Targeting precision medicine toxicity: recent developments

The European Society of Medical Oncology conference was held in Madrid, 26–30 September 2014. Its overriding theme was precision medicine in cancer care. A special symposium entitled ‘Targeting precision medicine toxicity’ looked specifically at the various toxicities caused by new targeted therapies.

Cardiac toxicity

Dr Lillian L. Siu (Princess Margaret Cancer Centre, Toronto, Canada) presented an overview of cardiac toxicities encountered with molecularly targeted agents. These include ventricular dysfunction, hypertension and corrected QT interval (QTc) prolongation. There are distinct mechanisms for drug-induced ventricular dysfunction. For example, cytotoxic agents such as anthracyclines can cause a type I injury, i.e. myocyte cell death that is usually cumulative-dose related. However, molecularly targeted agents, such as trastuzumab, may cause a type II injury, i.e. myocyte dysfunction without cell death that is not cumulative-dose related and potentially reversible. By way of examples, trastuzumab causes cardiotoxicity via ERBB2 signalling inhibition, whereas imatinib does this by ABL signalling inhibition [Force et al. 2007].

Hypertension has been commonly reported with angiogenesis inhibitors and is also induced by MEK inhibitors in some patients. Vascular endothelial growth factor (VEGF) inhibitors induce hypertension in a dose-dependent manner: almost all patients experience an increase in blood pressure but only a subset develops hypertension. Putative mechanisms of VEGF inhibitor-mediated hypertension include inhibition of nitric oxide synthesis, decreased prostacyclin signalling, increased synthesis of endothelin-1, increased reactive oxygen species, capillary rarefaction, renal dysfunction and increased arterial stiffness [Small et al. 2014]. Dr Siu suggests that, in affected patients, the dose of the VEGF inhibitor should be maintained (if possible) and blood pressure reduction attempted with angiotensin-converting enzyme inhibitors and/or dihydropyridine calcium channel blockers.

QTc interval prolongation has been reported with histone deacetylase inhibitors, ABL inhibitors, MET inhibitors and multi-targeted tyrosine kinase inhibitors. Predisposing factors include genetic causes (e.g. congenital long QT syndrome) and acquired causes, as follows:

• cardiac [decreased left ventricular ejection fraction (LVEF), left ventricular hypertrophy (LVH), cardiac ischemia, atrioventricular (AV) nodal block, mitral valve prolapse, sinus node dysfunction];

• metabolic [electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia), malnutrition, hypothyroidism];

• drug-induced (antiarrhythmic drugs such as quinidine, amiodarone and sotalol, psychotropic drugs such as amitriptyline and venlafaxine, antimicrobials such as azithromycin and moxifloxacin, antihistamines such as terfenadine and astemizole, and other drugs such as domperidone and ondansetron) [Strevel et al. 2007].

New HER2 targeted agents

Dr Siu presented a summary of the relative cardiac toxicities with some of the recent HER2 targeted agents (the information below, and for the other classes of drugs listed next, was given to Dr Siu in a personal communication from a colleague). Lapatinib shows a lower rate of LVEF decline than trastuzumab: 1.4% LVEF decline; 0.2% congestive heart failure (CHF). Pertuzumab (an HER2 dimerization inhibitor) when given with trastuzumab does not appear to increase cardiotoxicity (6.5% LVEF decline, 1.1% CHF). Trastuzumab-DM1 shows a lower rate of LVEF decline than trastuzumab alone (1.7% LVEF decline, 0.2% CHF).

Angiogenesis inhibitors

Angiogenesis inhibitors may cause a decreased LVEF (1–16%) and CHF (1–7%). The reported range is relatively wide because of the large number of drugs in this class. Hypertension has an incidence of 9–67% with this class of drugs and is severe in 2–19%. There is a rare risk of posterior reversible encephalopathy syndrome and thrombotic microangiopathy. QTc prolongation with multikinase inhibitors shows a 1–8% incidence and the diarrhoea that can accompany these drugs may also lead to electrolyte loss. Arterial thrombotic events occur in 1–8% of patients.

