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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recently published manuscript entitled, Long-Term Mental Health Service Utilization Among Survivors of Testicular Cancer: A Population-Based Cohort Study. I'm Chris Wallis, a fellow in urologic oncology at Vanderbilt. And with me is Zach Klassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is a citation of this work, recently published in the Journal of Clinical Oncology led by Dr. Michael Raphael and Dr. Christopher Booth.

By way of background, psychiatric disease is relatively prevalent in the general population with rates of major depression nearing 17%, alcohol abuse nearing 12, generalized anxiety disorder around 6%, and others listed below. In cancer patients, these rates may be even higher, and old data from nearly 30 years ago from the Psychological Collaborative Oncology Group showed that nearly half of adult patients with cancer are maladjusted to their crisis illness. And most commonly, this manifests with adjustment disorder with depressed mood and/or anxiety. More contemporary studies have shown that depression, delirium, adjustment disorder, and anxiety disorders, are found in between 10% and 34% of cancer patients.

A relatively recent systematic review demonstrated that the prevalence of depression in cancer patients is relatively high, although it is highest during treatment phases, and then tends to decline over time. This has been well assessed in the GU cancer population, particularly prostate cancer patients and bladder cancer patients, although also among those with kidney cancer. It's been less well assessed in testis cancer patients, though testis cancer is the most common solid cancer in men aged 15 to 44 years. It is additionally the most curable solid malignancy with a ten-year survival that exceeds 95%. And as a result, there is an increasing number of patients who are long-term survivors of testis cancer.

Secondary cancers, cardiac disease, pulmonary disease, kidney disease, and neurologic complications of treatment, as well as fertility-related toxicity, have been extensively examined both in testis cancer itself and its treatments. However, the mental health effects have been less well established. To address this, the author has performed a population-based retrospective cohort study among patients in Ontario, Canada, and they identified all incident testis cancer diagnoses between 2000 and 2010 using the Ontario Cancer Registry. They linked these to surgical pathology records, which were manually abstracted for the orchiectomy specimens and they quantified mental health use using validated codes for utilization, including outpatient or emergency department or hospitalization records.

They divided patients into three time periods with respect to their mental health use. First was the baseline, which was two years until one month prior to orchiectomy. In the peri-treatment period, they examined the window from one month before to one month after orchiectomy. And post-treatment, they examined the time from one month after orchiectomy onwards. Cases included all patients with incident testis cancer diagnosis, but it excluded those who did not undergo orchiectomy in the two months prior, or six months following diagnosis. Those for whom a pathology report could not be obtained, those with non-germ cell histology, and those who received systemic therapy prior to their orchiectomy.

Controls comprised all Ontario male residents who shared the first three-digit of their postal code with an eligible identified case-patient. Controls were excluded if they had any history of testis cancer or any other cancer diagnosis during the follow-up. And matching was performed in a one to five manner between cases and controls, based on age, sex, and postal code. Controls were assigned an index date that was the same as the date of orchiectomy of their matched case.

The authors assessed baseline differences between cases and controls using standardized differences and captured mental health utilization as a rate of mental health-related healthcare events, per 1000 person-years. Negative binomial regression was used to estimate the rate ratio of mental health utilization following orchiectomy while adjusting for pre-orchiectomy mental health utilization. At this point in time, I will now turn it over to Dr. Klaassen to walk us through the results.

Zachary Klaassen: Thanks Chris. So this is the CONSORT Diagram looking at the study. The authors looked at testicular cancer diagnosed from 2000 to 2010, finding 3,546 patients, of which 3,281 patients had testicular cancer with primary surgery during this time period. Pathology reports were available on 2,821 patients and testis cancer surgery cases included 2,650, which ultimately 2,619 patients were included in this study.

This looks at the characteristics of patients with testicular cancer compared to the matched controls. You can see here on the left are the characteristics, in the middle is cases and controls, and the standardized differences on the right. These were generally very well matched. You can see here that the median age was 34 years, the primary histology for the testis cancer patients was 59% seminoma and 41% non-seminoma. In terms of upfront treatment, the majority had surveillance at 63% and 37% of patients underwent subsequent chemotherapy, radiotherapy, or RPLND.

In terms of socioeconomic status, a pretty even breakdown between quintiles one, two, three, four, and five. A majority of these patients were not rural, 88% of them, and not surprisingly given the young cohort, the comorbidity score of zero was most common at 98%.

So this looks at the comparison of testicular cancer patients and controls with mental health stratified by location of visit and timing to orchiectomy. And what I've done here is highlight on the right with the orange asterisks, the significant standardized differences between cases and controls. So three rows down, you can see that in terms of visits to general practitioners after orchiectomy, 55% for cases compared to 45% of controls. Total outpatient visits in the perioperative period, 12% for cases, and 4% for controls. And finally, total outpatient visits post orchiectomy, 57% for cases and 47% for controls.

