Fatal chemotherapy overdose during clinical trial

This article by Mark Bowman, senior associate in our medical negligence department, first appeared in Clinical Risk 2010, volume 16, number 3

Abstract

Patient overdosed with bleomycin on seven occasions. Family not notified until after patient embalmed. Liability initially disputed despite coroner’s findings. Liability eventually admitted.

Quantum still in dispute.

Background

Mr F, a graphic designer, aged 27 years at the time, started to suffer symptoms of lower back pain between February and May 2007, during which time he visited his GP and various NHS walk-in centres on a number of occasions.

His symptoms were put down to a muscular strain, and in spite of him also reporting an inability to ejaculate, no further action was taken. Eventually on 15 May 2007 his GP palpated a mass on the right testis and referred him to a urologist at the Princess Alexandra Hospital. An ultrasound scan confirmed a mass in the right testis.

On 25 May 2007 Mr F underwent a right orchidectomy. Histology revealed a malignant teratoma of the right testis and Mr F was referred to UCLH, the Defendant hospital. Mr F was initially seen at UCLH on 4 June 2007 and an urgent CT scan was arranged. This revealed multiple lung secondaries, liver secondaries, and  mediastinal lymphadenopathy.

On 6 June Mr F was seen by a specialist registrar (SpR) as well as by a clinical trial research sister, who enquired as to whether Mr F wished to be included in the Medical Research Council (MRC) TE23 Clinical Trial, which compared standard chemotherapy with an experimental regimen comprising longer and more intensive and complicated scheduling of various cytotoxic drugs, most notably bleomycin. Mr F consented to enter the trial and was randomized into Arm 2, in which the experimental treatment would be given.

The TE23 Clinical Trial

This trial, funded by Cancer Research UK, sponsored by the MRC and run by the MRC’s Clinical Trial Unit, was a randomized phase II trial in patients with advanced, metastatic germ cell cancers classified as ‘poor prognosis’ according to the Germ Cell Classification.

The trial opened in June 2005 and closed to recruitment in December 2009 with 89 patients having entered. Analysis is currently awaited as to the success of the trial.

The author of this article also acts for the family of another patient who died following treatment on the trial; therefore, it is known that at least two of the 89 patients died on the trial.

The trial compared the most widely used standard chemotherapy for testicular cancer – four courses of a regimen known as ‘BEP’ which contains bleomycin, etoposide and cisplatin (cisplatin containing platinum, hence the ‘P’), together known as ‘Arm 1’, with an alternative regimen, which delivers six weeks of treatment using the four drugs of carboplatin, bleomycin, vincristine and cisplatin (vincristine, having previously been known as oncovin, hence the ‘O’), known together as ‘CBOP’ followed by three courses of ‘BEP’, together forming ‘CBOP-BEP’ or ‘Arm 2’.

Notably in Arm 2, bleomycin is to be given at a lower dose (50%) in the ‘BEP’ section, than in Arm 1. In Arm 1 a patient will receive 30,000 units of bleomycin on a weekly basis for a total of 12 weeks. In addition, etoposide and cisplatin are provided in weeks 1, 4, 7 and 10 at 500 mg/m2 and 100 mg/m2, respectively. In Arm 1, a patient will, therefore, receive a total of 360,000 units of bleomycin over a 12-week period.

Table 1 shows what doses a patient should receive in Arm 2. In Arm 2 a patient should, therefore, receive a total of 345,000 units of bleomycin over a 15-week period, less than in Arm 1, over a longer period of time. Given that Mr F’s case concerned the use of bleomycin, the below shall largely deal with the doses of bleomycin given as opposed to the doses of the other drugs also provided, all of which were correctly prescribed.

