Time Spent Receiving Cancer Care: Why It Matters for Patients with Prostate, Bladder, Kidney, and Testicular Cancers

Table of Contents

• Key Points
• Background: What Is Time Toxicity and Why Does It Matter?
• Why Genitourinary Cancers Are Important for Studying Time Toxicity
• How This Review Was Conducted
• How Researchers Measure Time Toxicity
• The Contact Days Method: Simple and Widely Used
• More Detailed Approaches to Measuring Time Toxicity
• What the Ideal Measurement Method Looks Like
• What Studies in Other Cancers Have Found
• Detailed Findings from Non-GU Cancer Studies
• What This Means for Patients
• Limitations of Current Research
• Recommendations and Future Directions
• Frequently Asked Questions
• Source Information

Key Points

• Time toxicity is the time patients spend in healthcare contact, including visits, tests, imaging, travel, and care for complications.
• Genitourinary cancers include prostate, bladder, kidney, and testicular cancers; many new treatments help patients live longer but require significant time.
• The contact days method counts days with any physical healthcare encounter as time away from home; it is simple but may over- or underestimate time.
• Studies in other cancers show time toxicity varies by treatment; for example, in one trial, median contact days were 28 with cetuximab versus 10 with supportive care.
• The authors call for dedicated research in genitourinary cancers to help patients and doctors make better treatment decisions.

Background: What Is Time Toxicity and Why Does It Matter?

Patients with genitourinary (GU) cancers — which include cancers of the prostate, bladder, kidney, and testis — make up a large group of cancer survivors worldwide. These patients have very different outcomes. Some have a good prognosis, while others face a high risk of illness and death. Many patients receive multiple rounds of treatment over time.

In the past decade, researchers have developed many new treatments that help patients with GU cancers live longer. However, these treatments also require significant time commitments from patients. This has led to growing interest in a concept called time toxicity.

Time toxicity refers to the time patients spend in contact with the healthcare system. This includes:

• Clinic visits for evaluation and treatment
• Laboratory tests and imaging studies
• Time spent addressing complications from the disease or its treatment
• Outpatient and inpatient care

This time spent on healthcare activities can significantly reduce the value of the extra survival time gained from treatment. For patients with advanced cancer, whose remaining time may be limited, this trade-off is especially important. Patients and their caregivers at any point in their cancer journey can end up investing a substantial amount of their day receiving cancer care. This often comes at the cost of time otherwise spent at work or doing personal activities.

The first studies of time toxicity focused mainly on patients with advanced solid tumors. There has been a surprising lack of research examining time spent with healthcare contact in patients with GU cancers specifically.

Why Genitourinary Cancers Are Important for Studying Time Toxicity

GU cancers offer an excellent opportunity to study the impact of time toxicity. In the past decade, patients with these cancers have seen the development of multiple life-prolonging treatments. These treatments may be used in the same clinical setting but may have very different impacts from a time toxicity perspective. This can influence treatment decision-making.

Consider the recently approved combination of enfortumab vedotin and pembrolizumab for patients with advanced bladder cancer. This combination has transformed the standard of care. However, the treatment plan has an indefinite duration. It also can cause side effects such as neuropathy (nerve damage that can cause pain, numbness, or weakness). These side effects may require additional visits and supportive measures over time.

Patients may need to consider whether to pursue treatment with these medications indefinitely until the cancer progresses, or to pause treatment at a point of acceptable disease control. They may compare this option with a more consolidated treatment course of chemoimmunotherapy.

Similarly, the approval of 177Lutetium-PSMA-617 for metastatic castrate-resistant prostate cancer (mCRPC) may offer prolonged disease control to a subset of patients. However, this treatment comes at the expense of increased laboratory and imaging monitoring. Patients also need to travel to tertiary care cancer centers to receive this therapy. Additionally, there is a required period of separation from loved ones for the days immediately following treatment.

The purpose of this review is to summarize the rapidly growing study of time toxicity in cancer. The authors place particular emphasis on its potential applications in supporting shared decision-making among patients with GU malignancies.

