Key PointsQuestion
What are reasons for watchful waiting in basal cell carcinoma (BCC), and what is the tumor behavior?
Findings
In this cohort study of 280 BCCs in 89 patients in the Netherlands, patient-related factors (eg, limited life expectancy or frailty) were the most important reasons to choose watchful waiting. The minority of tumors increased in size (46.8%); of those, infiltrative/micronodular BCCs were estimated at a tumor increase of 4.46 mm in 1 year, whereas nodular, superficial, or clinical BCCs were estimated at 1.06-mm growth in 1 year.
Meaning
Watchful waiting might be an appropriate approach in patients with BCC with a limited life expectancy and asymptomatic nodular or superficial BCCs.
Importance
Few studies have examined watchful waiting (WW) in patients with basal cell carcinoma (BCC), although this approach might be suitable in patients who might not live long enough to benefit from treatment.
Objective
To evaluate reasons for WW and to document the natural course of BCC in patients who chose WW and reasons to initiate later treatment.
Design, Setting, and Participants
An observational cohort study was performed at a single institution between January 2018 and November 2020 studying patients with 1 or more untreated BCC for 3 months or longer.
Exposures
Watchful waiting was chosen by patients and proxies regardless of this study.
Main Outcome and Measures
The reasons for WW and treatment were extracted from patient files and were categorized for analyses. Linear mixed models were used to estimate tumor growth and identify covariates associated with tumor growth.
Results
Watchful waiting was chosen for 280 BCCs in 89 patients (47 men [53%] and 42 women [47%]), with a median (interquartile range [IQR]) follow-up of 9 (4-15) months. The median (IQR) age of the included patients was 83 (73-88) years. Patient-related factors or preferences (ie, prioritizations of comorbidities, severe frailty, or limited life expectancy) were reasons to initiate WW in 74 (83%) patients, followed by tumor-related factors (n = 49; 55%). Treatment-related and circumstantial reasons were important for 35% and 46% of the patients, respectively. The minority of tumors increased in size (47%). Tumor growth was associated with BCC subtype (odds ratio, 3.35; 95% CI, 1.47-7.96; P = .005), but not with initial tumor size and location. The estimated tumor diameter increase was 4.46 mm (80% prediction interval, 1.42 to 7.46 mm) in 1 year for BCCs containing at least an infiltrative/micronodular component and 1.06 mm (80% prediction interval, −1.79 to 4.28 mm) for the remaining BCCs (only nodular/superficial component/clinical diagnosis). Most common reasons to initiate treatment were tumor burden or potential tumor burden, resolved reason(s) for WW, and reevaluation of patient-related factors.
Conclusions and Relevance
In this cohort study of patients with BCC, WW was an appropriate approach in several patients, especially those with asymptomatic nodular or superficial BCCs and a limited life expectancy. Patients should be followed up regularly to determine whether a WW approach is still suitable and whether patients still prefer WW and to reconsider consequences of treatment and refraining from treatment.
Basal cell carcinoma (BCC) is the most common type of skin cancer and is generally characterized by a relatively indolent nature.1 Although BCCs are often initially asymptomatic, long-term morbidity can be substantial because of local tissue invasion and destruction.2 Preventing both undertreatment and overtreatment can be a clinical challenge, especially in patients with a limited life expectancy (LLE). Because patients with LLE might not live long enough to develop bothersome symptoms from a BCC, the lag time until benefit from BCC treatment is achieved (“time to benefit”) might exceed life expectancy.3
Therefore, patients with LLE and asymptomatic BCCs might benefit more from a watchful waiting (WW) approach than active treatment. Watchful waiting entails the monitoring of the natural course of a disease without actively treating it. The main short-term advantage of WW is the avoidance of treatment-related risks and treatment burden. However, the risk of WW is further growth of the tumor, which could cause (more) tumor-related complaints and/or complicate treatment options (eg, more invasive therapies needed). In several other medical fields, WW and active surveillance (WW accompanied with more invasive manners of follow-up, such as additional biopsies) have been accepted treatment options in patients with LLE with nonlethal and asymptomatic conditions.4-7
However, because BCCs are mostly treated to avoid potential tumor burden, and limited data are available on the behavior of untreated BCCs and the consequences of refraining from BCC treatment,2,8,9 it is difficult to properly inform patients on the expected tumor growth, progression, and the chance of developing symptoms during a WW approach. Therefore, this study endeavors to provide more insight in the reasoning and clinical outcomes of a WW approach.
