Clozapine and cancer treatment: Adding to the experience and evidence.

The judiciousness of the use of clozapine in patients with schizophrenia in clinical practice is brought to an even sharper focus when it has to be used in combination with other agents that cause myelosuppression, for example, chemotherapy and radiation treatment. There are a few references till date illustrating the combination of clozapine and chemotherapy and/or radiation therapy. To the best of our knowledge, such a case has not been reported from India. We report the case of a 39-year-old gentleman with a diagnosis of schizophrenia, remaining psychiatrically stable on clozapine, who underwent combination treatment of chemotherapy and radiotherapy for the treatment of cancer of the tongue in a tertiary care oncology centre in India.

INTRODUCTION

The importance of the judicious use of clozapine in patients with schizophrenia in clinical practice is brought to an even sharper focus when it has to be used in combination with other agents that cause myelosuppression, for example, chemotherapy and radiation treatment. Chemotherapy can cause can cause marked bone marrow suppression, leading to neutropenia and thrombocytopenia. Radiation therapy can have acute effects on the bone marrow too. The use of clozapine with other agents, which cause leukopenia is a formal contraindication. Clozapine has to be usually discontinued if the white blood cell count drops below 3000 per cubic millimetre. Discontinuation of clozapine, however, may lead to a risk of relapse in those patients with schizophrenia who have been well controlled with this medication. This gives rise to a therapeutic tight spot and the effective management of both schizophrenia and cancer requires an intensive liaison between the oncology and the psychiatry teams responsible for care of the patient. There are a few references till date illustrating the combination of clozapine and chemotherapy and/or radiation therapy.[123] To the best of our knowledge, such a case has not been reported from India. We report the case of a 39-year-old gentleman with a diagnosis of schizophrenia, remaining psychiatrically stable on clozapine, who underwent combination treatment of chemotherapy and radiotherapy for the treatment of cancer of the tongue, in a tertiary care oncology centre in India.

CASE REPORT

A 39-year-old gentleman was being treated for paranoid schizophrenia since the onset of positive psychotic symptomatology in 1996 and had been on clozapine for 7 years prior to his presentation in our cancer hospital, in the dose of 300 mg (in daily divided doses). He was also on a combination of trifluoperazine 2.5 mg and trihexyphenidyl 1 mg 3 times a day. Though he did have occasional auditory hallucinations, overall he remained psychiatrically stable. He did not report any distressing side-effects of the medications except for excess salivation. He was diagnosed with cancer of the tongue T4N2bM0 moderately differentiated squamous carcinoma in August 2009. Detailed investigations showed that the tumor was borderline inoperable, which led to institution of platinum- and taxane-based neoadjuvant chemotherapy, each chemotherapy cycle lasting for 3 weeks.

As a formal nationally co-ordinated clozapine monitoring protocol in India is not present, previous annual complete blood count reports were lacking. However, there was no history suggestive of infection and the complete blood count done in the hospital prior to starting chemotherapy was essentially within normal limits (white blood cell count 10,400 per cubic millimetre (mm) and neutrophils 8,160 per cubic mm, hemoglobin of 13.3 g/dl, platelets 387,000 per cubic mm). The dose of clozapine was reduced by the institute-based liaison psychiatrist to 250 mg in daily divided doses before chemotherapy started in an attempt to reduce the hypersalivation, which was helpful and did not lead to any exacerbation of psychotic symptoms. A decision to continue on clozapine in this dose was taken following a detailed discussion between the liaison psychiatrist with patient and his brother, discussing the benefits and risks associated, with regular monitoring schedules fixed for mental state examination, complete blood counts and medications. Though the white blood cell count monitoring was advised 17 days following the start of the first cycle of chemotherapy, it was decided that it be done earlier than that, in view of the concurrent treatments.

A complete blood count done on the 10th day in a private laboratory following start of first chemotherapy cycle revealed a drop in the white blood cell count to 2300 per cubic mm, neutrophils were 79%, platelet count of 250, 000 per cubic mm and hemoglobin of 10.3 g/dl. The patient developed high grade fever and mucositis, for which he was assessed on the 11th day and daily subsequently for the next week by the medical oncologist. The white blood cell count repeated on the 12th day, this time in the hospital laboratory, revealed a further drop to 1000 per cubic mm. Patient was started on antibiotics and granulocyte colony stimulating factor, following which the white blood cell counts improved on the 17th day to 8910 per cubic mm. As the platelet count was low, patient received platelet transfusion.

