For decades, investigators have sought a strategy for finding ovarian cancer early enough to reduce the risk of dying of ovarian cancer. In this issue of the Journal, Lim et al. (1) report on their study in which women answered a dozen simple questions such as whether they felt pelvic or abdominal pain in the recent past and, if so, when, how frequently, and how severely. Symptom indices like this are being promoted as easier or better ways to find ovarian cancer early, under the assumption that early therapy can achieve a better outcome than if the women wait until more or worse symptoms prompt them to see a physician. The study revealed that symptom indices as ovarian cancer screeners can be sensitive to the presence of cancer in the period between 3 and 14 months before clinical diagnosis. On the other hand, they were not highly specific because a substantial fraction of women without disease registered as “positive.” Furthermore, these attractively simple screeners showed a disappointing capacity to find cancer early, largely because the symptom(s) arose close to the time of diagnosis. The study design permits no calculation of years of life that might have been saved or lost if such screeners actually were used—only a large and expensive randomized trial would do that—but clinical gains likely would be minor, and many women would undergo unnecessary diagnostic procedures to assure that they are cancer free.
This sobering news follows hard on the heels of a large US randomized trial finding no benefit, and indeed some harm, to women who were screened annually with a transvaginal ultrasound exam and a CA-125 blood test compared with a usual care control group (2). It is plausible that other markers could perform better, but here too, the results so far suggest caution. One serum marker, HE4, performs better than does ultrasound as a second-line screen following CA-125 (3), though it also suffers from bad timing: It spikes relatively late in the year before diagnosis (4). Furthermore, panels of other markers, some of which are in commercial use, did quite well in initial reports but completely failed as a screening method in confirmatory studies (5).
Why is the development of a sensitive and specific screening method to detect ovarian cancer early so hard? The biology of ovarian cancer, the arithmetic of screening, and the clinical characteristics of the disease and its treatment collude to make it difficult to find ovarian cancer early enough to matter. For instance, we now suspect that many ovarian cancers arise in the fallopian tubes. The cancer may stay there for months or years before either spreading or migrating to the ovaries, with unknown effects on serum levels of any biomarkers. Fortunately, ovarian cancer occurs only rarely, but it follows that even a small fraction of false-positive test results will produce many dangerous and costly follow-up procedures.
Most importantly, the clinical characteristics of ovarian cancer pose some simple but profound challenges. Because of the location of the ovaries deep in the pelvis, symptoms seldom announce the presence of disease when it is still in its earliest stages. The symptoms used to derive the indices in this observational study by Lim et al. (1) are most often associated with more advanced stage III and IV disease, and overall, 68% of cancers are stage III or IV at presentation (6). Bowel or urinary symptoms or bloating related to malignant ascites or a palpable mass all suggest a substantial tumor burden. At times, a large mass that is still confined to one ovary can cause these symptoms and will still be amenable to primary surgical removal. However, this scenario represents only a minority of early-stage disease.
If a 1-cm mass contains approximately 109 cells, it will often take several times that mass to actually cause clinical symptoms. Although it is true that the ability to surgically debulk ovarian cancer to a residual nodule of less than 1 cm—a tumor size that is associated with better responses to chemotherapy and overall long-term outcomes—the underlying biology of the disease may well be more important. Tumor grade is an important variable in determining ability to maximally debulk the tumor and response to cytotoxic chemotherapy.
The potential for poor outcomes even with small tumors is seen in other malignancies. In breast cancer, very small tumors with four or more lymph nodes involved have a worse prognosis compared with larger node-negative tumors that would be more likely to present with symptoms (7). In aggressive triple-negative breast cancer, once the cells metastasize to lymph nodes, the number of affected nodes is no longer prognostic (8,9). It appears that the underlying tumor biology is more prognostic than tumor size or even nodal involvement. In prostate cancer, early results from the PIVOT trial suggest that patients with a favorable prostate-specific antigen level and Gleason score do as well with careful observation as they do with immediate prostatectomy (10). Again, the underlying biology of the tumor, rather than its presence or size, seems to predict outcome.
What does this mean for ovarian cancer? Will an earlier detection of a few months and intervention help most patients? Patients already have a substantial tumor burden by the time they are symptomatic. Is it all dependent on the size and location of tumor spread or is it the kind of cancer cells that have determined that the cells will spread, how they will respond to treatment, and how the patient will eventually do?
For clinicians who employ a symptom index for screening, the report by Lim et al. (1) suggests that further revisions of the questions and words would have only a minor impact on their ability to distinguish the small number of women with silent ovarian cancer from the vast number of cancer-free women. The study by Lim et al. also shows that women respond to questions somewhat differently in person compared with by telephone. The key clinical question concerns what steps to take next if a woman scores high on the index. The relation between the symptom index and CA-125 and HE4 warrants investigation. For example, the most optimistic scenario for future designs of a screening program holds that the right combination of questionnaires, blood tests, and imaging will perform far better in finding the right women for diagnostic evaluation than do any of the separate components. If that combination can be found, the next question is whether the resulting earlier treatments will prolong life.
No one would advocate delayed action after symptoms indicate possible pathology. However, detecting ovarian cancer at an earlier time but when the patient is already symptomatic is unlikely to make a major difference in outcome. Should we be focusing our efforts on the time between when a tumor is large enough to cause mild symptoms and when it is large enough to cause symptoms that prompt women to call a physician? Or should we work harder to understand the etiology of the disease, to find methods of prevention, and to obtain better therapy for women with biologically aggressive disease? These other research directions remain critical as the search continues for better ways to find ovarian cancer early.