ABL inhibitors

This class includes imatinib, nilotinib, dasatinib, bosutinib and ponatinib. Imatinib and nilotinib may decrease LVEF by 1–7% (CHF <1–4%). Imatinib (>600 mg daily) may cause oedema without LVEF decline. Up to 4% of patients may experience QTc prolongation (>500 ms) most often with nilotinib, but this may be reduced if the drug is taken when fasted (food, especially a high-fat meal, has been shown to increase the bioavailability of nilotinib [Tanaka et al. 2010]). QTc prolongation occurs less with dasatinib versus bosutinib versus ponatinib. The US Food and Drug Administration (FDA) removed its approval for ponatinib because of the risk for severe arterial atherothrombotic events.

Other drugs

Trametinib (MEK inhibitor) causes LVEF decline in 8–10% of patients [mean time to decreased LVEF of 58 days (range 16–526 days); CHF <1%]. Peripheral oedema occurs in about 20% of patients and hypertension in 17% (severe in 13%). Crizotinib (an ALK/MET inhibitor) has a 3.5% incidence of QTc prolongation (i.e. >60 ms QTc increase) and peripheral oedema occurs in 20–25% of patients. Histone deacetylase (HDAC) inhibitors such as vorinostat and romidepsin have been associated with QTc prolongation in 1–2% of patients. Bradycardia has been reported in 0.12–5% of patients treated with thalidomide.

Checkpoint inhibitors

Immune checkpoint inhibitors are a promising new development in cancer immunotherapy. The pathways CTLA-4 and PD-1 (and one of its ligands, PD-L1) appear to regulate T cells in tumorigenesis. Their blockade by certain drugs seems to exert anticancer effects, for example, in non-small cell lung cancer and in melanoma [Brahmer and Pardoll, 2013]. Ipilimumab and tremelimumab are anti-CTLA4 monoclonal antibody agents, while nivolumab (BMS936558) and pembrolizumab (MK3475) are PD-1 inhibitors, and BMS936559 is a PD-L1 inhibitor.

In early clinical trials, cardiac toxicity with this group of drugs has been low. For example, no cardiac toxicity was reported with ipilimumab (10 mg/kg every 3 weeks in 88 melanoma patients) or tremelimumab (10 mg/kg single dose in 39 patients with solid tumours; 10 mg/kg every month or 15 mg/kg every 3 months in 117 melanoma patients). Nivolumab produced hypotension in 2% of 296 patients who received 10 mg/kg every 2 weeks. BMS936559 (10 mg/kg every 2 weeks) appeared to cause myocarditis in 0.5% of 207 patients with solid tumours. Hypertension was seen in 7% of 135 melanoma patients who received pembrolizumab (10 mg/kg every 2 weeks; Grade 3+ in 1% of patients) [Brahmer et al. 2010, 2012; Camacho et al. 2009; Hamid et al. 2013; Ribas et al. 2005; Topalian et al. 2012; Weber et al. 2008].

Dr Siu concluded that cardiac toxicity appears to be rare with immune checkpoint inhibitors. Indeed, of the current FDA approved checkpoint inhibitors, ipilimumab has a very low risk of cardiac toxicity (<0.1%, based on 1498 patients) and pembrolizumab has no cardiac risk notifications in its labelling at the recommended dosage of 2 mg/kg every 3 weeks.

European Society for Medical Oncology guidelines

European Society for Medical Oncology (ESMO) clinical practice guidelines have been published in order to manage cardiac risk with cancer therapies.

Potentially irreversible cardiac toxicity has been reported for drugs such as anthracyclines and some biologic agents, but targeted therapies are generally less toxic and better tolerated. However, serious complications have been described, some which are irreversible while others are reversible with no long-term sequelae. It is recommended that there is baseline clinical evaluation and assessment of cardiovascular risk factors and comorbidities, and that basal LVEF assessment be carried out before potential cardiotoxic treatment. A standard 12-lead electrocardiogram (ECG) is also recommended, and patients may be considered at risk for cardiac toxicity with high dosages such as doxorubicin >500 mg/m² or liposomal doxorubicin >900 mg/m² [Curigliano et al. 2012]. The cardiological complications of oncology treatments form part of the remit of the International CardiOncology Society.