Study Design and Participants
A single-institution observational real-world cohort study was conducted at the outpatient Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands, between January 2018 and November 2020. All physicians and physician assistants were requested to enroll patients with BCC who chose a WW approach after thorough consideration, regardless of tumor localization/subtype or patient age. To optimize the sample size and statistical power, physicians were able to also include patients in which a WW approach was initiated before the start of the study, in which case a medical record review was performed to collect additional data retrospectively. Basal cell carcinomas that were incompletely excised, for which WW was chosen directly after excision, were excluded. The diagnosis of BCC was made based on clinical judgment and was preferably confirmed by punch biopsy. Watchful waiting was defined as no active BCC treatment for at least 3 months after initial presentation, including patients who refused active BCC treatment even if this was strongly advised by treating physicians. The decision for WW was made after a regular (multidisciplinary) shared decision-making process between the treating physicians and patients or proxies, and the decision was made regardless of this study. All patients and proxies were informed on possible tumor progression and therapeutic implications as a consequence of a WW approach. Patients who chose WW were advised to remain under observation every 3 to 6 months. At each visit, the shared decision-making process was repeated, with explanation of diagnosis, prognosis, and therapeutic options, with potential tumor and symptom progression taken into consideration. The Medical Ethical Committee of the Radboud University Medical Center approved this study and waived the need for written informed consent according to Dutch legislation (Medical Research Involving Human Subjects Act [in Dutch: Wet medisch-wetenschappelijk onderzoek met mensen, WMO]). This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.10
The main study outcomes were patients’ reasons for WW (as reported in patient medical records) and the proportion and reasons for initiation of later treatment (when applicable). Reasons were categorized as the following: patient-related factors or preferences (eg, prioritizations of comorbidities, severe frailty, or LLE), tumor-related factors (eg, asymptomatic tumors), treatment-related factors (eg, the expected treatment burden), or circumstantial reasons. Secondary objectives were to evaluate the behavior of untreated BCCs, including tumor growth and tumor symptoms, and whether treatment was initiated at a later time point.
Electronic patient medical records were reviewed retrospectively to systematically obtain patient and tumor characteristics (eg, maximal tumor diameter measured at each visit, tumor complaints, other variables mentioned in Table 1). All follow-up variables were collected in regular daily practice. Reasons for WW and the reasons for treatment initiation after a period of WW (if applicable) were extracted from electronic patient medical records and/or verified by the treating physician.
Statistical analysis was conducted using SPPS Statistics for Windows, version 25.0 (IBM) and R, version 3.6.3 (R Foundation for Statistical Computing). Continuous data were presented as mean (SD) or median (interquartile range [IQR]) for normally or non-normally distributed data, respectively. Frequencies and percentages were used to summarize categorical data. Interrater agreement (intraclass correlation) on tumor measurements was evaluated in a separate pilot study including 40 BCCs assessed by 2 different observers; the agreement and corresponding 95% CIs were computed using a 2-way random-effect model with consistency. Quiz Ref IDTumors were defined as “growing” when the difference in tumor size between initial tumor diameter and final tumor diameter (≥3 months later) was at least 1 mm. A sensitivity analysis was performed with tumor growth defined as greater than 2 mm and assessed the associations with outcome measures. Missing values were excluded from analyses. Univariate analysis were performed using the χ2 or Fisher exact test. Mixed-model logistic regression analyses were used to determine odds ratios (ORs) and 95% CIs for covariates regarding occurrence of tumor growth. Linear mixed models were used to determine tumor growth (in mm), accounting for potential correlations with tumor subtype, initial tumor diameter, and tumor location. These models were used to calculate 80% prediction intervals for tumor growth, which is the range for the growth of a certain type of tumor in which 80% of the cases will be. P values <.005 were considered significant.
After extensive consultation, including explanation of the potential consequences of a possible WW approach, WW was chosen for a cumulative number of 280 BCCs in 89 patients (Table 1). In total, 227 (81.1%) tumors were included (partly) prospectively. In 47 patients (53%), a WW approach was chosen for more than 1 BCC, and in 19 patients (21.3%), for more than 3 BCCs. The median (IQR) age of the included patients was 83 (73-88) years, and 47 (53%) were male. One patient with Gorlin syndrome was included with 2 (0.7%) BCCs. Of all BCCs, 234 (83.6%) were histologically confirmed BCCs, and 144 (51.4%) were located in the head and neck area. Quiz Ref IDThe median follow-up duration of all tumors was 9 months, with a maximum of 78 months. A flowchart of the study design is shown in eFigure 1 in the Supplement. An intraclass correlation of 0.975 (95% CI, 0.953-0.987; P < .001) was seen in the pilot study on tumor measurements, indicating high interobserver agreement.
