Survival outcomes following treatment delays among patients with early-stage female cancers: a nationwide study

Cancer has become a critical public health concern worldwide, and the social burden of cancer will continue to increase along with the aging population [1]. The coronavirus disease 2019 (COVID-19) pandemic caused major disruptions in healthcare delivery worldwide, putting patients with cancer at higher risk for negative outcomes from prolonged delays in their diagnosis and treatment [2, 3]. Delays in the treatment of patients with localized cancers after their initial diagnoses increased their likelihood of developing locally advanced and even metastatic disease. Continuous updates of evidence derived from systematic reviews and meta-analyses show that discrepancies in the impacts of prolonged wait times from diagnosis to treatment on clinical outcomes were observed in patients with various types of cancers [4‐6].

Before the COVID-19 pandemic, several studies reported that delays in treatment increased the probability of all-cause mortality in patients with different types of cancers, including but not limited to, endometrial cancer [7], liver cancer [8], breast cancer [9], and oral cavity squamous cell carcinoma [10]. However, accumulative evidence showed that a prolonged delay in treatment was not associated with an increased risk of adverse outcomes in patients with some cancers, such as a 15-day delay for patients with acute myeloid leukemia [11] and 2 month delays for patients with curable gastric cancer [12] and advanced pancreatic cancer [13]. Therefore, the length of time that is acceptable (i.e., safe from disease progression) within the interval between the diagnosis and treatment of cancer is debatable. More population-based studies from different regions could help healthcare providers rethink the impact of prolonged time from diagnosis to treatment initiation on the progression of cancers and patients’ survival.

Current evidence shows that the incidence of cancer among women has increased (0.2% per year) annually in recent years, whereas cancer rates among men have generally decreased since the early 1990s. This change has resulted in the narrowing of the sex gap in incidence, with the male-to-female incidence ratio declining from 1.39 in 1995 to 1.14 in 2018 [14]. Recent data show that depression and anxiety were more pronounced among female patients during the COVID-19 pandemic [15, 16]. Unfortunately, female patients were more likely than their male counterparts to experience prolonged wait times between symptom presentation and diagnosis, as well as the initiation of treatment [17‐19]. Frequent sex disparities with a predominance of women have been reported in some cancers, such as differentiated thyroid carcinomas (DTC) [20]. Yet few studies have investigated this topic in samples with female-specific cancers, such as cervical cancer [21, 22]. Thus, a deep understanding of the association between treatment delay intervals and survival outcomes could provide useful and rational guidance for clinical practice.

Thus, we aim to investigate the impact of treatment delays on the long-term overall survival (OS) and cancer-specific survival (CSS) of patients with one of the five female cancers with the highest incidence rates, using a nationwide population-based dataset. We also analyze the 10-year predictions of OS patterns in patients with one of the five types of cancers and different treatment delay intervals.

Cancer-associated treatment delays were not uncommon during the COVID-19 pandemic, especially in patients with high incidence cancers [15, 27‐29]. Treatment delays increased anxiety and depression in patients with cancer, especially female patients, due to concerns about becoming infected with COVID-19 or because of strict nationwide policies [15]. Our model predicted an increasing number of deaths among patients with cancers, such as breast cancer, colorectal cancer, lung cancer, and esophageal cancer in the beginning and after the end of the COVID-19 pandemic [30]. Therefore, we thought an investigation of the impact of treatment delays on the long-term survival of patients with the most common female cancers could help physicians develop interventions for this population that were more rational. In the present study, we examined discrepancies in the impact of delays in the initiation of treatment on the survival of females with five different cancers.

In this large population-based study, the probability of OS was found to be worse (_adjustedHR = 1.23, p < 0.001) among patients with stage I breast cancer. Unlike patients whose treatment initiation was timely, a borderline negative association was found between long-term treatment delays and OS among patients with stage II cancer (_adjustedHR = 1.09, 95% CI 0.99–1.19, p = 0.059). However, treatment delays did not impair the CSS of this population, regardless of the cancer stage at diagnosis. An observational study conducted using the National Cancer Database (NCDB) determined that the outcomes of even stage I patients could be influenced by a delay in the initiation of treatment. A delay in treatment from 61 to 120 days after diagnosis was associated with a 1.3% and 2.3% increased mortality after 5 years and 10 years, respectively [24]. In contrast, the results of a study conducted in Singapore by Ho et al. did not find any significant differences in long-term survival between patients with non-invasive breast cancer who received treatment after a 90-day wait-time interval and those who received treatment within the 90-day interval. Notably, the ethnic composition of the participants was different in the two studies (White and Asian). Recent studies have confirmed inconsistent survival patterns among patients with cancer of different ethnicities and races [14, 31]. Specifically, the survival probability of Black patients has been reported to be relatively lower than the survival of Asian/Pacific Islanders. Although underlying mechanisms of survival are under investigation, factors such as lifestyle and socioeconomic status are thought to play a pivotal role in survival [31, 32]. Nevertheless, the results of our analysis support the importance of timely definitive treatment, even for early-stage breast cancer. Patients with ductal carcinoma in situ breast cancer (DCIS) were not included in this study because of their limited number of cases and most of these patients had a satisfactory prognosis after surgical intervention. Minami et al. found that prolonged wait times for operations to treat DCIS were associated with a slight increase in pathological upstaging in the patients, although this delay did not affect their OS [33].