Conclusion

Dr Siu concluded that cardiovascular toxicities such as LV dysfunction, QTc prolongation and hypertension are seen with various classes of targeted agents but that they are generally manageable and reversible. Risk prevention, detection, reporting and management should be integral part of the management plan with any of these drugs.

Pulmonary toxicity

Dr Guy Meyer (Paris Descartes Hospital, Paris, France) discussed pulmonary toxicity of targeted therapies, which includes acute or subacute pneumonitis, alveolar haemorrhage, haemoptysis, pleural effusion, pulmonary arterial hypertension (PAH) and pulmonary embolism. He focused on acute or subacute pneumonitis and PAH.

It is often difficult to determine if the lung pathology is primarily due to drug-related complications, infectious disease, or from cancer per se. Infection, left-sided heart failure and cancer lung involvement may usually be ruled out by chest-computed tomography, bronchoscopy with bronchial biopsies, microbial specimens and bronchoalveolar lavage (BAL). Then, drug toxicity may be confirmed by the clinical and radiological picture, and rarely by BAL or lung biopsy.

Acute or subacute pneumonitis has been reported among several targeted therapies. Dr Meyer summarized as follows:

• gefitinib [incidence 1% (2% Japan, 0.3% USA), 30% lethal]. Risk factors were identified by Kudoh and colleagues: older age, poor World Health Organization (WHO) performance score, smoking, short duration since cancer diagnosis, reduced normal lung volume on computerized tomography (CT) scan, pre-existing interstitial lung disease and concurrent cardiac disease [Kudoh et al. 2008].

• erlotinib [incidence 0.6% (5% Japan), 30% lethal]

• mammalian target of rapamycin (mTOR) inhibitors (everolimus, temsirolimus): in a systematic review and meta-analysis of 22 trials (4242 patients), the incidence of any grade of pneumonitis was 11% (6–17%), and grade 3–4 pneumonitis was 3% (1–4%); the incidence ratio was 19.0 (6.5–55.4). It is often asymptomatic with a low mortality rate [Gartrell et al. 2014].

Signs of acute or subacute pneumonitis include cough, dyspnoea and fever. Imaging patterns include diffuse alveolar damage (extensive airspace consolidation, posterior predominance), hypersensitivity pneumonia (peribronchiolar nodules), nonspecific interstitial pneumonia (reticular peripheral pattern, ground-glass attenuation, traction bronchiectasis), acute eosinophilic pneumonia (peripheral ground-glass attenuation, eosinophils in broncho-alveolar lavage), and organizing pneumonia (areas of consolidation, reversed halo sign: central ground-glass opacity surrounded by denser consolidation) [Sakai et al. 2012]. There is a lack of correlation between imaging patterns and pathological findings.

Treatment involves stopping the drug if the patient is symptomatic. Supportive care (oxygen, ventilation) may be required and steroids can be administered in severe cases. Re-challenge with gefitinib and erlotinib has been recorded; see the paper by Togashi and colleagues for one report and a literature review [Togashi et al. 2012]. There are 10 reports in the literature (7 with reduced doses and 8 on steroids): gefitinib then gefitinib (3 patients); gefitinib then erlotinib (5 patients); erlotinib then erlotinib (2 patients). There was recurrence of pneumonitis in one case (this patient did not receive steroids); the author suggested that steroids may prevent recurrence by way of their anti-inflammatory action.

