Forum

American Society of Clinical Oncology

The annual meeting of the American Society of Clinical Oncology was held in San Francisco, California, from May 12 to 15. Maxwell Summerhayes, principal oncology pharmacist at Guy’s and St Thomas’ Hospital, London, reports

Ways to make cancer treatment smarter
Managing toxicity
Posters

Dr Summerhayes carries out consultancy work for a number of pharmaceutical companies, including Roche Products, which paid for his attendance at this conference

Ways to make cancer treatment smarter

The meeting heard many presentations dealing with new classes of anticancer drugs that interact with cellular growth factors and their receptors, and antiangiogenic agents designed to starve tumours by preventing them from developing an adequate blood supply. Although these presentations attracted a huge amount of interest, most were of data from preclinical studies or early clinical trials with agents still some way from routine clinical use.

Exceptions were the papers given pride of place in the plenary session which described the use of imatinib (STI-571, Glivec; Novartis) in the treatment of gastrointestinal stromal cell tumours (GISTs). As Dr Charles Blanke, Oregon Sciences University, explained, GISTs are rare tumours, with about 5,000 new cases diagnosed in the US each year. They can affect any part of the gut, but most commonly arise in the stomach and are highly resistant to standard cytotoxic therapies.

Dr Blanke said that GISTs all exhibit high levels of KIT — a growth factor receptor which incorporates a tyrosine kinase (TK) enzyme, which is usually involved in transmission of the growth stimulus from the cell surface to the cell nucleus. In most GISTs, the KIT is mutant and the TK is activated even in the absence of growth factor. These KIT abnormalities seem to be crucial to the malignant behaviour of GIST cells.

Therefore, Dr Blanke said, GISTs had seemed an ideal target for treatment with imatinib. This drug is at advanced stage in development as a treatment for chronic myeloid leukaemia, where it acts by the inhibition of the bcr-abl TK, but it also inhibits the KIT TK with even greater potency.

Dr Blanke’s research team managed to recruit 148 patients to a randomised phase II study. Patients received 400mg or 600mg oral imatinib once daily for up to 24 months. Of those patients receiving the higher dose, 68 per cent had an objective antitumour response and only 5 per cent had progressive disease as their best response. Furthermore, after a median follow-up of 4.5 months, no responding patient had progressed. This was despite the fact that there had been only a 1 per cent response rate to cytotoxic chemotherapy among the 55 per cent of patients who had previously received such treatment. Imatinib was generally well tolerated, though bleeding from the tumour, possibly related to tumour necrosis and regression, was a problem in some cases.

Managing toxicity

New ways of managing the toxicity associated with chemotherapy were also reported. Two presentations concentrated on the use of recombinant keratinocyte growth factor (rKGF) to prevent the painful mouth ulcers that often attend chemotherapy. The first was by Dr STEPHEN CLARKE, Royal Prince Alfred Hospital, Camperdown, Australia, who explained that rKGF stimulates the proliferation and damage resistance of epithelial cells lining the gastrointestinal mucosa and protects animals against experimentally induced mucosal injury, making it an obvious candidate as a mucosal protective during chemotherapy.

Dr Clarke and his colleagues tested rKGF in patients receiving the “Mayo” combination of 5-fluorouracil and folinic acid for the treatment of colorectal cancer.

He said that they selected this patient group because the Mayo regimen reproducibly causes some mucositis in around 70 per cent of patients, with 20 to 30 per cent experiencing severe ulceration.

In their study, Dr Clark’s group randomised 64 patients to receive rKGF (40µg/kg) or placebo subcutaneously once a day for three days before each of the first two cycles of chemotherapy.

They found that the incidence of World Health Organization grade 2–4 mucositis dropped from 78 per cent to 32 per cent (P=0.001) in rKGF recipients and the duration of ulceration declined from 10.2 days to 3.4 days (p=0.001). The reduction in mucosal toxicity enabled chemotherapy intensity to be maintained. Only 14 per cent of rKGF recipients required a greater than 10 per cent reduction in their chemotherapy dose between their first and second courses compared with 31 per cent of those receiving placebo. Treatment withdrawals were also much less common in the rKGF recipients — 4 per cent versus 17 per cent of placebo patients. Toxicity of rKGF was limited to a slight excess of skin reactions, taste disturbances and a sensation of “tongue thickening” in recipients of active drug.

In another study, Dr Ricardo Spielburger, of Duarte, California, had found rKGF to be useful in ameliorating mucositis in patients receiving high doses of chemoradiotherapy before stem-cell transplantation for haematological malignancies. Patients were randomly allocated to one of three treatment groups. All patients received two three-day blocks of treatment, one just before chemotherapy and the other immediately after stem cell return. One group received placebo throughout, one received active drug during the first period only and the last cohort got active drug during both treatment periods. rKGF was administered intravenously at a dose of 60µg/kg/day. Even against this severe challenge, rKGF significantly reduced the duration of severe mucositis from 7.7 days in the placebo group to 5 days and 4 days in the pre- and pre-plus-post rKGF groups, respectively. The use of rKGF was also associated with mucositis-related problems, such as difficulties in swallowing, drinking, eating, talking and sleeping and a reduced requirement for IV opiate analgesia and parenteral nutrition.

Posters

Two interesting poster presentations dealt with the use of older drugs to counteract troublesome chemotherapy side effects.

Dr Florian Eckel (Munich, Germany) and colleagues reported successfully using carbamazepine to prevent the development of the dose-limiting toxicity that complicates oxaliplatin treatment. In a pilot study, they added oral carbamazepine, at doses sufficient to produce serum concentrations of 3–6mg/L, to the treatment regimen of patients receiving chemotherapy which included 85mg/m2 oxaliplatin once every fortnight. Among a group of 10 patients, who had received a median dose of 510mg/m2 oxaliplatin plus the anticonvulsant, 60 per cent had developed some signs of neuropathy, but this was never worse than WHO grade 1 in severity. This compared favourably with an 87 per cent incidence (30 per cent grade 2–4) of neuropathy in patients previously treated with the same dose of oxaliplatin without carbamazepine co-treatment.

Dr Mary Kay Lauman and colleagues from Washington University did a retrospective analysis of the value of pyridoxine in the management of capecitabine-induced palmar-plantar erythrodysasthesia (PPE; hand-foot syndrome) — a reddening, drying and soreness of the palms of the hands and soles of the feet associated with chronic exposure to a variety of cytotoxic drugs, especially fluoropyrimidines.

Pyridoxine is widely used to prevent and treat this problem, but the evidence underpinning its use is modest. Having analysed the medical notes of 198 patients receiving capecitabine they found that pyridoxine at doses above 100mg daily experienced some reduction in PPE and that doses in excess of 300mg/day were substantially more effective. They concluded that because pyridoxine appears to reduce PPE , with no obvious impact on the efficacy of capecitabine, a prospective trial of this approach to toxicity reduction is warranted.