How This Review Was Conducted

The authors performed a targeted search of peer-reviewed publications in publicly available journal databases. These databases included MEDLINE and Embase. The search covered the period from April 2016 up to July 2024.

The researchers used keywords such as:

• "Time toxicity"
• "Contact days"
• "Home time"
• "Healthcare contact"

They also searched for terms related to GU malignancies, including "prostate cancer," "kidney cancer," "bladder cancer," "testicular cancer," and related cancer-specific terms. The authors identified 22 relevant studies that were included in this review.

Since the majority of studies on time toxicity have equated it with time spent with healthcare contact, these two terms are used interchangeably throughout the review. However, the authors recognize that there are many ways time may be indirectly dedicated to cancer care and its complications that do not qualify as healthcare contact. These additional ways are discussed in the review.

How Researchers Measure Time Toxicity

Clinical trials offer reliable information on the expected likelihood and length of cancer control and rates of adverse effects. However, there is little definitive information describing the time investment associated with receiving cancer therapies.

At best, patients receiving treatments administered in clinical settings have predictable schedules for the days that require treatment or associated supportive care. However, these estimates rarely quantify several important factors:

• The need for monitoring with laboratory studies and imaging
• Travel time to and from healthcare settings
• The likelihood of additional healthcare interactions related to complications from cancer or its treatment

These complications can force patients to seek urgent medical care. In addition, patients who live a significant distance away from healthcare institutions may need to dedicate more time to receive the same care than those who reside in urban areas.

The Contact Days Method: Simple and Widely Used

The earliest proposed method for evaluating time spent in versus out of healthcare settings by cancer patients receiving therapy was the Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) measure. As the name suggests, Q-TWiST characterizes the time that patients spend with and without symptoms from cancer and/or treatment. It does this by incorporating adverse event rates and survival data from clinical trials.

Q-TWiST was conceived in the late 1980s to supplement traditional clinical outcomes. It laid the groundwork for the current interest in time toxicity. Q-TWiST rapidly gained popularity across a variety of cancer and non-cancer settings, including in GU populations. However, it mostly remains a research methodology. It requires an equation using utility coefficients to determine the quality time trade-offs. This limits its accessibility by unfamiliar clinicians and patients.

In the development of time toxicity as an outcome, a number of mechanisms have been proposed for best measuring time spent with healthcare contact. The most pragmatic, intuitive, and widely adopted method involves separating days with and without physical healthcare contact. These are labeled as "contact days" or "home days," respectively.

Any physical encounters with the health system are considered whole days away from home and thus "time spent toxic." These encounters include:

• Ambulatory clinic visits
• Nursing-administered treatments
• Ancillary testing
• Inpatient level of care

Telehealth has rapidly risen and become established as a type of healthcare encounter. This could prompt its inclusion in the contact day model. Arguably, the time commitment for patients is drastically reduced when visits and other discussions occur through virtual methods of communication. Thus, currently, only physical encounters are included in this binary contact/home day model.

Most studies have abstracted contact days from electronic medical record systems or trial protocols. Other studies were able to quantify healthcare contact based on medical insurance claims. Some studies have proposed variations of the contact/home day model. These variations include:

• Reporting home days (the inverse of contact days)
• Sharing the proportion of contact days with respect to overall survival time

The adoption of contact days as the preferred method for quantifying time toxicity can be ascribed to its simplicity to quantify and interpret. Some limitations of the contact days method include:

• The risk of overestimating the time commitment for patients (not every patient encounter involves multiple hours of the day)
• The risk of underestimating healthcare contact due to confounders (such as decreased appointments due to limited access to care)

More Detailed Approaches to Measuring Time Toxicity

An innovative study suggested an alternate mixed methods approach for quantifying healthcare contact. This study was conducted in patients with metastatic breast cancer. Time receiving cancer-related healthcare was established using data derived from:

• Direct observation of patients in the clinic
• Patient surveys
• Administrative claims

Ultimately, cancer care-related time was calculated using an equation. This equation combined:

• Time spent traveling to and from outpatient appointments
• Services received during appointments
• Ancillary testing
• Inpatient care
• Healthcare-related activities outside of the clinic

This method likely offers the most comprehensive and realistic quantification of the time investment required by patients receiving cancer care. However, the multiple steps required through this method can limit its clinical implementation.