PAH

PAH often develops symptomatically as progressive onset of exertional dyspnoea. Clear chest sounds with normal chest X-ray are common findings, whereas echocardiography and right-heart catheterization will document a mean pulmonary arterial pressure > 25 mmHg. PAH has been reported in nine patients given dasatinib in a study from the French Pulmonary Hypertension Registry [Montani et al. 2012]. The lowest estimate of incident pulmonary hypertension was 0.45% in chronically dasatinib-exposed patients. Improvement was noted after discontinuation (median 9 months of follow up) but was not fully reversible.

Skin toxicity

Caroline Robert (IGR, Villejuif, Paris, France) provided a concise summary of skin toxicities associated with targeted agents. The skin is a major target for eliciting various visible side effects of targeted agents. Some of the dermatological side effects are mild ‘associated events’ that do not need specific management. However, there are more severe manifestations that can impair quality of life and/or cause significant safety issues. Of considerable importance to the patient is that skin changes may be profound over the course of their therapy; while some may not be life-threatening, they can alter appearance and be of considerable distress.

Epidermal growth factor receptor (EGFR) inhibitors

EGFR inhibitors may cause a range of skin toxicities. Dr Robert explained that folliculitis affecting the face and trunk occurs 1–3 weeks after commencing therapy with an incidence of 60–100% (grades III–IV 5–20%). Xerosis in the fingers becomes apparent after 2–4 weeks on therapy in 15–35% of patients. Paronychia occurs (mostly in the first toenail) among 10–20% of patients within 4–8 weeks of therapy. Finally, hair modifications affecting the scalp (fuzzy hair, frontal alopecia), facial hair and eyelash growth occur in virtually all patients given EGFR inhibitors, usually after 4–8 weeks of therapy. Osio and colleagues have reported similar findings [Osio et al. 2009]. There are differences among EGFR inhibitors; Dr Robert provided a comparison between sorafenib and sunitinib, where there are overlaps in skin manifestations, such as hand–foot skin reaction, subungual haemorrhage and genital rash, but also differences, likely related to different receptor affinities (Table 1). For example, keratoacanthoma and squamous cell carcinoma may be linked to RAF inhibition. (Dr Robert commented that clinicians should ask about genital rash, as most patients do not volunteer to reveal this side effect without prompting.)

Table 1.

Skin manifestations observed with sorafenib and sunitinib.

Drug	Sorafenib	Sunitinib
Targets	VEGFR 1-3, RAF, PDGFR, FLT3	VEGFR 1-3, KIT, PDGFR, FLT3
KA, SCC	+	-
Nevi	+	-
HFSR	++	+
Folliculitis	+/-	+/-
Hair	Alopecia, curly	Depigmentation
Paronychia	-	-
Skin colour	Red (face)	Yellow
Oedema	-	-
SUH	+	+

HFSR, hand-foot skin reaction; KA, keratoacanthoma; PDGFR, platelet-derived growth factor receptor; SCC, squamous cell carcinoma; SUH, subungual haemorrhage; VEGFR, vascular endothelial growth factor receptor.

BRAF inhibitors

BRAF inhibitors, such as vemurafenib and dabrafenib, are effective among patients with active mutations of the BRAF oncogene. The BRAF v600E mutation, found in about half of cutaneous melanomas (and among some patients with non-small cell lung cancer, colorectal cancer and papillary thyroid cancer), leads to activation of the mitogen activated protein kinase (MAPK) pathway and cell growth [Morris and Kopetz, 2013].

The effectiveness of vemurafenib has been proven in metastatic melanoma, but keratoacanthoma and squamous cell carcinoma were observed in 25% of patients, a phenomenon thought to be related to wildtype RAF kinase activation [Chapman et al. 2011]. Dabrafenib is a newer generation V600E-mutant BRAF inhibitor with proven efficacy in metastatic melanoma [Hauschild et al. 2012]; its toxicity profile seems to be more favourable than vemurafenib (Table 2).

Table 2.

Skin manifestations associated with the BRAF inhibitors, vemurafenib and dabrafenib.