Patients’ Reasons for Choosing WW
Overall, most patients chose WW because of patient-related factors or preferences (n = 74; 83%)—for example, prioritizations of comorbidities, severe frailty, or LLE (Figure 1). Tumor-related factors, such as absence of symptoms and the indolent nature of BCCs, were important reasons for 49 patients (55%). Treatment-related factors, such as the expected treatment burden, were mentioned by 31 patients (35%), and circumstantial reasons (eg, planning or transportation difficulties) by 41 patients (46%). Lastly, insufficient understanding or processing of the information on BCC were reasons for 4 patients (4%). Of the 28 patients who chose WW because of LLE, 8 (29%) died of non–BCC-related causes, compared with 9 patients (15%) with other reasons than LLE (P = .12). In 59 patients (66%), multiple reasons for WW were noted in electronic patient medical records (eg, LLE and asymptomatic).
During follow-up, 317 (65.8%) exact measurements were performed by 2 observers per visit and 142 (29.5%) by 1 observer. Eight (1.7%) measurements were additionally retrieved from histopathology and 15 (3.1%) measurements were based on pictures. In 7 BCCs, no residual tumor was seen after initial diagnostic punch biopsy was taken. As is shown in eTable 1 in the Supplement, most of these tumors were 5 mm or smaller, although there was also 1 micronodular BCC of 25 mm located on the lower back regressed after punch biopsy. Examples of the tumor growth are shown in Figure 2.
In 124 (68.8%) BCCs, at least 2 tumor diameter measurements were suitable for analyses. Quiz Ref IDWhereas 58 (46.8%) BCCs showed tumor size increase, 66 (53.2%) BCCs did not show tumor growth over time (including 2 and 8 clinically diagnosed BCCs without histologic confirmation, respectively). Of the latter, 21 (31.8%) even showed a decrease in tumor diameter (including 3 clinically diagnosed BCCs). Quiz Ref IDSignificantly more low-risk BCCs (nodular/superficial/clinical BCCs) showed a stable or decreasing tumor diameter compared with high-risk BCCs (infiltrative/micronodular) in univariate analyses (61.9% vs 35.0%; P = .006). Moreover, 78.6% of low-risk BCCs showed a maximum tumor growth of 2mm, vs 45.0% of high-risk BCCs (P < .001). Furthermore, a significant association was seen between tumor growth (>1 mm) and high-risk BCC subtype in multivariable mixed-model logistic regression (OR, 3.35; 1.47 to 7.96; P = .005). Results were robust when sensitivity analysis was performed defining tumor growth as greater than 2 mm (n = 40), whereas the predictive capability of the model increased (eTable 2 in the Supplement). Tumor size and tumor location were not associated with tumor growth (Table 2).
In the 58 (46.8%) BCCs that showed tumor growth greater than 1 mm, only BCC subtype was associated with tumor growth. The estimated tumor diameter growth was 4.46 mm (80% prediction interval, 1.42 to 7.46) in 1 year for high-risk BCCs and 1.06 mm (80% prediction interval, −1.79 to 4.28) for low-risk BCCs.
As expected, the majority of BCCs (81; 60.9%) were reported to be asymptomatic at initial presentation, although the absence or presence of symptoms was frequently underreported (in 150 BCCs; 53.0%). Most frequently, BCCs were reported as causing bleeding (19 BCCs; 36.5%), itch (13 BCCs; 25.0%), and/or crustae (12 BCCs; 23.1%). For 11 (8.0%) BCCs, patients developed symptoms (eg, bleeding) during a median (IQR) follow-up time of 18 (9-25) months. It should be noted that not all patients were bothered by these symptoms (eg, they experienced bleeding without being bothered by it).
After an initial WW approach, 107 (38.2%) BCCs in 54 of 86 (63%) patients were treated later. Three (3%) patients were lost to follow-up. The median (IQR) time until treatment was 7 (5-11) months, and conventional excision was most frequently initiated (n = 81, 73.6%; eFigure 1 in the Supplement). In total, 160 reasons were recorded; in several BCCs, more than 1 reason was recorded. Potential tumor burden was the most important reason to initiate treatment in 65 (59.1%) BCCs, followed by resolved (circumstantial) reason(s) for WW (38 BCCs; 34.5%), and reevaluation of patient-related factors (30 BCCs; 27.3%) and expected treatment burden in case of tumor growth (27 BCCs; 24.5%). Quiz Ref IDIn 3 (2.8%) BCCs, a more invasive intervention (eg, reconstructive surgery instead of expected primary closure) was needed than the estimated intervention at initial presentation. In total, 8 surgically treated tumors initially classified as low-risk histologic subtypes were discordant with the initial biopsy histologic subtype (eg, mixed nodular/infiltrative subtype instead of nodular subtype only). In 2 tumors, subsequent histopathology turned out to be squamous cell carcinoma instead of basal cell carcinoma (Figure 2).