So this looks at the crude rate per 1000 person-years, looking at mental health visit, location, and timing. Once again, I've highlighted the statistically significant differences between testis cancer cases and controls with the asterisks on the right. When we look at the general practitioner visits in the perioperative period, the adjusted relative risk was 2.98 with a 95% confidence interval of 2.49 to 3.57. This is favoring cases over the controls.

Looking at total outpatient visits in the peri-operative period, 1,162 per 1000 person-years for the orchiectomy patients compared to 533 for controls, with an adjusted relative risk of 2.45, and a 95% confidence interval, 2.06 to 2.92. Finally, looking at total outpatient visits post orchiectomy, 731 versus 588, with an adjusted relative risk of 1.30 and a 95% confidence interval of 1.12 to 1.52.

This curve looks at the cumulative incidents of outpatient mental health visits in patients with testis cancer and controls from two years before, until two years after orchiectomy. So looking at this figure in the middle is time zero, at the time of orchiectomy. So on the left of zero is before orchiectomy, on the right of zero is post orchiectomy. And these lines essentially are almost completely overlapped up until the time of orchiectomy, at which point the cases in red, lines above the blue line, indicating more mental health visits during that timeframe after the orchiectomy.

This looks at the cumulative incidents with longer follow-up. And so this is reaching out to 19 years and you can see that this line separates again for cases versus controls at the time of orchiectomy to 9.0, all the way out and even further increasing the difference between the two up to 19 years from orchiectomy. Thus, the mental health burden for these patients after orchiectomy is not only substantial but also prolonged with longer follow-up.

This looks specifically at the percentages of all outpatient mental health service use episodes. And so you can see here on the left are pre-treatment, peri-treatment, and post-treatment, and they looked at several different types of mental health disorders, including depression, anxiety, schizophrenia, psychotic disorders, as well as substance-related and addictive disorders. Looking at the pre-treatment cases versus controls, more depressive disorders in the cases, 11.05% to 7.05% slightly higher anxiety disorders, 60.68% compared to 50.58%. In the peri-treatment timeframe, we see the anxiety go up much higher in the cases at 80.85% compared to 46.49% in the controls. And finally, in the post-treatment, we see this anxiety does go down to almost the level of the controls at 45.81% in cases, compared to 40.62% in controls. I also want to point out here that even after post-treatment, depression disorder is slightly higher in the cases of 9.37% versus 7.55% in the controls.

This looks at the number of outpatient visits for mental health service concerns stratified by pre, peri, and posttreatment. Cases are in blue and the controls in red. And you can see here that the majority of patients and cases did not have pretreatment visits. However, we start to see as we go all the way through to post-treatment on the right, that the number of patients that had greater than or equal to two visits was not insignificant at about almost 40%. So certainly this trend that we are seeing in post-treatment utilization of mental health resources does increase.

This is an unadjusted look at the cumulative incidents of outpatient mental health visits in patients treated with upfront early treatment or active surveillance, surveillance is in blue and early treatment is in red. And in this unadjusted analysis, there is really no difference between those that opted for surveillance and those that underwent early treatment. However, in this multi-variable analysis, which is adjusted, you can see here about halfway down this table, upfront treatment with surveillance as the reference, those that had early therapy, whether it be chemotherapy, radiotherapy, or RPLND, did have a significant utilization of mental health resources with a relative risk of 1.34 and a 95% confidence interval of 1.14 to 1.58.

Also in this table, we can see that with increasing socioeconomic status compared to low socioeconomic status, there were fewer frequent visits from mental health services. And finally, not surprisingly, patients that had pre-orchiectomy mental health service use had a relative risk of 5.64% risks of having post-orchiectomy mental health use. So certainly if you had used mental health resources in the past, post-orchiectomy, you were very likely to use mental health resources as well.

So several discussion points from this important population-based study. This study showed that several notable findings, namely that compared to healthy match controls, testicular cancer survivors have a substantially higher rate of mental health care visits, which does persist through long-term follow-up, as we saw, up to 19 years after surgery.

Interestingly, the majority of mental health concerns were with the family physician. And I think this is important, especially in the equal access system in Canada, that where family physicians are usually the first point of contact. Post-treatment mental health service use was most common among those with baseline mental health service use, and those who underwent early upfront additional treatment compared to those that opted for surveillance. There is no question that there is vital importance to developing care plans for testicular cancer survivors that support their mental health care needs, and these care plans should include knowledge transfer to general practitioners to support these patients.

In conclusion, this population-based study showed that testicular cancer survivors have a significantly higher rate of healthcare visits for mental health concerns compared with healthy controls. And this increased rate of utilization and mental health resources does extend into the long-term survivorship period. Without question, testicular cancer programs should consider the routine screening of mental health distress, and efforts to increase awareness of mental health consequences and ensure appropriate resources and support are in place beyond the acute phase of diagnosis and treatment for long-term mental health and testicular cancer survivors is certainly warranted. Thank you very much, we hope you enjoyed this Journal Club Discussion for UroToday.