Manifestations	Vemurafenib incidence (%)	Dabrafenib incidence (%)	Comments
Rash	37–52 (Grade 3: 6-8)	22	Maculopapular; keratosis pilaris
Photosensitivity	33–49	3	UVA induced
HFSR hyperkeratosis	10–50	50	Rubbing, pressure areas
Hair modification	100	100	May be reversible
Cystic lesions	30	?	Multiple, face
Papillomas	20–50	?	Multiple
KA, SCC	20–30	7	Multiple
Eruptive nevi	?	?	Median time to occurrence 6–8 weeks

HFSR, hand-foot skin reaction; KA, keratoacanthoma; SCC, squamous cell carcinoma; UVA, ultraviolet A.

Single-agent targeted treatments tend to become ineffective over time (disease progression within 6–7 months after starting treatment). This resistance is thought to occur because of activation of MAPK through alternative pathways, such as MEK. A phase I/II trial of dabrafenib plus trametinib (MEK inhibitor) showed that both drugs could be combined safely: compared to mono-treatment, rate of pyrexia was increased (71% versus 26%) whereas rate of squamous cell carcinoma was non-significantly decreased (7% versus 19%) [Flaherty et al. 2012].

In addition to these side effects, there is a case report of severe skin (and liver) toxicity following close administration of radiotherapy with vemurafenib [Anker et al. 20013]. The authors recommend that vemurafenib should be withheld 7 days before and after radiotherapy.

Patients should be warned, before starting treatment, that skin adverse effects will occur and that most of them are manageable. It can be useful to have a dermatologist as part of the management team. Skin side effects might have a significant impact on quality of life. With regard to managing a rash, it is important to look for the presence of severity indicators such as systemic symptoms, eosinophilia, bullous lesions, epidermal detachment and mucosal lesions. Infection, or the effect of other medications, needs to be ruled out. Severity markers include DRESS (drug rash with eosinophilia and systemic symptoms): symptoms are diffuse rash, eosinophilia >1500, systemic signs (fever plus lymphadenopathy, hepatitis, nephritis, neurologic signs), and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (bullous lesions, mucosal lesions and systemic signs).

Symptoms that need to be treated are summarized in Table 3. Symptoms that do not need to be treated (or have no known treatment) include subungual haemorrhage, hair modifications, asymptomatic nail changes, early facial rash (with sorafenib) and yellow skin colour (with sunitinib.

Table 3.

Skin manifestations and possible treatments.

Manifestations	Treatments
HFSR	Prevention, pedicure, keratolysis, emollients
Folliculitis	Topical steroids, oral tetracyclines
Genital rash	Rule out infection, topical steroid
Paronychia	Rule out superinfection, silver nitrate, TCA, surgery
Oral ulcers	Xylocaine, clobetasol
KA, SCC	Surgical excision

HFSR, hand-foot skin reaction; KA, keratoacanthoma; SCC, squamous cell carcinoma; TCA trichloroacetic acid application.

Endocrine toxicity

Fausto Roila (Santa Maria Hospital, Terni, Italy) provided a summary of the most important endocrine toxicities elicited by targeted therapies, covering thyroid dysfunction, hypogonadism, hypopituitarism and secondary hyperparathyroidism.

Hypothyroidism

Thyroid dysfunction, mainly hypothyroidism, is common among patients receiving tyrosine kinase inhibitors (Table 4).

Table 4.

Thyroid dysfunction by tyrosine kinase inhibitors (TKIs).

TKI	Hypothyroidism (%)	Hyperthyroidism (%)
Sunitinib	53–85	10
Sorafenib	20–36	2.6–5
Imatinib	90–100*	0
Motesanib	22	0
Vandetanib	89	0
Axitinib	83–92	16
Pazopanib	10–29	0

^*Only patients who underwent thyroidectomy.

Symptoms of hypothyroidism, such as fatigue, weakness, constipation, depression and cold intolerance may be wrongly attributed to cancer or other chemotherapy agents. In some cases, the dose of chemotherapeutic drug may be reduced or the drug stopped. Also, hypothyroidism can alter the kinetics and clearance of medications, which can lead to undesirable side effects impacting on quality of life.

