Research
ICON3
The debate continues!
The debate about what the results of the ICON3 trial actually mean continues and we have had many comments following the article by Dr Helena Earle in our Autumn 2002 edition. Dr Geoff Newman, Oncologist at the Sussex Cancer Centre in Brighton, takes a different view.
It must be very confusing for your readers to have conflicting advice on the best treatment for ovarian cancer. Women starting treatment are now faced with a choice between carboplatin alone and carboplatin and paclitaxol (Taxol) in accordance with NICE guidelines, which were reviewed after the reporting of ICON3 (as discussed in the Winter edition, 2003 of Ovacome). Yet why are there still differences of opinion when the doctors all read about the same studies? Unfortunately medicine is full of controversy. For example there is still debate about whether screening for breast cancer saves lives.
I would disagree with Dr Helena Earle who wrote in the Autumn 2002 edition of the newsletter. The analysis in the ICON3 trial of stage 3 and 4 patients with more than 2 cm residual bulk disease shows a small trend in favour of paclitaxol/carboplatin. We need to use statistical tests to find out if this difference is real or more likely due to chance. The tests tell us that all the trends are probably due to chance and there are no groups of patients who fare better with two drugs than with carboplatin alone. This is in agreement with the American GOG 132 trial. The survival outcome was the same whether women received cisplatin, followed by further drugs if there is a relapse or cisplatin and paclitaxol (Taxol). We know that the most active drug for ovarian cancer is cisplatin or carboplatin (which is just as effective with fewer side effects).
Dr Earle suggests that adding early stage patients into ICON3 diluted the result and prevented the trial from showing an advantage for paclitaxol/carboplatin in women with more advanced disease. This is unlikely. As the trial was randomised any dilution of effect would be balanced in both arms, and separate analysis of subgroups of patients did not show any group benefitting from the combination. If, as she suggests, carboplatin is inferior to paclitaxel/carboplatin then we would expect many more relapses in the carboplatin treated patients, especially in the stage 3 and 4 patients. This was not seen - the progression free survival is not significantly different for carboplatin alone or paclitaxel/ carboplatin.
To conclude, the ICON3 study has shown that carboplatin is an effective treatment with fewer side effects than paclitaxel/carboplatin. The American studies showed that cisplatin and paclitaxel is only a better treatment when compared to the combination of cisplatin and cyclophosphamide. Cisplatin and cyclophosophamide is an untested form of chemotherapy that can be criticised for using low doses of cisplatin, the most potent drug.
Closing in on the ovarian cancer gene
You will all have seen recent headlines about the discovery of the 'ovarian cancer gene'. The press release from Cancer Research UK puts the position into perspective. Although work is in an early stage, the potential could be revolutionary for all Ovacome members. We'll be watching for further news and will update you when we can.
Cancer Research UK scientists have discovered a gene that has the power to stop ovarian cancer developing according to a report published today in Nature Genetics.
Researchers found that the gene, OPCML, was 'switched off' in almost 90% of the ovarian tumours tested. And experiments in the laboratory have shown that when fully functioning OPCML genes are inserted into human ovarian cancer cells, tumour growth is dramatically suppressed.
Dr Hani Gabra, who led the research at Cancer Research UK's Edinburgh oncology unit, says: "This is a very important discovery in identifying what seems to be a key tumour suppressor gene in ovarian cancer. We have found that these genes are frequently 'switched off' at very early stages of the disease and fail to make essential proteins. But when we switch these genes back on in the cancer cells tumours are suppressed."
In normal ovarian tissue, OPCML seems to prevent cells from being cancerous but defects in the gene may open the way for development of the disease.
Scientists believe it may be possible to devise drugs to mimic the effects of OPCML in order to block the growth of ovarian cancer cells.
Ovarian cancer, known as the silent killer, has no obvious symptoms in the early stages and is particularly difficult to detect. There is no effective screening procedure that can indicate pre-cancerous cells as there is in cervical and bowel cancer.
