing abdominal distension and tenderness developed. A repeat AXR (Fig. 1a) and CT scan revealed small bowel obstruction, and a subsequent laparotomy involved excision of the parietal omentum with two small bowel resections and side-to-side anastomosis, with no suspicion of peritoneal metastases. The post-operative AXR is shown in Fig. 1b. Pathology review of the resected bowel specimen and omentum demonstrated areas of ulceration and oedema. Histology showed severe ulceration and transmural necrosis with haemorrhage and quite extensive brosis (Fig. 2). A few submucosal and subserosal blood vessels contained organised thrombi, and there was no evidence of, inammatory bowel disease or neoplasia or any neuronal degeneration suggestive of paraneoplastic phenomenon. In February 2006, the second cycle of chemotherapy commenced. However, on day 3, the patient experienced severe sudden onset lower abdominal pain, associated with vomiting. The abdominal symptoms deteriorated rapidly with guarding and absent bowel sounds associated with oliguria

Fig. 2 Small bowel showing ulceration with loss of full thickness of the mucosa (top half of picture) and underlying granulation tissue formation and brosis. Viable but inamed mucosa is present in the lower half of the picture. There is no evidence of neoplasia

and hypotension. The AXR (Fig. 1c) and CT scan showed evidence of dilated small bowel and an abdominal purulent collection that was subsequently drained. Furthermore, despite evidence of an interval response after the rst cycle of chemotherapy, disease progression was conrmed within the thorax. After 1 week of conservative treatment, the clinical state improved and his stable condition facilitated transfer to a hospice. In view of the poor performance status and rapid disease progression on platinum-based treatment, second-line therapy was not considered.

Discussion This case highlights recurrent unexpected toxicities secondary to carboplatin and etoposide treatment in a patient

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with no pre-existing bowel co-morbidity, evidence of intestinal paraneoplastic syndrome secondary to SCLC, or abdominal metastases by CT. Although platinum agents are associated with neurotoxicity, due to the predominant effect on large myelinated nerves, the neuropathy usually manifests in the peripheral as opposed to autonomic nervous system [5]. Etoposide has dual chemotherapeutic properties in that it is a synthetic podophyllotoxin derivative that also behaves as a topoisomerase II inhibitor that results in S-phase/early G2 cell cycle growth arrest and the maintenance of torsional stresses in DNA that inhibit strand breakage. However, the podophyllotoxic effect of etoposide relates to microtubular binding and inhibition of fast axonoplastic transport [6, 7]. In view of the autonomic bowel dysfunction commonly associated with other microtubular toxins such as vinca alkaloids, it is feasible that the symptoms outlined in this report were attributable to etoposide. Nevertheless, this is a symptom that has only been rarely reported, and in one such case etoposide was administered with amsacrine, another topoisomerase II inhibitor [8]. Furthermore, although podophyllotoxin poisoning is certainly associated with paralytic ileus [9, 10], to our knowledge, this is the rst report of bowel obstruction secondary to etoposide given as a standard dose in the absence of other expected toxicities. Conversely, intraperitoneal etoposide has been shown to relieve symptoms secondary to abdominal carcinomatosis in metastatic lung adenocarcinoma that was refractory to treatment with chemo-immunotherapy [11]. Hence, the observations previously described in this report appear to be paradoxical. Whilst we cannot completely exclude intra-abdominal metastases that might have been apparent on PET-CT in our case, no evidence of intra-abdominal tumour was evident at laparotomy. Similar to many other cytotoxic agents, intestinal mucositis is associated with etoposide and is depicted by villous atrophy, signicant crypt disruption and lymphoid cell inltrates [12]. In addition, a recent report has shown that such bowel injury is preceded by endothelial damage [13]. The events observed in this report emphasise the need for physicians to be aware of additional bowel toxicities that are associated with etoposide-based regimens.
Acknowledgments JC and SP acknowledge NHS funding to the NIHR Biomedical Research Centre. SP is in receipt of a Clinical

Senior Lecturer Award from the Higher Education Funding Council for England. PWS is in receipt of a Clinician Scientist fellowship from Cancer Research UK. Conict of interest None.

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