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open access: Ovarian cancer screening: UKCTOCS trial – Authors' reply - The Lancet
Ovarian cancer screening: UKCTOCS trial – Authors' reply (June 2016)
We are grateful for the positive comments about the conduct of UKCTOCS.1
The total cost was roughly £27 million for 2·19 million woman-years of
screening or follow-up, which is a remarkably low cost of about £12·30
per woman-year.
A mortality reduction of around 20% or
more would be an important advance in a disease with such a poor outcome
and limited progress in effective therapy. Contrary to the comment by
Jim Thornton and Susan Bewley, we were clear that the “mortality
reduction was not significant in the primary analysis”. Nevertheless,
all of our analyses provide encouraging, but not definitive, evidence of
a mortality benefit (figure).
Four additional years of follow-up will provide clarity one way or the
other. Although the primary outcome will continue to be ovarian or tubal
cancer, the change in definition of primary peritoneal cancer by WHO in
2014 will ensure that most cases currently classified as primary
peritoneal cancer will be reclassified as ovarian or fallopian tube
cancer.
Figure
Summary of mortality analysisSignificant at the critical value adjusted for multiple comparisons against a control (Dunnett's correction; α=0·0258).
The
analysis that excluded prevalent cases was a prespecified secondary
analysis and not “data-driven” as suggested by Thornton and Bewley. We
do not believe that a bias between the no screening and multimodal (MMS)
groups explains these findings as was suggested by Peter Sassieni and
colleagues. We do not follow their explanation for a bias, but note that
matching patients from the no screening group to MMS patients on CA125
at baseline and diagnosis and years on study showed no average
difference between MMS and no screening group change-points, which
suggests no bias in advanced cancers at randomisation. The weighted
log-rank analysis was included precisely because it was the primary
statistical method used in the Prostate, Lung, Colorectal and Ovarian
(PLCO) trial,2
although we acknowledge the limitations of a post-hoc analysis. Using a
weighted log-rank test with weights increasing with time or
Royston-Parmar non-proportional hazards model was important because a
late mortality benefit was observed in keeping with several other large
randomised trials of cancer screening (eg, 7 years in the European
Randomised Study of Screening for Prostate Cancer [ERSPC] trial,3 9 years in the Norwegian Colorectal Cancer Prevention [NORCCAP] trial4). This delayed effect, which means that hazards cannot be proportional,5 is at least in part due to the delay in healthy participants developing cancer and dying from the disease after randomisation.
The
suggestion by Paul Hoskins and Walter Gotlieb that ultrasound screening
(USS) was as effective as MMS is incorrect. There was a significant
stage shift in invasive epithelial ovarian or tubal and peritoneal
cancer in the MMS group compared with the no screening group (stage I or
II 36·1% vs 23·9%, p=0·00013), but not in the USS group (24·0% vs
23·9%, p=0·57). We have considered the possibility that one of the
screening strategies could reduce mortality through prevention rather
than early detection. We have no evidence to support this at present as
the incidence of invasive epithelial ovarian, tubal, or peritoneal
cancer was not significantly reduced in the screening groups, although
there was an intriguing trend of lower incidence in the USS group, which
might become clearer on longer follow-up. We are doing numerous
additional analyses, which include investigating stage and morphology in
the different groups over time as proposed by Hoskins and Gotlieb.
There
was no industry sponsored funding or involvement in the design,
conduct, or analysis of the UKCTOCS trial. Our declared interests as
investigators arose through standard knowledge transfer activity
developed through our employing institutions. The ROCA test, which is
owned by Queen Mary University of London and Massachusetts General
Hospital, pre-dates the trial and no commercial exploitation or sales
occurred during the trial.
The
UKCTOCS trial was funded by the Medical Research Council (G9901012 and
G0801228), Cancer Research UK (C1479/A2884), and the Department of
Health, with additional support from The Eve Appeal. Researchers at
University College London were supported by the National Institute for
Health Research, University College London Hospital, and Biomedical
Research Centre. SJS received additional research support from the
National Cancer Institute Early Detection Research Network (CA152990).
IJJ reports personal fees from and stock ownership in Abcodia as the
non-executive director and consultant; personal fees from Women's Health
Specialists as the director; has a patent for the Risk of Ovarian
Cancer algorithm and an institutional licence to Abcodia with royalty
agreement; is a trustee (2012–14) and Emeritus Trustee (2015 to present)
for The Eve Appeal; and has received grants from the Medical Research
Council (MRC) UK, Cancer Research UK, the National Institute for Health
Research, and The Eve Appeal. SJS reports personal fees from the
LUNGevity Foundation and SISCAPA Assay Technologies as a member of their
Scientific Advisory Boards; consultant fees from Abcodia; has grants
from the US National Cancer Institute; and his institution Massachusetts
General Hospital has licensed software to Abcodia. UM has stock
ownership in and research funding from Abcodia; has received grants from
the MRC, Cancer Research UK, the National Institute for Health
Research, and The Eve Appeal. MP declares no competing interests.
References
- Jacobs, IJ, Menon, U, Ryan, A et al. Ovarian
cancer screening and mortality in the UK Collaborative Trial of Ovarian
Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;
387: 945–956
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- Buys, SS, Partridge, E, Black, A et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA. 2011; 305: 2295–2303
- Schröder, FH, Hugosson, J, Roobol, MJ et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012; 366: 981–990
- Holme, O, Loberg, M, Kalager, M et al. Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial. JAMA. 2014; 312: 606–615
- Warwick, J and Duffy, SW. A review of cancer screening evaluation techniques, with some particular examples in breast cancer screening. J R Stat Soc Ser A Stat Soc. 2005; 168: 657–677
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