Recurrent hypothyroidism

Recurrent hypothyroidism, described with imatinib, sorafenib and motesanib, occurs in thyroidectomized patients on stable doses of levothyroxine. Characteristics include increased thyrotropin (TSH) levels within 2 weeks of starting therapy, possible due to enhanced triiodothyronine (T3) and thyroxine (T4) metabolism (clearance by increased activity of 3 deiodinase). Screening involves TSH measurement before treatment and every 4 weeks [titrate levothyroxine (LT4) as requested]. When TSH and dose are stable, it is recommended that TSH be measured every 2 months. In patients receiving imatinib, Dr Roila suggests considering doubling the dose of LT4 at the start of therapy.

De novo hypothyroidism

This has been described with sunitinib, sorafenib and axitinib. It is diagnosed in patients who had regular thyroid function before treatment, and may be caused by thyroid capillary regression that leads to inadequate vascularity and acute or subacute gland destruction. It is recommended that, in patients starting multikinase inhibitors, TSH and T4 concentrations are monitored at baseline and every 4 weeks, then every 2–3 months.

Hypogonadism

Hypogonadism has been reported in 80–100% of male patients receiving the ALK inhibitor, crizotinib, which appears to be a central effect on the hypothalamic–pituitary axis [Sarquis and Salgia, 2013]. It occurs within 2–3 weeks of starting the drug. Symptoms include erectile dysfunction, decreased libido, fatigue, loss of muscle mass and decreased axillary and pubic hair. These symptoms are not routinely assessed in oncology patients, so it is important to ask about them during crizotinib therapy and to check testosterone concentrations. It may be diagnosed by reduction of free and total testosterone concentrations, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations. It is reversible with treatment interruption and symptoms improve with testosterone replacement therapy.

Hypophysitis and/or hypopituitarism

Hypophysitis has been documented with ipilimumab use [Faje et al. 2014]. The dose of ipilimumab seems to influence the rate of hypophysitis. It is thought that CTLA4 blockade by ipilimumab, which allows for T-cell activation and proliferation, is not only responsible for its therapeutic effect, but also for immune-mediated side effects including hypophysitis. Life-threatening adrenal insufficiency may result; however, it is easily diagnosed and treated.

Headache, nausea, vertigo, behaviour change, visual disturbances (e.g. diplopia) and weakness occur an average of 6 weeks after starting therapy. Differential diagnosis includes occurrence of new brain metastases. Magnetic resonance imaging (MRI) scans with gadolinium and selective views of the pituitary can show enlargement or heterogeneity, and confirm diagnosis.

A blood sample should be taken before starting ipilimumab therapy to measure pituitary, thyroid, adrenal and gonadal status [serum morning cortisol, adrenocorticotrophic hormone (ACTH), free T3, free T4 and TSH. Testosterone concentrations should also be determined in males, and FSH, LH and prolactin in females.

There are typically low concentrations of thyroid, adrenal and gonadal hormones in patients with hypophysitis. It is recommended that thyroid function tests, chemistry profile and liver function tests be assessed before each ipilimumab dose.

If symptomatic panhypopituitarism or any grade 3–4 endocrinopathy is found, the ipilimumab dose should be held and an initial dose of intravenous (IV) methylprednisolone (1–2 mg/kg/day) be given, followed by oral prednisone (1–2 mg/kg) once daily, tapered over 4 weeks and accompanied by replacement of deficient hormones. Symptoms usually improve after a few days; radiological observation will show reduced swelling and heterogeneity of the pituitary gland.

Severe dehydration, hypotension or shock may signal adrenal crisis, and IV corticosteroids (with mineralocorticoid activity such as methylprednisolone) are then required. Sepsis or infection also needs to be checked for.

