St Vincent's scandal: what's the protocol for chemotherapy and are low doses less effective?

The New South Wales government this week released the final report of its investigation into chemotherapy “underdosing” of patients with locally advanced head and neck cancer in a Sydney hospital.

The report was commissioned after the ABC reported in February that up to 70 cancer patients at St Vincent’s Hospital had “received significantly less than the recommended dose of a chemotherapy drug”. This week, it emerged more than 100 people were treated with the same low dose.

The oncologist at the heart of the scandal used off-protocol doses of carboplatin chemotherapy treatment, giving each of his patients a flat 100mg. The government’s report stated:

It would be expected that, on a population basis, a failure to adhere to protocol puts every person at risk of higher rates of cancer recurrence and overall mortality.

Without knowing the patients' medical details, we can’t say whether the doctor’s chosen treatment method was inadequate in treating their cancer. But we can say there is no existing evidence a flat carboplatin dose of 100mg provides inferior outcomes; particularly when it is given together with radiation therapy, called chemoradiation.

As the NSW report states, the 100 or so patients treated with low doses of carboplatin were receiving chemoradiation.

Most cancer treatment is individualised – patients receive doses based on gender, height, weight and other factors. But there are many other treatments, such as the oestrogen-blocking drug tamoxifen used in breast cancer, where everyone receives an identical dose.

What’s the actual evidence?

Despite years of research, we still don’t know the best dose of carboplatin to use in any patient. The specific carboplatin dose for each patient is determined in one of two ways. The first is based on how much is circulating in their system (called Area Under the Curve, or AUC). Alternatively, it is based on their body surface area (BSA).

One study evaluated four carboplatin doses in head and neck cancer. It found the efficacy for the lowest dose (AUC 3.5 every three weeks for two doses) was equal to that at the highest dose (AUC 5 every three weeks for two doses).

Usually, chemotherapy’s main role is to kill cells. But when given with radiation treatment, it has a secondary purpose, which is to sensitise cells to the radiation. Low-dose chemotherapy in this instance appears to change the structure and function of cells, without severely damaging them, making them more susceptible to the lethal effects of the primary radiation treatment.

In India, which has a high incidence of head and neck cancer, a flat dose as low as 150mg has been used in a randomised trial and compared to radiation alone. The remission rates were almost doubled and comparable with higher doses of carboplatin or cisplatin.

In cases such as these, the radio-sensitising chemotherapy is the support treatment and must not increase the treatment toxicity to a level that delays the primary radiation treatment. Recent data reveals it is the completion of the scheduled radiotherapy within the defined protocol time, and not the completion of the protocol chemotherapy, that determines the outcome for patients.

There are several protocols

Protocols are created using evidence-based treatments that have been tested in clinical trials and found to be as good as, or better than, current standard treatment. There are many possible drugs and combinations of drugs for most cancers, all given at different doses and for differing lengths of time.

As the NSW government’s report states, treatment of combined chemotherapy and radiation is considered the best treatment for localised head and neck cancers. Although carboplatin is at times considered the third-line chemotherapy choice, there is a good amount of evidence it is equivalent in efficacy and less toxic than the more popular cisplatin.

The NSW report states treatment options for locally advanced cancer are clearly outlined in the National Comprehensive Cancer Network guidelines and in the eviQ Cancer Treatments Online information.

But eviQ has a list of possible treatment protocols for patients with locally advanced head and neck cancer, which includes six very different chemotherapy protocols. Under the heading of Definitive Chemoradiation in the medical oncology section, one of the options is to use carboplatin at a calculated dose of AUC 1.5. This would give a range of doses for varying individuals from 100mg to over 250mg.

In its radiation oncology section, there are also six protocols for chemoradiotherapy. The option with carboplatin has the dose as AUC 2 (giving doses of 150mg to over 350mg). As with many medical treatments, different oncology units choose different protocols depending on various considerations.

They are all acceptable because there is no evidence that one is better than the other. Confusingly, the two carboplatin doses here differ by 33% and the NSW report states a deviation of more than 25% either way in the protocol dose of carboplatin is unacceptable.

Why all the confusion?

The confusion often arises because early phase one and two trials of cancer drugs are designed to establish the “maximum tolerated doses” (MTD) and anti-cancer activity of the drug, or tumour response rates, in highly selected patients.

However, while there is a dose-response relationship for many chemotherapy drugs in cancer, shrinking cancers a little bit more with higher and more toxic doses rarely has meaningful benefits for patients in randomised phase three studies.

Despite the lack of evidence about dose, no oncologist or patient wants to give or receive sub-optimal treatment; most will invariably err on the side of too much rather than too little just to be safe.

The belief that more chemotherapy must be better has underpinned cancer treatment protocols and research for more than 40 years. But we’ve moved past that. A recent Cochrane review, for instance, found treating breast cancer with a very high dose of chemotherapy doesn’t improve survival any more than if using a standard dose.

As an editorial in the Journal of Clinical Oncology stated in 2000:

A new paradigm for dosing chemotherapy … uses low-dose continuous chemotherapy … More is not always better, and this is high time for low-dose.

The St Vincent’s Hospital episode is an opportunity for all involved in caring for patients with cancer to re-examine the evidence underpinning current practice and protocols.