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This simulation study showed that patients aged 58 years at diagnosis and in complete clinical remission after primary treatment for ovarian cancer have a mean life expectancy of 10.8 years. Life expectancy in case of withholding follow-up, i.e. all recurrences detected symptomatically, and a perfect follow-up scenario, i.e. all recurrences detected asymptomatically, was also 10.8 years. New treatment options may alter the effectiveness of routine follow-up if the response to treatment is significantly better in patients with their recurrence detected asymptomatically as compared with patients with their recurrence detected symptomatically.

A strong point of this study is the use of individual patient data. The use of mathematical functions to estimate the transition rates and the small patient numbers may be limitations. The mortality probability in relapsed patients was assumed to be proportional, whereas it is expected to decrease with an increasing length of relapse-free survival. The impact of the use of mathematical functions to estimate survival duration is, however, expected to be small, as the 10-year survival curve derived from the Markov model simulation was similar to the Kaplan-Meier survival curve derived from the representative patient sample, which indicates a good internal validity of the model.

In addition, the 10-year survival curve derived from the validation set showed a good agreement with the simulation results, especially during follow-up years 4 to 10. One can argue whether this comparison represents an external validation, because the patients included in the validation set were derived from the same patient population as the patients included in this simulation study. Gadduci et al14 _{performed an Italian} multicentre observational study which was similar to our study.8 _{The mortality rate in} relapsed ovarian cancer patients was quite similar in both studies: 0.082 as reported by Gadduci et al14 _{versus 0.089 and 0.096 in our study. In addition, Gadduci et al}14 observed no difference in survival time in patients detected asymptomatically and symptomatically as well. These observations suggest a good external validity of the model.

The life expectancy of 10.8 years, however, should be interpreted with caution. We have simulated the course of disease in patients aged 58 years. Younger patients will have, as a consequence, a longer, and older patients a shorter life expectancy. In addition, we assumed all cause mortality to be equal to the mortality of the general population. Nevertheless, ovarian cancer patients may have a shorter life expectancy due to the intensive primary treatment. Furthermore, we included all patients in complete clinical remission after primary treatment, because the follow- up programme is the same for all patients, irrespective of cancer stage. Risk of recurrence was, however, lower in patients diagnosed with early stage ovarian cancer than in patients diagnosed with advanced stage cancer, which was also observed in a large population-based study.15 _{Repetition of the Markov cohort simulation showed} that patients treated for advanced stage ovarian cancer had a mean life expectancy

Current symptomatically detected recurrences may be timely detected due to the regular appointments with the medical specialist. In practice, withholding follow-up, that is abolishing regular contact with the medical specialist, may lead to a larger delay in recurrence diagnosis as patients may not seek help if they have complaints. The potential gain in life expectancy by regular follow-up visits may, therefore, be underestimated.

In addition, length-time biased sampling may have distorted the life expectancy estimates in case of withholding and perfect follow-up.8 _{The impact of this potential} bias was simulated by altering the lead time and mortality rates, see Table 5.3, which did not change the modelled life expectancy significantly.

Our findings were consistent with previous observational studies.5 _{Tanner et al}16 formed an exception and showed an improved survival duration in patients with their recurrence detected in the asymptomatic phase as compared with patients with a symptomatic recurrence (HR=0.4). This difference is, however, likely to be explained by length-time biased sampling, induced by a difference in relapse characteristics. Our model findings were also in line with the simulation study performed by Hopkins et al.17 _{Hopkins observed no improved life expectancy of the current follow-up} programme as compared with a less intensive follow-up scenario, in which routine CA125 testing was excluded. This observation suggested no survival benefit of routine CA125 monitoring as part of routine follow-up practice and was later reinforced by the results from the RCT by Rustin et al.4 _{This example of a simulation study by} Hopkins and a RCT by Rustin shows that Markov simulation studies can give valid results when evaluating the effectiveness of routine follow-up examinations.

One explanation for observing no survival gain through routine examinations can be the absence of a curative-intent treatment for recurrent ovarian cancer.10,18 _Notably, most patients with ovarian cancer have already received chemotherapy at initial diagnosis. This implies that once there is a relapse, tumour cells have shown to be resistant for the most effective systemic treatment that is available. Further, the number of systemic treatment lines for ovarian cancer is quite limited in contrast to the armamentarium that is available in for instance breast cancer patients.

The effectiveness of routine follow-up is, beside treatment efficacy, associated with the advancement in diagnosis of a recurrence through routine testing. In ovarian cancer, the median lead time between elevated CA125 levels and clinical evidence of recurrence was three to five months.4,5 _{Given current treatment options, this lead} time was too short to induce a survival benefit through early initiation of recurrence treatment.4

We have shown that routine follow-up is not expected to influence the life expectancy, irrespective of follow-up strategy. Therefore, the focus of follow-up should shift to the other aims of routine follow-up: providing psychosocial care and monitoring the effects of primary treatment.19-21 _{In addition, an intensive follow-up schedule is} associated with high surveillance costs17,22 _{and early initiation of recurrence treatment} with decreased quality of life.4 _{We therefore recommend to consider studying}

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alternative, potentially more cost-effective alternative follow-up programmes, like for example nurse-led telephone follow-up20,23 _{or patient-initiated follow-up.}24 According to the official European Society of Gynaecologic Oncology statement,25,26 routine CA125 monitoring should not be abandoned in all patients. CA125 monitoring may, for example, be part of a clinical trial. Further, it is unknown what the impact is of timing of recurrence treatment in patients with early stage ovarian cancer at diagnosis and no chemotherapy at primary treatment. In addition, if second cytoreductive surgery is found to be effective, timing of surgery may be important. The decision on whether to monitor CA125 values may depend on patient preferences and should include weighing of the potential harms of routine CA125 monitoring and the uncertainties in potential benefit. It is, therefore, essential to facilitate informed decision making in patients regarding routine CA125 testing.

Defining the optimal follow-up policy is a ceaseless process guided by new evidence. In future, treatment of recurrent ovarian cancer may improve, new diagnostic techniques may become available to detect recurrences earlier, or subgroups of patients with curable recurrence may become evident.26 _{The impact of improved recurrence} treatment options was simulated in this modelling study. Given the current relapse rate, a hazard ratio between the mortality rate in patients with asymptomatically versus symptomatically detected recurrences of 0.8 or smaller, is expected to be associated with a survival gain through routine follow-up. However, a hazard ratio of 0.8 is exceptionally low and unrealistic as improvements in recurrence treatment are expected to change the mortality rate in both patients with asymptomatically and symptomatically detected recurrences. In addition, improved recurrence treatment options are anticipated to effect primary treatment as well, and thus risk of recurrence and survival duration. Our Markov model can be used to explore the impact of new findings on the effectiveness of routine examinations when empirical data become available.

In conclusion, routine follow-up examinations are not expected to influence the life expectancy of ovarian cancer patients as recurrences are mainly detected in an advanced, palliative phase. Future studies should focus on ovarian cancer treatment and exploring cost-effective alternative follow-up scenarios.