In the course of these events in these 8 days from 10th to 17th day following start of chemotherapy, the liaison psychiatrist after discussing with patient and his brother had earlier reduced the dose of clozapine to 200 mg daily in divided doses on the 5th day, considering the possible synergistic effect of the drug, as reported in literature[4] and a watch was kept on the mental state. But further discussion between the psychiatrist and the consultant medical oncologist and also between the former and the patient with his brother, led to the decision of maintaining patient in the same dose of clozapine, keeping in view the patient's psychiatrically stable condition and to prevent rebound psychosis leading from any further reduction, as this neutropenia seemed to be related to the chemotherapy.

By the 18th day, which was originally suggested as the day for monitoring post first chemotherapy cycle, when the complete blood count was repeated, the white blood cell count was 10,800 per cubic mm and neutrophil count 7680 per cubic mm, (essentially within normal limits), but still a low haemoglobin of 10.3 g/dl and a manual platelet count of 100,000 per cubic mm.

The pre-planned second cycle of chemotherapy was delayed by just 6 days following completion of the first cycle and a third cycle was added at the scheduled time after imaging and reassessment by the multidisciplinary Head and Neck Joint Clinic of the hospital. Growth factors were started on day 6 of each of these cycles as a preventive measure, in view of the experience of the first cycle. The white blood cell and neutrophil counts remained within normal limits after the second cycle but dropped to 2400 per cubic mm and 570 per cubic mm respectively after the third cycle. These stabilized to normal limits within the next 2 weeks. The dose of clozapine that the patient was on remained unchanged [Figure 1].

Figure 1

White blood cell count during cancer treatment course. 1 CT – First chemotherapy cycle; 2 CT – Second chemotherapy cycle; 3 CT – Third chemotherapy cycle; Wk – Week; D – Day; Pall RT – Palliative radiation therapy; MT – Metronomic therapy

At this stage, a further reassessment by the head and neck oncology group advised radiation therapy with a palliative intent in view of progressive disease. The psychiatry team liaised with the consultant radiation oncologist prior to scheduling of radiotherapy sessions, with continuation of weekly monitoring protocols for mental state examination and complete blood counts. The patient underwent palliative external radiotherapy to face and neck to a dose of 50 Gy in 20 fractions, which led to partial relief in pain and swallowing. During this period, his mental state remained stable and white blood cell counts were maintained within normal limits, continuing so during the 2 months following completion of radiation treatment. To palliate further, metronomic therapy was then advised, which the patient underwent, with regular psychiatric review and weekly complete blood counts over the next 2 months. There was no resurgence of psychotic symptoms. Unfortunately, he had a rapid progression of disease and developed local infection. The white blood cell count increased to 13,600 per cubic mm and later to15,600 per cubic mm. He passed away 2 weeks later, nearly 8 months following his initial diagnosis.

DISCUSSION

The sequence of events described above underlies the importance of frequent monitoring of white blood cell counts when clozapine and cancer treatments are concomitantly administered. The normal white blood cell count prior to the onset of chemotherapy and subsequent drop following it, with improvements after the chemotherapy cycles, were maintained during and after radiation treatment. This makes the possibility of a synergistic effect less likely in this particular case, and no persistent neutropenia is noted, unlike in other cases reported in the literature.[5]

In previously reported cases, clozapine replaced by haloperidol[67] and olanzapine[8] following neutropenia led to a psychotic relapse, which necessitated reintroduction of clozapine. Considering this evidence, the continuation of clozapine despite the steep drop in the total white blood cell and the absolute neutrophil count following the first chemotherapy cycle, though a difficult decision to make, was aided by extensive discussion and shared decision making between the liaison psychiatrist and medical oncologist, and also with the patient and his brother, who was the primary caregiver. This step was followed during radiation therapy too. The proactive use of colony stimulating factor in the subsequent chemotherapy cycles proved useful, as reported in the literature.[7]

CONCLUSION

It is possible to continue clozapine in a patient with chronic schizophrenia undergoing chemoradiation for cancer with close supervision and collaboration with oncology clinicians. As the evidence in this topic is limited and controlled trials would not be possible, it is important to share the experience and add to the existing literature to facilitate an informed decision making by the clinicians in managing dually vulnerable patients with comorbid schizophrenia and cancer.