Table 1 Dosage received in Arm 2
Week Dosage
1 Bleomycin 15000 iu Vincristine 2 mg Cisplatin 100 mg/m2 over two days
2 Bleomycin 75 000 iu over five days Vincristine 2 mg Cisplatin 40 mg/m2 Carboplatin dose 3 sum of GFR þ 25 mg
3 Bleomycin 15000 iu Vincristine 2 mg Cisplatin 100 mg/m2 over two days.
4 Bleomycin 75 000 iu over five days Vincristine 2 mg Cisplatin 40 mg/m2 Carboplatin dose 3 sum of GFR þ 25 mg
5 Bleomycin 15000 iu Vincristine 2 mg
6 Bleomycin 15000 iu Vincristine 2 mg Conclusion of ‘CBOP’ phase of treatment and start of modified ‘BEP’ treatment
7 Bleomycin 15000 iu Cisplatin 100 mg/m2 given over five days Etoposide 500 mg/m2 given over five days
8 Bleomycin 15000 iu
9 Bleomycin 15000 iu
10 Bleomycin 15000 iu Cisplatin 100 mg/m2 given over five days Etoposide 500 mg/m2 given over five days
11 Bleomycin 15000 iu
12 Bleomycin 15000 iu
13 Bleomycin 15000 iu Cisplatin 100 mg/m2 given over five days Etoposide 500 mg/m2 given over five days
14 Bleomycin 15000 iu
15 Bleomycin 15000 iu

Treatment at UCLH

Chemotherapy commenced on 7 June 2007 and Mr F received the correct dose of bleomycin of 15,000 units. On 15 June 2007 Mr F received the correct dose of bleomycin, 75,000 units, to be spread over five days. The treatment provided on 7 and 15 June 2007 marked the conclusion of the first cycle of treatment.

A second and third cycle of treatment, both in two parts as per the first cycle, were provided on 22 June, 29 June, 6 July and 13 July 2007. Mr F received appropriate doses of bleomycin on each occasion. Mr F also received the correct doses of etoposide and cisplatin throughout this period. On 13 July 2007 Mr F in fact received no bleomycin as opposed to the 75,000 units that were due, as a result of some low blood counts. No criticism was made of this decision.

The conclusion of the third cycle marked the end of the six-week period in which Mr F received ‘CBOP’ chemotherapy.

No errors were made up until this point. From 31 July 2007, Mr F, therefore, moved into the ‘BEP’ phase of the ‘CBOP-BEP’ regimen. Had Mr F been in Arm 1, he would have been due to receive 30,000 units of bleomycin weekly from 31 July 2007. As he was in fact in Arm 2, he was meant to receive 15,000 units on a weekly basis.

Tests

Within the TE23 trial there are a number of procedures set out to assess a patient’s wellbeing throughout the course of his chemotherapy. The trial documentation in force at the time (it has subsequently been amended) clearly set out that patients should, before each cycle of treatment, receive physical assessments and assessment of WHO performance status, full blood count and chest X-rays.

Chest X-rays were performed on 15 June, 31 July, 22 August and 12 September 2007. None of the reports raised any concerns as to Mr F potentially suffering the sideeffects of bleomycin toxicity.

Bleomycin toxicity

Bleomycin is known to have a number of serious sideeffects. Within the TE23 Trial’s own documentation the most important of these were noted to be pneumonitis and lung fibrosis. It also stated that the risk of such complications increased with the total dose employed.

In the event of such symptoms, shortness of breath or fine rales on auscultation (crackling noises on listening to the lungs), then bleomycin should be immediately stopped. It also advises that patients presenting with a dry cough should inform their doctor immediately.

It was, in 2007, broadly accepted that around 10% of patients receiving bleomycin for treatment of germ cell cancers would suffer bleomycin toxicity.

In 10–20% of those cases (i.e. 1–2% overall) such a condition would prove fatal. Therefore, in most cases, patients would survive such toxicity, if indeed they developed symptoms at all. It was hoped that the TE23 trial would improve on these figures.

Diagnosis of bleomycin toxicity

At the end of August, Mr F started to develop a dry cough. This was reported to his GP on 6 September 2007. On 11 September 2007 Mr F was given further bleomycin. On 14 September 2007 the cough was noted in the Defendant’s records, as was a lack of sensation in Mr F’s feet. An annotation within the records confirmed that the chest X-ray of 12 September 2007 was unchanged from that of 22 August 2007. On 18 September 2007 it was recorded that Mr F had started to become tired and breathless and his lung function tests deteriorated markedly. A diagnosis of bleomycin toxicity was made.