Secondary hyperparathyroidism

Dr Riola stated that secondary hyperparathyroidism has been shown with sorafenib, sunitinib, imatinib and nilotinib therapy. It is characterized by reduced serum phosphate and urinary calcium concentrations together with increased parathyroid hormone (PTH) concentrations (compared with pretreatment), with or without reduced serum calcium concentrations. Dr Roila stated that routine biochemical monitoring may not be necessary with sunitinib, imatinib and nilotinib therapy. However, hypovitaminosis D, in association with hyperparathyroidism, may contribute towards sorafenib-induced sarcopenia and may lead to osteomalacia. Vitamin D supplementation in these patients may correct hypophosphataemia and PTH concentrations.

Hypophosphataemia occurs frequently with everolimus [Toffalorio et al. 2014] and has also been reported for HDAC, MEK and ALK inhibitors. Dr Roila believes that periodic monitoring is recommended with phosphate supplementation and drug interruption need only occur in severe cases.

Conclusions

Endocrine toxicity induced by some targeted therapies may have a negative impact on quality of life. Symptoms such as fatigue and headache may be ascribed to the cancer or accompanying chemotherapy, but may in fact be due to endocrine toxicity by a targeted therapy. Collaboration with an endocrinologist as part of the treatment team is beneficial.

Gastrointestinal toxicity

Lactose intolerance, small intestinal bacterial overgrowth (SIBO) and bile acid malabsorption frequently develop during or after a course of chemotherapy. The symptoms experienced, e.g. bloating, wind, diarrhoea and urgency [Andreyev et al. 2014; Gillespie et al. 2007], negatively impact on quality of life [Andreyev et al. 2012] and may impair optimal cancer therapy. Dr Jervoise Andreyev (Royal Marsden, London, UK) stated that their recognition and management is below par. Indeed, some gastrointestinal toxicities may be rated as extremely debilitating by patients yet are widely regarded as unimportant by healthcare professionals.

Diarrhoea as an example

Dr Andreyev presented a summary of the occurrence of grade 3–4 diarrhoea across recent randomized controlled trials (Table 5). He cited a personal communication from Professor David Ferry (New Cross Hospital, Wolverhampton, UK), which showed that, in the UK, there are 75,000 persons treated with fluorouracil (5-FU) where grade 3 diarrhoea occurs in at least 15% (i.e. 11,000/year) with 1–5% mortality (750–3750/year). The mechanism of diarrhoea is still under debate with no proven genetic polymorphism [Andreyev et al. 2014]. Dr Andreyev contended that symptoms are unlikely to assist diagnosis. He presented a case of a 32-year old female patient (cord blood transplant) who developed diarrhoea on successive occasions over a 35-week period. At week 7, graft-versus-host disease (GvHD) was diagnosed as the cause and her diarrhoea settled after a course of tacrolimus plus steroids. At week 11, diarrhoea recurred and Klebsiella was found with a possible diagnosis of SIBO; this was treated with ciprofloxacin and the diarrhoea settled again. At week 14, SIBO occurred again, this time Escherichia coli was found and was treated with doxycycline. At week 17, cytomegalovirus was found after the diarrhoea occurred once again, and the patient received valgancyclovir. Diarrhoea recurred again at week 20 because of small intestinal Candidal overgrowth and she was treated with fluconazole/amphotericin. Finally, at week 35, diarrhoea occurred again. This time, history was reviewed and it showed that lansoprazole use throughout may have been the cause. Thus, identical symptoms may arise for many different reasons.

Table 5.

Frequency of grade 3–4 diarrhoea across randomised clinical trials.