A subsequent study sought to directly observe time spent on ambulatory care. This study incorporated real-time location badges to track time patients spent in the clinic. It also included estimates of travel times to obtain a total "home to home" time. However, this approach ultimately provided a narrower scope of time toxicity than other studies.

What the Ideal Measurement Method Looks Like

The ideal way of determining time spent engaging with healthcare likely involves a combination of approaches. This includes measuring contact versus home days, with a more in-depth characterization of time involvement at each clinical encounter.

The rise of tracking technology and computer-driven algorithms may refine how healthcare contact is collected and computed. Many healthcare systems are using real-time tracking services on patients and providers to improve care delivery. The information gained can also be used to study time toxicity.

Personal devices equipped with tracking technology, such as smartphones or watches, could provide real-world evidence of the time spent in different health settings outside of clinic visits. This includes picking up medications at pharmacies or receiving physical therapy at home.

The aid of patients in capturing time toxicity outside of clinical settings will prove invaluable to derive precise measurements. A sufficiently comprehensive yet intuitive method of assessment is needed by researchers and clinicians. The objective is to precisely quantify time estimates that can be considered in clinical decision-making.

What Studies in Other Cancers Have Found

The past 5 years have seen multiple studies evaluating time spent with healthcare contact in patients with cancer. The authors highlighted studies conducted in non-GU populations where time toxicity outcome measures were the primary endpoint, rather than part of a larger healthcare utilization analysis.

Several studies were able to retrospectively retrieve healthcare contacts using clinical trial protocols and available trial data. These post hoc analyses provide clinically applicable findings by comparing time toxicity between different treatment approaches.

In one analysis, patients with advanced gastroesophageal cancer had significantly fewer contact days if treated with immunotherapy. The median was 28 days (interquartile range 24 to 41 days). This compared with 39 days (interquartile range 21 to 51 days) for chemotherapy and 39 days (interquartile range 30 to 52 days) for chemoimmunotherapy.

Data derived from trials evaluating a later-line treatment compared to best supportive care can be similarly meaningful. These data help patients with advanced cancer who are interested in the actual time spent at home if they were to forgo treatment.

Several studies used large population-based datasets to evaluate time toxicity in patients with advanced cancer. These studies compared time toxicity between therapeutic approaches. One study analyzed home time in patients with acute myeloid leukemia using a SEER-Medicare dataset. This study found a higher proportion of home time among patients who received hypomethylating agents compared with patients treated with anthracycline-based chemotherapy (60.8% versus 51.9%).

A primary advantage of population-based analyses includes the potential for precise estimates of healthcare contact. These estimates are based on linked billing claims data from large populations of patients treated in real-world settings. Moreover, these large datasets allow for covariate analysis. This can identify differences in time toxicity between groups of patients.

Detailed Findings from Non-GU Cancer Studies

The review summarized findings from multiple studies across different cancer types. These studies varied widely in size, from 107 patients to 12,378 patients.

Pancreatic cancer: In a study of 107 patients with locoregional pancreatic cancer from a single institution, the median time spent receiving care was 5% of total survival time and 11% of overall survival. This study provided a comprehensive evaluation of time receiving multidisciplinary care. However, it mixed contact days with hours, which complicates data interpretation. Times spent during appointments and travel were not directly captured.

Acute myeloid leukemia: In a study of 113 patients with newly diagnosed acute myeloid leukemia aged 60 or older, the adjusted mean proportion of home days was 0.67 (95% confidence interval: 0.63 to 0.71). There was no significant difference between treatment groups. This study was overall underpowered for subgroup analysis.

Another study of 197 patients with newly diagnosed acute myeloid leukemia aged 60 or older found that the mean home time was 9.1 months during the first year. Home time improved in the high-intensity treatment group compared with intermediate- and low-intensity treatment groups (13.1 versus 5.5 versus 7.6 months). This study captured the evolution of contact days and trade-offs with induction therapies. However, it had insufficient granularity on the type of contact days and their association with patient characteristics.