Deterioration in health

At this stage bleomycin was stopped and Mr F was prescribed with prednisolone (a steroid). Mr F’s health continued to deteriorate and he was admitted to the ICU on 8 October 2007. Examination revealed surgical emphysema in the neck and bilateral basal crackles on auscultation of the lungs. The diagnosis was of increasing bleomycin lung toxicity. The dose of prednisolone was increased.

A CT scan at the time revealed an almost complete resolution of Mr F’s mediastinal lymphadenopathy and no visible lung secondaries. However, there was extensive volume loss in both lungs together with linear and fibrotic shadowing and bilateral pleural thickening.

Despite ventilatory treatment, Mr F died on 14 October 2007.

Postmortem?

On 17 October 2007, Mr F was taken to the funeral directors by his family and was embalmed. On 18 October his family received a call from UCLH to inform them that there had been issues with Mr F’s treatment. The family were told that UCLH had first appreciated this on 16 October 2007, prior to Mr F being embalmed.

In fact the MRC, on suspecting that Mr F (and indeed another patient where a similar error was made but without fatal consequences), had been overdosed, wrote (as opposed to calling immediately) to UCLH on 3 October 2007 to inform them of this suspicion.

The letter was not opened at UCLH until 16 October 2007. On 19 October 2007, Mr F’s family received a call from the coroner asking them to return the body for a postmortem. They explained this was no longer possible as he had already been embalmed. No postmortem was performed.

Subsequent to the above, the TE23 trial was suspended at UCLH.

The inquest

Following Mr F’s death, instructions were received to represent the family at his inquest and also to investigate a potential medical negligence claim. The inquest was held at St Pancras Coroner’s Court on 2 September 2008. During the course of the inquest, the Principal Investigator for the Trial at UCLH confirmed the following:

1. At the outset of his treatment, even with liver disease, Mr F had a 60% chance of survival;
2. Generally 1–2% of patients treated with bleomycin will die of damage to their lungs;
3. Mr F probably had symptoms (of bleomycin toxicity) on 11 September 2007 when he complained of having a dry cough;
4. If damage is sufficiently severe to cause symptoms you should stop bleomycin and confirm the diagnosis. If the radiological appearances are worrying you then should give a high dose of steroids;
5. Mr F’s tumour was in remission and had shown a good response to treatment;
6. Mr F had been overdosed on seven occasions, by being given 30,000 units as opposed to 15,000 units of bleomycin.In fact, Mr F was incorrectly prescribed 30,000 units of bleomycin on 31 July, 7 August, 14 August, 21 August, 28 August, 4 September and 11 September 2007 (weeks 7–13). This represented an overdose of some 105,000 units, almost 33% of the total bleomycin he was due to receive. The total dose of bleomycin given to Mr F was, therefore, 405,000 units;
7. In his opinion, Mr F died of pulmonary fibrosis as a result of bleomycin toxicity;
8. Had Mr F received a smaller dose of bleomycin, his chance of dying would have been considerably less.

In concluding the inquest, the Coroner confirmed that he was: ‘satisfied on the evidence that I’ve heard that the cause of Mr F’s death was interstitial pulmonary fibrosis or interstitial lung disease that was due to, or as a consequence of, a bleomycin overdose. . . I am satisfied on balance that the cause of Mr F’s death was due to the overdose of bleomycin that he received.’

Admission?

Following the inquest, a letter of claim was promptly served on UCLH. A large number of allegations were made, based on the evidence heard at the inquest. UCLH admitted breach of duty insofar as they overdosed Mr F on the above seven occasions but failed to respond to the other allegations raised.

In addition, in spite of the evidence given at the inquest and the coroner’s verdict, causation remained firmly in dispute and UCLH wished to obtain their own evidence.

A lengthy period (12 months) was given for UCLH to undertake such investigations but in the absence of any progress, the author was left with no alternative but to obtain expert evidence in order to examine the position as to causation and also to examine further potential breaches of duty, so that proceedings could be issued in order to minimize any further delay.