Study	Regimen	Grade 3–4 diarrhoea (%)
Saltz et al. [2001]	Irinotecan	6
	Irinotecan + infused 5-FU/FA	15
O’Shaughnessy et al. [2002]	Docetaxel	5.4
	Docetaxel + capecitabine	14.4
Chau et al. [2005]	Bolus 5-FU + FA	16
	Infused 5-FU	5
Falcone et al. [2007]	FOLFOXIRI	20
	FOLFIRI	12
Fuchs et al. [2007]	FOLFIRI	14
	mIFL	19
	capeIRI	47
Van Cutsem et al. [2011]	FOLFIRI	10.5
	FOLFIRI + cetuximab	15.7
Tviet et al. [2012]	FLOX	10

5-FU, 5-fluorouracil; capeIRI, capecitabine plus irinotecan; FA, folinic acid; FLOX, 5-FU/FA/oxaliplatin; FOLFIRI, FA/5-FU/irinotecan; FOLFOXIRI, 5-FU/FA/oxaliplatin/irinotecan; mIFL, modified irinotecan/FA/5-FU.

An insult to the gastrointestinal tract may result in carbohydrate malabsorption, dysmotility (promoting bacterial overgrowth), fat malabsorption, vitamin and bile acid malabsorption, and altered sphincter function. However, there has been little research effort to identify the cause for cancer therapy induced gastrointestinal symptoms, even though they are frequent. As a result, they are rarely identified or properly treated.

Easily treated conditions

SIBO

SIBO accounts for 39% of the diagnoses for cancer therapy induced symptoms in Dr Andreyev’s clinic. Symptoms associated with SIBO are shown in Table 6.

Table 6.

Symptoms associated with SIBO [Grace et al. 2013].

Symptom	% of patients
Abdominal pain	10–50
Belching	54
Bloating	13–86
Borborygmi	63
Diarrhoea	13–89
Flatulence	55
Gastric stasis	20
Nausea/vomiting	23–27
Steatorrhoea	11–38

Diagnosis of SIBO involves a glucose hydrogen/methane breath test and a duodenal aspirate. If the test is positive, and there are >1 × 10³ colony-forming units (cfu), then antibiotics may be given empirically (rifaximin, ciprofloxacin, doxycycline, metronidazole) [Grace et al. 2013].

Bile acid malabsorption (BAM)

Dr Andreyev regards this as a forgotten condition. It may affect 1% of the population and is usually misdiagnosed as irritable bowel syndrome (IBS). It affects 21% of patients in his clinic. Diagnosis involves SeHCAT (23-seleno-25-homo-tauro-cholic acid) scanning (nuclear medicine) and is 98–100% sensitive and specific.

Dr Andreyev and colleagues conducted a retrospective chart review of the efficacy of colesevelam in 45 patients who developed BAM after cancer chemotherapy [Wedlake et al. 2009]. Colesevelam produced a general improvement in symptoms (diarrhoea, frequency of defecation, urgency of defecation, steatorrhea, abdominal pain and faecal incontinence).

Lenalidomide, prescribed long-term in multiple myeloma, causes diarrhoea in 5% of patients. In one small study [Pawlyn et al. 2014], in 12 patients, gastrointestinal function deteriorated 1–15 months after starting lenalidomide therapy; symptoms included diarrhoea (100% of patients), frequency (6 times a day), urgency (92%), faecal incontinence (58%) and abdominal cramp (42%). SeHCAT scan was abnormal in all patients (mild BAM = 1, moderate BAM = 2, severe BAM = 9). Two patients received a low fat diet alone and 10 were given off-label colesevelam. A reduction in stool frequency and improvement in Bristol Stool Chart was seen in all patients, and 50% attained normal bowel habit. No dose reduction or withdrawal of drug was necessary.

Conclusions

While cancer-treatment induced nausea and vomiting has been tackled successfully, this is not the case for other, often neglected, gastrointestinal symptoms. However, some of these symptoms are easily treated. Oncologists should actively measure, assess and manage gastrointestinal symptoms in patients who are receiving cancer treatments.

Practical guidance on the management of chemotherapy-induced diarrhoea has been published recently by Dr Andreyev and colleagues [Andreyev et al. 2014]. Patients and their carers need to be told about the risks associated with chemotherapy-induced diarrhoea and how it may be managed. Items such as when to use loperamide, and how to replace fluids is the next step. If diarrhoea can be treated, it will likely prevent unnecessary drug reduction/withdrawal, potentially improving outcomes.