Early-phase clinical trials: A study of 219 patients in early-phase clinical trials at a single Australian institution found that the median contact days were 29% of time alive. There were higher contact days in the first 2 cycles. This study provided helpful characterization of contact days according to study protocol. However, it had limited analysis of the type of contact days.

Multiple myeloma: In a study of 252 patients with multiple myeloma after autologous stem cell transplant (auto-SCT) from a single institution, 40% of patients reported time toxicity. Time toxicity was more prevalent in patients on treatment than on surveillance. This study tested for association with financial toxicity and quality of life. It included phone calls as time toxicity, which is not standard. There was no direct quantification of healthcare contact, and there was a risk of recall bias.

Metastatic cancer: A study of 362 patients with metastatic cancer from a single institution found a median of 22 encounter days (10% of survival time) and a median visit time of 4.6 hours. This study used an intuitive outcome and practical findings. The estimated time was derived from electronic medical record localization software. However, it was limited to outpatient encounters.

Phase I/II clinical trials: A study of 408 patients from phase I/II clinical trials at a single institution found a mean of 21.3 contact days (standard deviation 19.74). Contact days were highest during the first month of trial. This study provided insightful multivariable analysis and tested for association with clinical outcomes such as response rate and overall survival. However, it was missing information on the type of contact days.

Ambulatory care time: A study of 435 patients from a single academic institution found that the median total ambulatory time was 197 minutes. Of this, 119 minutes were spent in the clinic and 50 minutes in travel. This study provided accurate time quantification using a tracking system. However, estimates of travel time have limited generalizability.

Advanced gastrointestinal malignancies: A study of 468 patients in a single Veterans Affairs (VA) institution who died of advanced gastrointestinal malignancies found a median of 44 contact days, representing 35% of total survival time. This study graphed contact days to show a "U-shaped" trajectory. The population was relatively sick, with over half untreated.

Advanced colorectal cancer: In a study of 572 patients with advanced colorectal cancer in the CCTG CO.17 trial comparing cetuximab versus supportive care, the median contact days were 28 with cetuximab versus 10 with supportive care. The median home days were similar (140 versus 121). This study provided intuitive and applicable findings. However, the current standard of care has evolved since this trial.

Relapsed/refractory large cell lymphoma: A study of 619 patients with relapsed/refractory large cell lymphoma in the CCTG LY.12 trial comparing GDP versus DHAP found a median of 18 contact days with GDP versus 19 with DHAP. There were higher home days with GDP (33 versus 28). This was an informative and practical study. However, it was unable to determine contact days for consolidation therapy such as auto-SCT.

Stage II or higher melanoma: A study of 731 patients with stage II or higher melanoma in a longitudinal, propensity score-matched Canadian cohort found a median of approximately 30 contact days in the first year from treatment start. Contact days were higher with stage IV disease. This study included a sensitivity analysis including home care and virtual visits. It had a diverse cohort across years. However, the diversity across cancer stage obscures interpretation of findings, and no raw data were provided.

Advanced gastrointestinal malignancies: A study of 809 patients with advanced gastrointestinal malignancies from a single institution found that median contact days were 25.8% of overall survival. Of these, 83.6% were spent in outpatient care. This study graphed contact days to show a "U-shaped" trajectory. However, it provided limited insight into the type of contact days.

Older cancer survivors: A study of 1,168 cancer survivors aged 65 or older using the Medicare Current Beneficiary Survey linked with Medicare claims data found a mean of 28.4 contact days (standard deviation 27.6) during one year. Of these, 64% were not linked with a clinician visit. This study provided subtle characterization of contact days and associated covariates. However, the population was heterogeneous in the survivorship spectrum.

Metastatic breast cancer: A study of 2,949 patients aged 67 or older from SEER-Medicare with metastatic breast cancer found a mean of 41 outpatient days (standard deviation 30) within the first year of treatment. There was no association with older age, but there was a noted association with comorbidities and treatment modality. This study focused on covariates that can affect healthcare contact. However, no raw data were provided on encounter days for all patients.