Expert evidence

Expert evidence was obtained from Professor Peter Clark, Consultant Oncologist, and from a consultant radiologist.

Following receipt of their reports, the Claimant’s position could be broadly summarized below.

Breach of duty

1. UCLH failed to take chest X-rays before each cycle of treatment as they should have done according to the TE23 trial’s own documentation. In particular, chest X-rays were not taken before the fourth and fifth cycles commencing on 31 July and 21 August 2007, respectively.
2. The chest X-rays that were taken, were taken after the commencement of each cycle of treatment, as opposed to before each cycle. It was argued that the primary purpose of the chest X-rays is to identify any potential damage to the lungs and, therefore, it is imperative that they take place before the next cycle of treatment commences.
3. The chest X-rays that were taken were misreported. In particular, the X-ray of 31 July was alleged to have shown bilateral areas of atelectasis and a raised left hemi-diaphragm. The X-ray of 22 August 2007 was alleged to have shown a raised left hemi-diaphragm and continued to show bilateral basal atelectatic changes and some areas of reticular shadowing in both lung lower zones. It was argued that while the chest X-ray of 31 July 2007 showed signs that were merely suspicious of bleomycin toxicity, the chest X-ray of 22 August 2007 revealed bleomycin toxicity. In both cases, bleomycin should have been stopped.
4. Mr F was overdosed on the seven occasions referred to above.

Causation

1. Bleomycin should have been stopped following the chest X-ray of 31 July 2007, which revealed signs suspicious of bleomycin toxicity.
2. Had this taken place, then Mr F would never have been overdosed. Instead he would have been started on an alternative treatment regimen in respect of his testicular cancer without the use of bleomycin.
3. Given the excellent response that he had made to his treatment thus far, such treatment would have cured his testicular cancer in any event.
4. Furthermore, the deceased would not have died from bleomycin toxicity.

The claims made at 3 and 4 above were based on the following European Society of Medical Oncology guidelines:

• With regard to the argument that the testicular cancer would have been cured in any event, this was based on the contents of the current European Society of Medical Oncologyguidelines for the management of teratoma. This confirmed that patients in the poor prognostic category (of which MrF was one) are thought to have a long-term cure rate of their disease of 60%.

The Royal Marsden Study

With regard to the argument that Mr F would not have died from bleomycin toxicity, a study conducted at the Royal Marsden Hospital was referred to.

This study is the largest study into bleomycin toxicity. Within it, 835 patients with metastatic germ cell tumours were studied. Of the 835 patients, 57 developed bleomycin toxicity (7%), and eight (1%) died from such a condition. Within the study it was clear that, in particular, there were four factors which adversely influenced the likelihood of a patient developing bleomycin toxicity and dying from such a condition. These were:

1. Glomerular filtration rate of , 80 mls/min;
2. Stage IV disease;
3. Age over 40 years;
4. Cumulative dose of bleomycin of over 300,000 units.

At the outset of Mr F’s treatment, though he was under 40 years old, he fell within the risk categories for items 1, 2 and 4 above. However, with appropriate treatment it was alleged that Mr F would not have received any further bleomycin following the chest X-ray of 31 July 2007.

Had this X-ray been performed before Mr F had received the latest dose of bleomycin, he would have only have ever received a total dose of 195,000 units (210,000 units if the dose of 31 July 2007 had been given).

Mr F, therefore, should not have received a cumulative dose of over 300,000 units. Therefore, according to the figures contained within the study, the risk of Mr F developing bleomycin toxicity would have been 22%.

The risk of developing fatal toxicity would have been far less.

Full admission

On the basis of the above evidence preparations were made to serve proceedings. As it was, just prior to the service of proceedings, on 26 November 2009, over two years after he passed away, UCLH admitted liability for Mr F’s death, having concluded their own investigations into causation. Quantum remains firmly in dispute with investigations being undertaken relating to the dependency claim as well as the secondary victim claims of Mr F’s fiance´e and his parents, who all witnessed his demise. It is hoped that the claim will reach a conclusion via settlement or trial listed in December 2010.