Dr Gabra believes that identifying OPCML is a vital component in the mystery that continues to surround the onset and development of ovarian cancer. "It takes us further in the urgent quest to find a method for earlier diagnosis and treatment of ovarian cancer. We now need to work on understanding more about this gene and exactly how it works and what makes it switch off."
Cancer Research UK's medical director Dr John Toy says: "It is always heartening to make headway when investigating a cancer, like ovarian cancer, which is difficult to treat entirely successfully unless caught early. This work still has a long way to go in the laboratory before patients could benefit but results so far are promising."
Randomised trials in women with relapsed 'platinum-sensitive' ovarian cancer ICON4 and AGO-OVAR-2.2
These two trials are the largest ever reported in relapsed 'platinum-sensitive' ovarian cancer. Results are now available. This article explains the implications for women who took part in the trials and their relatives, and why they are important for all women with relapsed ovarian cancer.
Background
Women with cancer of the ovary are generally treated with surgery followed by platinum-based chemotherapy (usually carboplatin or cisplatin regimens, sometimes with paclitaxel). Despite improvements in treatment, a proportion of patients whose cancer has spread beyond the ovary will develop a recurrence within five years of initial diagnosis.
In women whose disease recurs, the chance of a good response to more treatment with platinum-based chemotherapy appears to depend on the length of time between first-line treatment and recurrence. This length of time is sometimes referred to as the 'treatment-free interval' or the 'platinum-free interval'.
If ovarian cancer recurs within six months of completion of first-line treatment, the disease is considered to be 'platinum-resistant'. This means that there is less likely to be a good response to further platinum-based chemotherapy. Patients with 'platinum-resistant' disease are often re-treated with non-platinum containing regimens.
Patients whose disease recurs after a treatment-free interval of six months or more may be considered to have 'platinum-sensitive' disease. This means that there is likely to be a reasonable chance of responding to further treatment with platinum-containing regimens.
In the early 1990s, a chemotherapy drug called paclitaxel (also known as Taxol) was tested as first-line treatment in ovarian cancer, and early results seemed to be very promising. Paclitaxel works in a different way from platinum-based chemotherapy, and it was thought that giving paclitaxel in combination with platinum-based chemotherapy may be of greater benefit to women with recurrence of 'platinum-sensitive' ovarian cancer.
ICON4 & AGO-OVAR-2.2 trials
ICON4 and AGO-OVAR-2.2 were set up to see if giving paclitaxel with platinum-based chemotherapy would be of more benefit to women with relapsed 'platinum-sensitive' ovarian cancer than conventional platinum-based chemotherapy.
In both ICON4 and AGO-OVAR-2.2, women with relapsed 'platinum-sensitive' ovarian cancer, who agreed to participate in either trial, were randomly allocated into one of two treatment groups. Women had to have platinum as part of their first treatment and could also have received paclitaxel. One group was to receive paclitaxel plus platinum-based chemotherapy, and the other group was to receive conventional platinum-based chemotherapy (without paclitaxel).
Information was collected on chemotherapy given, any side effects experienced, and progress of disease. Women were also asked to complete quality of life questionnaires. This was an essential part of the study because it was important to establish if adding paclitaxel to conventional platinum-based chemotherapy would have a negative effect on quality of life compared with conventional platinum-based chemotherapy (without paclitaxel).
Results
Because the trials were so similar in design, the data from the ICON4 trial were combined with those from the AGO-OVAR-2.2 trial. The trials were run between January 1996 and March 2002, and 802 women participated in total. 392 women were allocated to receive paclitaxel plus platinum-based chemotherapy, and 410 women were allocated to receive conventional platinum-based chemotherapy (without paclitaxel).
After two years of follow-up, 57% of women in the paclitaxel plus platinum-based chemotherapy group are alive, compared with 50% in the conventional platinum-based chemotherapy group. This means that two-year survival rate is 7% better in the paclitaxel group than the non-paclitaxel group.