Stage IV non-small-cell lung cancer: A study of 5,785 patients from a Canadian cohort who died from stage IV non-small-cell lung cancer found a median of 36 contact days, which comprised 33% of median survival days. This study provided helpful subset analysis by systemic therapy and graphed contact days to show a "U-shaped" trajectory. However, the cohort had shorter survival than expected.

Acute myeloid leukemia: A study of 7,946 patients with acute myeloid leukemia from SEER-Medicare found that adjusted home time was 52.4%. Home time was higher with hypomethylating agents than anthracyclines (60.8% versus 51.9%). This study provided visually intuitive graphing of home time. The large dataset empowered covariate analysis. However, the treatment paradigm has since evolved.

Advanced esophageal/gastric cancer: A study of 12,378 patients from phase III randomized controlled trials found a median of 37 contact days (range 7 to 52 days). Contact days were significantly lower only with immunotherapy, but not for chemotherapy or chemo-immunotherapy. This study had a large sample size due to pooled analysis. However, there was indirect calculation of contact days.

Metastatic breast cancer: A study of distinct cohorts with newly diagnosed metastatic breast cancer from a single institution and SEER-Medicare found that mean cancer-related time was 34.1 to 75.6 hours during a 3-month period. This was a pioneering mixed method analysis of time toxicity. However, time toxicity measurement is cumbersome and difficult to implement.

What This Means for Patients

Time toxicity is a relevant patient-centered metric. It can be incorporated into clinical trial design and routine clinical care to influence clinical decision-making.

For patients with GU cancers, understanding time toxicity is especially important. These patients often face multiple treatment options that may offer similar survival benefits but very different time commitments. For example:

• Some treatments require indefinite duration with regular monitoring visits
• Some treatments require travel to tertiary care centers
• Some treatments require periods of separation from loved ones
• Some treatments cause side effects that require additional visits and supportive care

By understanding the time commitment associated with each treatment option, patients and their doctors can make more informed decisions. This is particularly important for patients with advanced cancer, whose remaining time may be limited.

The concept of time toxicity also highlights the importance of considering a patient's individual circumstances. Patients who live far from healthcare institutions may need to dedicate more time to receive the same care. Patients who work or have caregiving responsibilities may find the time commitment of certain treatments particularly burdensome.

Limitations of Current Research

The review identified several limitations in the current research on time toxicity:

• Lack of GU cancer studies: Despite the rising study of time toxicity across cancer populations, there has been a surprising lack of work evaluating time toxicity in patients with GU cancers.
• Varied measurement methods: Different studies use different methods to measure time toxicity, making it difficult to compare findings across studies.
• Limited granularity: Many studies do not provide detailed information on the type of contact days or the specific activities that contribute to time toxicity.
• Underpowered subgroup analyses: Some studies are underpowered for subgroup analysis, limiting the ability to identify differences between patient groups.
• Recall bias: Some studies rely on patient-reported data, which may be subject to recall bias.
• Evolving treatment paradigms: Treatment standards change over time, which can limit the applicability of older study findings.
• Limited generalizability: Some studies are conducted at single institutions or in specific populations, limiting the generalizability of findings.

Additionally, the contact days method has inherent limitations. It may overestimate the time commitment for patients because not every patient encounter involves multiple hours of the day. Conversely, it may underestimate healthcare contact due to confounders such as decreased appointments due to limited access to care.

Recommendations and Future Directions

The authors call for dedicated research on time toxicity in patients with GU cancers. They provide a dedicated section focused on scenarios and best practices to measure and collect data on time toxicity. This section can serve to spark interest in evaluating this novel health outcome in GU cancer survivors.

