Lung Cancer (2008) 61, 270—273

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Acute and fatal diarrhoea after erlotinibplus abdominal palliative hypofractionatedradiotherapy in a metastatic non-small celllung cancer patient: A case report

Giovanni Silvanoa,∗, Grazia Lazzari a,Monica Lovecchiob, Carmela Palazzob

a Radiation Oncology Unit, S.G. Moscati Hospital, ASL TA/1, Italyb Medical Oncology Unit, Villa Verde Private Hospital, Taranto, Italy

Received 14 January 2008; received in revised form 1 March 2008; accepted 4 March 2008

KEYWORDSEGFR inhibitor;Targeted therapy;NSCLC;MSCC;Diarrhoea;Erlotinib;Hypofractionatedradiotherapy;Combined modality

Summary The management of advanced non-small cell lung cancer (NSCLC) has progressedover the last 3 decades due to advances in chemotherapeutic drugs and targeted agents improv-ing survival and quality of life. In particular erlotinib, an orally available human epidermalgrowth factor receptor (HER1/EGFR) tyrosine kinase inhibitor advancing through clinical tri-als for the treatment of various human malignancies in a large placebo-controlled phase IIIstudy, has shown a significantly better OS vs. placebo suggesting its potential benefits in thirdline and possibly in second line treatments. The association of erlotinib with ionizing radiationhas been recently published showing an enhancing antitumor activity and good tolerance. Noinformation are available on side effects when erlotinib is associated with abdominal hypofrac-tionated radiotherapy although diarrhoea is the most known side effect dose-limiting toxicity

when the abdomen is treated. Here we report a fatal acute diarrhoea in a metastatic NSCLCpatient taking erlotinib during abdominal hypofractionated radiotherapy for metastatic spinalcord compression (MSCC).© 2008 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author at: S.C. Radioterapia Oncologica, PresidioOspedaliero S.G. Moscati, Via per Martina Franca 74100, Taranto,Italy. Tel.: +39 099 4585721; fax: +39 099 4585821.

E-mail address: gisilva@tin.it (G. Silvano).

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0169-5002/$ — see front matter © 2008 Elsevier Ireland Ltd. All rights redoi:10.1016/j.lungcan.2008.03.004

. Introduction

urvival benefits in metastatic and pretreated NSCLCatients have recently been published and improved survivalas been recorded thanks to recent advances in targetedherapy [1,2]. In November 2004 erlotinib (TarcevaR) waspproved for monotherapy in the treatment of locally

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Acute and fatal diarrhoea after radiotherapy in NSCLC patie

advanced or metastatic NSCLC patients after failure of atleast one prior chemotherapy regimen [3]. Skin rash anddiarrhoea have been described as the most common adversegrades 3 and 4 side effects due to EGFR inhibitors. Diarrhoeais described when erlotinib is taken over 150 mg daily [3,4].Few experiences on severe diarrhoea as dose-limiting toxic-ity have been reported in abdominal cancer chemoradiationusing EGFR inhibitors and conventional radiotherapy [5,6]while no information, apart from what we hereby, are avail-able on acute and fatal diarrhoea when erlotinib is combinedto palliative abdominal hypofractionated radiotherapy.

Metastatic spinal cord compression (MSCC) is an emer-gency and prognosis in NSCLC spinal cord compression ispoor. Split course hypofractionated radiotherapy (8 Gy × 2)has been reported to be an effective and safe regimen inMSCC unfavorable histology cancers as NSCLC for patientswith or without clinical evidence of neurological deficit anda poor life expectancy [7]. No fatal acute toxicities have sofar been reported using hypofractionated radiotherapy only.

2. Case report

P.V., a 74-year-old man with a metastatic locally not con-trolled NSCLC, was referred to our observation as anin-patient for a lumbar spinal cord compression in Decem-ber 2006. Smoking was accounted in his anamnesis; BUN andliver serological tests were normal. He was a pretreatedpatient who had proven refractory to several chemotherapylines. From November 2006 he was put on erlotinib 150 mgdaily as the last line. Anamnesis was positive for a grade 1skin rash occurring 3 weeks after erlotinib assumption whileno other side effects as dyspnea or diarrhoea had been com-plained at that time. Metastatic spinal cord compressionconsisted of a left paraspinal mass invading the transverseprocess and the spinal cord on L1 vertebra without clinicalevidence of neurological impairment (Fig. 1). In accordancewith our protocol for spinal cord compression in poor progno-sis patient, a short-course radiotherapy 8 Gy × 2, 1 fr/weekwas prescribed.

Planning treated volume (PTV) consisted of T11-L3 ver-tebrae plus 2.5 cm margin on each side of vertebral bodies.Margin of 4 cm on the left side was kept only on the L1vertebral body to cover the pathological mass (Fig. 2).

Fig. 1 CT-scan of the lumbar column showing the spinal cordcompression on L1 vertebra.

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Fig. 2 Simulation field of the antero-posterior field.

wo AP-PA opposed isocentric MLC customized fields and8—10 MV photons were adopted. Fields dimensions were0.9 cm × 14.8 cm and MLC customized involved beam areaeasured 147.1 cm2. Prescription dose was calculated atcm of depth from the PA side. Beams weights wererranged as 35% in AP and 65% in PA sides. Portal visionictures were taken before each fraction to verify thenterfraction set-up. Prophylactic 8 mg dexamethasone and2-receptors inhibitors were administered for the wholereatment time in accordance with our protocol.