The trials collected information on further progression of disease. At one year, 50% of women in the paclitaxel plus platinum-based chemotherapy group showed no further progression of disease, compared with 40% of women in the conventional platinum-based chemotherapy arm. This means that one-year progression-free survival is 10% better in the paclitaxel group than the non-paclitaxel group.
There is no evidence that paclitaxel plus platinum-based chemotherapy was better or worse in terms of delaying progression or improving survival in different groups of women. For example, there was no evidence of a difference in benefit in older women compared with younger women, or in women who received paclitaxel as first-line treatment compared with those who did not receive paclitaxel as first-line treatment.
Paclitaxel plus platinum-based chemotherapy was associated with higher rates of hair loss and neurological problems. Moderate or severe hair loss occurred in 86% of women who had paclitaxel compared with 25% of those who did not receive paclitaxel. Moderate or severe neurological toxicity (e.g. numbness or tingling in hands and feet, and weakness) occurred in 20% of women who had paclitaxel compared with 1% who did not. However, overall there was no evidence of a difference in quality of life during treatment in the two groups of women.
Conclusion
ICON4/AGO-OVAR-2.2 is the largest trial ever reported in relapsed 'platinum-sensitive' ovarian cancer.
The results of the trial are of great importance since they provide the first clear information on the best way to treat women with this disease. The results show that treatment of women with relapsed 'platinum-sensitive' disease with paclitaxel plus platinum-based chemotherapy can improve survival and delay progression. Hair-loss and neurological problems are associated with this chemotherapy regimen; however this usually recovers once treatment has stopped.
The main conclusion of this trial is that all women who relapse more than six months after the completion of previous platinum-based chemotherapy should be considered for paclitaxel plus platinum-based chemotherapy, even if they received paclitaxel as part of their previous treatment.
Rosalind Franklin, the Dark Lady of DNA
"Since 2003 is the 50th anniversary of the discovery of the double helix structure of DNA, it seemed appropriate to include a short article on Rosalind Franklin," wrote Sarah Hutton, who subscribes to Ovacome out of solidarity with her sister, Rebecca, who is undergoing treatment for ovarian cancer.
2003 sees the 50th anniversary of the discovery by Richard Watson and Francis Crick of the structure of the 'molecule of life', DNA (deoxyribonucleic acid). Crick and Watson's epoch-making demonstration that the DNA molecule was a double-helix opened up huge developments in microbiology, and the possibility of an entirely new approach to medical treatment, not least in new gene-therapies for cancer which are now on the horizon.
The importance of the discovery of the double-helix was recognised when Watson and Crick were awarded a Nobel Prize in 1962. Also included in the prize was Maurice Wilkins, whose work helped prepare the ground for Watson and Crick's discovery. Controversy has surrounded the fact that another scientist, Rosalind Franklin, received no recognition for her part in the discovery. As Brenda Maddox makes clear in her biography, Rosalind Franklin, The Dark Lady of DNA (Harper Collins 2002), it is unlikely that Crick and Watson would have solved the structure of DNA when they did without sight of Rosalind Franklin's X-ray photographs of cross-sections of the DNA molecule.
What is perhaps less well known is that Rosalind Franklin died of ovarian cancer at the age of 37. Her death cut short the promising career of a brilliant woman scientist. Had she lived, it would have been more difficult to overlook her claims for recognition, and she would have been eligible for nomination for the Nobel Prize alongside Crick and Watson.
As Brenda Maddox recounts, Rosalind Franklin was a very private person, not given to discussing personal and private matters, and she would have been uncomfortable with public discussion of her health. The treatment available at that time was primitive by current standards - surgery and cobalt therapy. There was no support network - no Ovacome!
She probably could not have anticipated the enormous benefits of the discovery of the structure of DNA. Had she been able to, she, more than any of the scientists involved, would have appreciated the hope their collective scientific work now holds for a cure for ovarian cancer.