Although considerable research has been performed in dermato-oncology, it remains difficult to estimate the time to benefit from BCC treatment.15 Active treatment of BCCs is indicated in cases in which the time to benefit is estimated to be shorter than the residual life expectancy (eFigure 2 in the Supplement), whereas refraining from treatment could be in the best interest of patients with a LLE or specific reasons outweighing the benefit of early treatment.2 In this study, patient-related factors and/or preferences were most commonly reported as reasons for WW. In BCCs for which treatment was performed later (38.2%), more invasive treatment (eg, reconstruction instead of expected primary closure when treated at first presentation or Mohs micrographic surgery instead of conventional excision) was needed in only 2.8%.
Whereas LLE, frailty, and patient preferences were considered important factors for patients choosing WW, in line with a previous study,16 integration of these items in clinical guidelines remains limited.2,17 These aspects can be difficult to estimate in daily dermatology practice, which is underscored by the substantial proportion of treatment initiation after reevaluation of patient-related characteristics. It could be useful to learn from geriatric care and geriatric assessments to evaluate LLE and frailty. Frailty is defined as a state of vulnerability and physical deterioration, which leads to disproportionally decreased ability to cope with stressors.18 In several medical fields, frailty has been associated with increased mortality.19 Although research on frailty and frailty-related patient characteristics in dermatology is sparse, results appear to be in accordance with those found in other medical fields (eg, associated with LLE).3,8,15,20-22 However, the definition of LLE and the natural tumor behavior naturally influence the time to benefit. For instance, if the time to develop BCC-related complaints in an individual patient is hypothetically 2 years, this patient probably still benefits from treatment if life expectancy is estimated at 5 years. Therefore, future studies are highly needed to define relevant LLE and patient characteristics predictive of LLE in dermato-oncology.23-25 Because it currently remains challenging to predict life expectancy in individual patients, a multidisciplinary approach involving other specialists or general practitioners could aid in decision-making. In patients with an LLE and asymptomatic low-risk tumors, the time to benefit from treatment might exceed life expectancy, and WW should be discussed as a potentially appropriate approach (Figure 3).
Moreover, in cases of personal preferences or circumstances, a WW approach can be initiated, as long as follow-up (eg, every 3-6 months) and observation are maintained. At each follow-up visit, management options should be reconsidered, including whether WW remains medically justified or if the risk-to-benefit ratio has changed over time. Naturally, the frequency of hospital visits should be adjusted to what is feasible for individual patients (ie, should not be more burdensome than the treatment burden associated with active treatment). The rationale for follow-up is to gain insight on the tumor behavior in every individual patient, either strengthening previously made decisions or strengthening the advice for initiating curative BCC treatment. Remarkably, this study showed that a majority of tumors (53.2%) remained stable in diameter over time or even decreased in size. The results should be interpreted with caution; contraction of the tumor may have occurred after initial punch biopsy, and tumor behavior, patient characteristics, and follow-up duration and frequency varied widely among the included patients. However, the results are comparable with those found by Wehner et al,26 who described that only 49% of 39 clinical BCCs showed tumor growth during a mean follow-up of 15.8 months. In the present study, 46.8% of BCCs increased in size, estimated at 4.46 mm in 1 year for infiltrative/micronodular and 1.06 mm for remaining BCCs. The broad prediction intervals found in the present study accentuate the heterogeneity regarding tumor behavior and the need for follow-up visits to evaluate tumor progression. Nonetheless, these results raise the question of whether nodular and superficial BCCs might be overtreated in current clinical care, as the vast majority (61.9% and 78.6%) of these tumors did not increase more than 1 mm or 2 mm, respectively.