Key recommendations include:

1. Develop standardized measurement methods: A sufficiently comprehensive yet intuitive method of assessment is needed. This method should precisely quantify time estimates that can be considered in clinical decision-making.
2. Incorporate time toxicity into clinical trial design: Time toxicity should be measured as an outcome in clinical trials for GU cancers.
3. Use technology to improve measurement: The rise of tracking technology and computer-driven algorithms may refine how healthcare contact is collected and computed. Personal devices such as smartphones or watches could provide real-world evidence of time spent in different health settings.
4. Engage patients in data collection: The aid of patients in capturing time toxicity outside of clinical settings will prove invaluable to derive precise measurements.
5. Consider time toxicity in shared decision-making: Patients and clinicians should discuss time toxicity when considering treatment options.
6. Study time toxicity across the cancer journey: Time toxicity can be studied at any point along the cancer journey, from diagnosis through survivorship.

The authors conclude that time toxicity is a relevant patient-centered metric. It can be incorporated into clinical trial design and routine clinical care to influence clinical decision-making. For patients with GU cancers, understanding time toxicity can help ensure that treatment decisions align with their values and priorities.

Frequently Asked Questions

What is time toxicity in cancer care?

Time toxicity is the time patients spend in contact with the healthcare system. This includes clinic visits, laboratory tests, imaging studies, time addressing complications from the disease or its treatment, and outpatient or inpatient care. This time can reduce the value of extra survival gained from treatment, especially for patients with advanced cancer whose remaining time may be limited.

Why is time toxicity important for people with genitourinary cancers?

People with genitourinary cancers often have multiple treatment options that may offer similar survival benefits but very different time commitments. Some treatments require indefinite duration with regular monitoring, travel to tertiary care centers, or periods of separation from loved ones. Understanding the time commitment can help patients and doctors make more informed decisions aligned with their values and priorities.

How do researchers measure time toxicity?

The most widely used method separates days with and without physical healthcare contact, called contact days and home days. Any physical encounter with the health system counts as a whole day away from home. More detailed approaches combine travel time, appointment time, ancillary testing, inpatient care, and healthcare activities outside the clinic, but these are more complex to implement.

What did studies in other cancers find about time toxicity?

Studies in other cancers found varying results. For example, in one study of 12,378 patients with advanced esophageal or gastric cancer, median contact days were 37. In a study of 572 patients with advanced colorectal cancer, median contact days were 28 with cetuximab versus 10 with supportive care. These findings show that different treatments can have very different time commitments.

What are the limitations of current time toxicity research?

Current research has several limitations: there is a lack of studies in genitourinary cancers, different studies use different measurement methods, many studies lack detail on the type of contact days, some are underpowered for subgroup analysis, and some rely on patient-reported data subject to recall bias. Treatment standards also change over time, limiting the applicability of older findings.

What do the authors recommend for future research?

The authors recommend developing standardized measurement methods, incorporating time toxicity into clinical trial design for genitourinary cancers, using technology like tracking devices to improve measurement, engaging patients in data collection, considering time toxicity in shared decision-making, and studying it across the cancer journey from diagnosis through survivorship.

How can understanding time toxicity help patients make treatment decisions?

By understanding the time commitment associated with each treatment option, patients and their doctors can make more informed decisions. This is especially important for patients with advanced cancer, whose remaining time may be limited. It also highlights the need to consider individual circumstances, such as distance from healthcare institutions or work and caregiving responsibilities.

When should a patient with prostate, bladder, kidney, or testicular cancer seek a second opinion about treatment time commitments?

Patients with genitourinary cancers often face multiple treatment options that may offer similar survival benefits but very different time commitments. Some treatments require indefinite duration with regular monitoring visits, travel to tertiary care centers, or periods of separation from loved ones; others cause side effects needing additional visits and supportive care. Because time toxicity has rarely been studied in these cancers, patients and doctors may lack clear time estimates for each option. A second opinion can help clarify how each choice fits individual circumstances, such as distance from care or work and caregiving responsibilities. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Time's up: the urgency to investigate time toxicity in patients with genitourinary malignancies.

Authors: Sentana-Lledo D, Morgans AK.

Author affiliations: Dana-Farber Cancer Institute, Boston, MA, USA

Journal: Therapeutic Advances in Medical Oncology

Publication details: 2024, Volume 16, pages 1-12

DOI: 10.1177/17588359241305088

Article type: Review article

Received: 29 July 2024

Revised manuscript accepted: 19 November 2024

This patient-friendly article is based on peer-reviewed research.