Ovarian cancer (OC) is the second most common gynaecologic cancer and the leading cause of
death from gynaecologic malignancy among women in industrialized countries. The global
incidence in both developed and developing countries can be estimated as 165,000 new cases
per year. A heavy difference in prognosis exists between the early-stage disease FIGO I-II
(International Federation of Gynaecology and Obstetrics and the advanced stages (FIGO
III-IV). Unfortunately, at present, we do not have an effective screening strategy for this
malignancy; most (70-80%) of the cases are diagnosed as advanced-stage disease, and this
explains the high mortality rate. These aggressive features of the OC encouraged in recent
years a big effort in order to find new strategies for early diagnosis of OC. These studies
focused dominant on new markers and diagnostic algorithms among new markers. HE4 is one of
the most promising. It is a protein initially identified in the epithelium of the distal
epididymis and may be involved in sperm maturation. Despite its wide distribution, it is
overexpressed only in pathological tissue, and it has demonstrated good sensitivity and
specificity in detecting OC, overcoming the traditional role of CA-125. Despite an aggressive
upfront treatment strategy (surgery plus chemotherapy), leading to clinical remission in more
than 80% of patients, the relapse-free survival varies from 95.8% (for early FIGO stages) to
33.6% (for advanced stages) at 2 years. At present, periodical evaluation of CA-125 combined
with physical examination is the recommended strategy for OC follow-up, typically every 3 to
4 months in the first 2 years after primary treatment and then every 6 months until the fifth
year. Five years' overall survival rate, however, is 49.7% (ranging from 83%-89% in stage I
OC to 18% in stage IV). New markers should be tested in the follow-up of patients with OC to
improve the surveillance program performance: the challenge is to try to anticipate the
diagnosis of OC recurrence and to translate this early diagnosis of relapse in a survival
improvement. Few studies only are available to date about HE4 use in follow up of ovarian
cancer. All of these studies analyzed a small number of women (8-73). HE4 was shown as an
earlier indicator of recurrence of OC with respect to CA-125, with a lead-time of 5 to 8
months. Only 1 prospective controlled study has been published. In this study the sensitivity
and specificity of HE4, alone or in association with other markers (CA-125, CA-72-4), seems
to be higher in the diagnosis of the OC relapse with respect to CA-125 alone. The other side
of the question is whether the patient is advantaged by an earlier detection of the recurrent
disease, in terms of overall survival, disease-free survival, and quality of life. Early
detection and treatment of cancer in general or its recurrence are usually associated with
better outcomes for patient, this being the rationale behind screening programs and follow-up
strategies. In OC follow-up, periodical CA-125 evaluation can detect recurrence of cancer
about 5 months before clinical signs or symptoms. At the same time, we have to remind, that
treatments of relapsing OC are rarely curative and have heavy adverse effects, and elevation
of CA-125 is often cause of anxiety in patients undergoing follow-up. The main study, that
tried to clarify the role of CA-125 in OC follow-up was MRC OV05/EORTC (European Organisation
for Research and Treatment of Cancer) 55955 trial a randomized study comparing early versus
delayed treatment in women with relapsed OC. Patients in the delayed treatment group were
treated only at clinical or symptomatic relapse. Women assigned to early treatment started
chemotherapy 4.8 months earlier than those allocated to the delayed treatment. With a median
follow-up of 56.9 months, there was no evidence of a difference in overall survival between
the 2 groups. In particular, the results provided no evidence of an improved overall survival
or a better quality of life in the early treatment group. The authors' explanation for these
findings was that the lead-time between CA-125 rise and the clinical recurrence could be too
short for chemotherapy to give a beneficial effect. At present, periodical evaluation of
CA-125 combined with physical examination is the recommended strategy for OC follow-up,
typically every 3 to 4 months in the first 2 years after primary treatment and then every 6
months until the fifth year. Five years' overall survival rate, however, is 49.7% (ranging
from 83%-89% in stage I OC to 18% in stage IV).