Naturally, we do not advocate a WW approach in each individual patient; the decision for WW should be considered very carefully. It should be noted that several of the included patients had been advised not to proceed with WW but refused treatment. This might be an explanation for the relatively high proportion of patients with BCCs located in the head and neck area. Surprisingly, multivariable analysis did not show an association between tumor growth with known risk factors of tumor location and tumor size, although this could be owing to a lack of power. Therefore, more research is highly needed to provide evidence-based guidance on the expected natural tumor behavior and prognostic factors on both tumor growth and patient prognosis and to aid in identification of those tumors that might show rapid tumor growth and lead to substantial patient burden. Expected treatment burden was mentioned as a reason for WW in a substantial part of the included patients, although previous studies have shown that older adults mostly tolerate BCC treatment well.15 Physicians should therefore be aware of information framing; patients heavily rely on the way information is formulated.27 However, the option of WW should be discussed and considered, as the relatively large population included in this observational study accentuates that not all patients prefer to be actively treated initially. The use of decision aids might lead to more personalized medical care without sacrificing feasibility in daily clinical care.28,29
A cautious approach should be maintained in tumors developing unexpectedly. In line with previous research,1 this study showed a discrepancy between initial biopsy histologic subtype and eventual histologic subtype after excision in several tumors. Mostly, another histological subtype of BCC was found (eg, mixed nodular/infiltrative subtype after excision vs nodular subtype only at biopsy), but also 2 squamous cell carcinomas were seen. It is unclear whether the discrepancies found in this study can be attributed to biopsy sampling errors (eg, basosquamous component not seen in the small punch biopsy sample) or development of more aggressive types of skin cancers (eg, squamous cell carcinoma arising in long-existing ulcers). Reevaluation of the tumor behavior should occur at each follow-up visit to determine whether the original diagnosis appears to be correct or if additional biopsies are needed in case of unusual clinical behavior.
Certain limitations should be addressed. A selection bias might exist owing to the preselection of patients who visit a university hospital and patients generally fit enough to be referred by general practitioners. This, too, appears from the fact that a relatively high proportion of patients (26.2%) were treated with radiotherapy before. Furthermore, the limitations of a clinical observation should be taken into consideration; although the pilot study on tumor measurements showed excellent interobserver agreement, individual tumor measurements can vary (eg, when tumors were poorly defined), and only tumor diameter was included in analyses (ie, degree of infiltration was not included in analyses). Also, in this study, real-world data were evaluated, leading to relatively limited follow-up duration, and reasons for WW, treatment, and tumor-related symptoms were extracted from patient medical records retrospectively, which might have been underreported. Moreover, although patient education was performed with caution, the retrospective part of this study might have led to additional bias. Nonetheless, this is one of the first studies to evaluate a WW approach in a large number of BCCs, and valuable information has been gained for daily clinical care.
In this cohort study of patients with BCC, findings showed that WW might be an appropriate approach, especially in cases of LLE and asymptomatic nodular/superficial BCCs. However, all patients should be followed up regularly to determine whether a WW approach is still suited and if patients still prefer WW and to reconsider the consequences of refraining from treatment. Patient preferences, treatment goals, and the option for proceeding with a WW approach should be discussed as part of personalized shared decision-making. As data on WW and the natural course of BCCs are extremely sparse, additional prospective studies and real-world evidence are needed to further develop evidence-based guidance in this growing patient group.
Accepted for Publication: July 4, 2021.
Published Online: September 8, 2021. doi:10.1001/jamadermatol.2021.3020
Corresponding Author: Marieke E. C. van Winden, MD, MSc, Department of Dermatology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands (marieke.vanwinden@radboudumc.nl).
Author Contributions: Drs van Winden and Bronkhorst had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: van Winden, Hetterschijt, van de Kerkhof, de Jong, Lubeek.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: van Winden, Bronkhorst, van de Kerkhof, Lubeek.
Critical revision of the manuscript for important intellectual content: Hetterschijt, Bronkhorst, van de Kerkhof, de Jong, Lubeek.
Statistical analysis: van Winden, Bronkhorst.
Obtained funding: van de Kerkhof, Lubeek.
Administrative, technical, or material support: van Winden, Hetterschijt, de Jong.
Supervision: van de Kerkhof, de Jong, Lubeek.
Conflict of Interest Disclosures: Dr de Jong reported receiving research grants from AbbVie, Novartis, Janssen Pharmaceuticals, Leo Pharma, and UCB for research on psoriasis and serving as a consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Almirall, Janssen Pharmaceuticals, Novartis, Lilly, Celgene, Leo Pharma, Sanofi, and UCB outside the submitted work; all funding goes to the independent research fund of the Department of Dermatology of Radboud University Medical Center, Nijmegen, the Netherlands. Dr Lubeek reported serving as a consultant/paid speaker for Sun Pharma and Sanofi Genzyme outside the submitted work; all financial compensations were paid to the independent research fund of the Department of Dermatology of the Radboud University Medical Center, Nijmegen, the Netherlands. No other disclosures were reported.
Additional Contributions: We thank the patients or their family members for granting permission to publish this information. We also thank all physicians who included patients for this study or who participated in the pilot study.
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