Two days after the first 8 Gy fraction the patient com-lained of a grade 1 dyspnea and a grades 1 and 2iarrhoea lasting for 2 days so erlotinib was not discon-inued. After 1-week short-course palliative radiotherapyas completed with the last 8 Gy fraction as planned.ne day later diarrhoea worsened; loperamide, octreotidend every 6 h rifaximina were supplied but diarrhoea didot ameliorate evolving into dehydration and electrolyticmpairment. Intravenous dopamine, high-dose hydrocorti-one and hydration were administered immediately but theatient developed a hypovolaemic shock and died 3 daysfter radiotherapy completion. Necropsy was not permitted.

. Discussion

espite advances in the treatment of primary lung can-er, skeletal-related events still affect many patients duringheir clinical course allowing to complications as bone pain,ymptomatic pathologic fractures and spinal cord compres-ion. Metastatic spinal cord compression is an emergency inradiotherapy unit. Recent data have shown that radiother-

py alone is an effective approach for very elderly patientsith spine metastases [8]. Hypofractionated radiotherapy

s often used in the management of MSCC and split-courseGy × 2 regimen has been reported to be advantageous foratients with a poor survival prognosis [9]. This approach is

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afe; severe abdominal pain and diarrhorea have not beenescribed in lumbar spine hypofractionated radiotherapy.n a recent report of a multicenter phase III trial compar-ng 8 Gy × 2 to 8 Gy single fraction [10] on 300 randomizedatients with MSCC, grade 3 diarrohoea was recorded in 1.5%atients, equally distributed in both arms. No grades 4 andabdominal toxicity was reported with hypofractionated

adiotherapy.Erlotinib has been defined as an appropriate choice as

hird line therapy in NSCLC and may be considered an alter-ative in selected patients as no smokers [11]. In a NCI-Ctudy [12] examining the use of erlotinib plus BSC ver-us placebo plus BSC, erlotinib was associated with severeatigue and rash, diarrhoea and anorexia. Rash and diar-hoea led to a dose reduction in 12% and 5% of patients,espectively. Diarrhoea in erlotinib occurs in 30% of patientsnd is dose-limiting toxicity (DLT) only when taken over50 mg daily dose. The median time to onset of diar-hoea has been reported at around 12 days [3]. Clinicalharmacokinetics studies of erlotinib in patients with solidumors support the current once-daily dosing regimen at50 mg/die due to its long half-life. While a statistically sig-ificant correlation between drug exposure and rash (p < 0.5)as found, no significant correlation has been recordedetween exposure and diarrhoea. Severity of these sideffects has been related to factors affecting clearance asotal bilirubin, alpha1-acid glycoprotein and smoking status13].

The concomitant use of EGFR inhibitors and radiother-py in human malignancies is accounted by in vitro [14]nd in vivo [15] studies suggesting an effective and safenhanced antitumor response but few information on sever-ty of combined treatment toxicity are reported. There arenly some phase I clinical trials reporting EGFR inhibitorsoxicity when combined to chemotherapy and standard frac-ionated radiotherapy in pancreatic and rectal cancer [5,6].zito et al. in a phase I trial on gefitinib, capecitabine andadiation in ten pancreatic cancer and six rectal canceratients recorded diarrhoea as the primary dose-limitingoxicity in both groups. No phase II trial was determinedue to the significant toxicity recorded [5]. Iannitti et al.n a phase I study on erlotinib and chemoradiation forocally advanced pancreatic cancer suggested the erlotinibosages equal to or over 75 mg daily as dose-limiting severeiarrhoea. They found that 50 mg daily was the maxi-um tolerated dose when erlotinib given concurrently to

hemotherapy and conventional fractionated radiotherapy6]. Despite these investigations and in the absence ofefinite information on severe toxicity due to erlotiniboncomitant to hypofractionated radiotherapy, we did notonsidered advisable for this patient a dose reduction ofrlotinib because the severity of disease, the short coursereatment time and limited dimension of the irradiatedeld.

To explain this fatal unexpected toxicity we hypothesizehat standard daily dose erlotinib concomitant to hypofrac-ionated radiotherapy on a limited upper abdominal area in

predisposed patient (smoker) has triggered an extensive

nflammatory reaction on the irradiated small bowel despiteteroids assumption and anti-H2 receptors prophylaxis. Thiss only a supposition since no other data are available toupport this hypothesis.

G. Silvano et al.

. Conclusion

ccording to the reported data grade 3 diarrhoea is anown side effect during EGFR inhibitors therapy whileevere diarrhoea in abdominal hypofractionated radiother-py rarely occurs. Enhanced radiation responses by erlotinibre described in in vitro and in vivo studies and toxic,nexpected, effects due to this combination should beccounted. Until now a fatal diarrhoea has not yet beenescribed in clinical studies adopting this concomitantpproach. Because the use of erlotinib in metastatic NSCLCatients is widespread and association with palliative radio-herapy might occur frequently, oncologists could be on thelert for potential risks of a fatal diarrhoea when erlotinibs combined to abdominal hypofractionated radiotherapy.recautionary erlotinib reduced dose or temporary discon-inuation may be considered in this case and 3D conformaladiotherapy may be scheduled to spare the small bowel.evertheless more information are necessary on this issueecause unexpected toxicity by the concomitant use of tar-eted therapies and radiotherapy are emerging.

onflict of interest

ll authors disclose any financial and other relationships withntities that have investment, licensing, or other commer-ial interest in the subject matter under consideration inhis article.

All authors declare this report is original and does notontain any material previously presented or published.

All authors declare they had no writing assistance.

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