To date, the conclusions of investigations of the association between prolonged wait times and the survival of patients with NSCLC are still debatable [6, 34‐36]. As one review concluded, the impact of treatment delays was lowest for subcentimeter nodules, and probably the highest in stage II disease. However, in an evidence-based large-scale study from Taiwan (42,962 cases), the authors reported a negative impact of treatment delays on patients with whole-stage NSCLC; those with late-stage tumors or longer wait-time intervals showed even larger increases in mortality [37]. Compared with the Taiwan cohort, the females in our study with NSCLC showed a paradoxical result. An increased risk of mortality due to treatment delays was observed in the stage I patients with NSCLC (_adjustedHR = 1.11, 95% CI 1.01–1.23, p = 0.044), compared with the patients who were treated immediately. These results were found for the OS group but not for CSS. Cone et al. found an increased risk of all-cause mortality among patients with stage I NSCLC from a large cancer database in the US [24], regardless of sex. However, this phenomenon was not present in stage II patients because the survival curves did not show a significant discrete distribution among the different treatment delays of the subgroups, as described. The explanations for this difference could reflect a potential bias. First, the definitions of treatment delays varied among existing studies, which could have led to inconsistencies in reported trends. The study populations and sample sizes among the various studies might have also contributed to this difference. Although existing studies have limitations, their results mostly support the association of timely treatment and better OS in patients with non-metastatic stage NSCLC [34]. Whether this finding applies to CSS requires further evaluation. Recommendations derived from more robust evidence could improve future research, policies, and healthcare practices.

Although different strategies to treat stages I-II DTC can be implemented, surgical intervention is the pivotal first-line treatment modality. Thus, we only included patients who underwent surgical resection in the present study. As expected, we observed no significant effects of treatment delays on the long-term survival of patients with early-stage cancer. In contrast, a significantly higher probability of survival was observed in stage I patients with intermediate delays in treatment (_adjustedHR = 0.70, 95% CI 0.53–0.93, p = 0.012). In recent years, DTC has been regarded as a type of indolent cancer and the consensus of experts in developed countries suggests that active surveillance could be a safe and effective strategy for dealing with DTC in low-risk patients [38]. Up to now, few studies have evaluated the influence of treatment delays on DTC survival. However, a study on this topic by Fligor et al. determined that delayed surgery among patients with papillary thyroid carcinoma was associated with reduced OS [39]. Some differences among these studies should be acknowledged. First, the median follow-up time in the study by Fligor et al. was 55 months, which was relatively shorter than the follow-up of our study (78 months). Second, longer intervals were examined in their study (90 days), whereas 90 days was further divided into two subgroups in our study. In addition, their subgroup analysis was based on the T stage, while our study was based on the tumor stage. Our results support the application of an acceptable wait time that is safe for the initiation of treatment for early-stage female patients with cancer. Future studies should be conducted to analyze the impact of treatment delays on the risk of disease progression and recurrence-free survival in this population, which could enhance the evidence supporting the use of active surveillance for these patients.

No significant difference among patients with stage I colorectal cancer was found between those with prolonged treatment delays and their counterparts who received immediate treatment. However, a trend persisted (_unadjustedHR = 1.60, p < 0.001; _adjustedHR = 1.21, p = 0.090): two studies on patients from the NCDB with different cutoffs for wait-time intervals (40 days and 60 days) revealed significantly worse outcomes among the patients with curable-stage colorectal cancer and a delay in the initiation of treatment [24, 40]. However, a recent high-volume single-center study in China did not find any negative effects of prolonged preoperative wait times on the prognosis of outcomes (including OS and disease-free survival) of patients with stages I-III colorectal cancer [41]. However, an earlier meta-analysis reported that inconsistent findings were frequent in studies on colorectal cancer, with the majority of findings showing “no association” [6]. Of note, when our study population was further divided into two subgroups (immediate treatment: < 1 month and intermediate delay: ≥ 1 and < 3 months), intermediate delays in treatment was associated with better OS (_adjustedHR = 0.83, 95% CI 0.75–0.92, p < 0.001) in stage I patients and (_adjustedHR = 0.70, 95% CI 0.65–0.75, p < 0.001) in stage II patients, and CSS rates (_adjustedHR = 0.64, 95% CI 0.57–0.71, p < 0.001) in stage II patients. Nevertheless, we cannot interpret this association as presented, because whether an intermediate delay was caused by a pre-treatment evaluation or a referral to a specialized center providing better clinical care remains unknown. Thus, delaying treatment of the patients with colorectal cancer for relatively prolonged time intervals is questionable by deserves further exploration.

Recent systematic reviews and meta-analyses have been conducted on the association between delayed initiation of treatment and the survival time of patients with cervical cancer [42]. To the best of our knowledge, this is the largest nationwide cohort to examine the impact of treatment delay intervals on the long-term survival of patients with early-stage cervical cancer. Our results showed that delayed initiation of treatment did not adversely affect the OS of patients with early-stage cervical cancer, but it increased the risk of CSS in stage I patients with intermediate treatment delays. In a review of the recent literature on cervical cancer, the disparity in survival patterns was found to be an effect of prolonged wait times for different treatment modalities [21, 22, 43‐45]. Most of the studies on this topic were limited to single-centers or had small samples. For instance, Umezu et al. [44] (n = 177 cases), Perri et al. [45] (n = 321 cases), and Matsuo et al. 41 (n = 217 cases) found that a delayed time from the initial visit (and diagnosis) to the intervention did not impair outcomes of patients with cervical cancer. However, evidence from a large population-based study in Asia [21] showed that patients with early-stage cervical cancer and longer wait-time intervals (especially those exceeding 180 days) exhibited a significantly lower probability of OS than the patients who received treatment within 90 days did. Hence, the different cutoffs of the wait-time intervals (which ranged from 14 to 90 days) might have contributed to this divergence in OS rates.

The conclusions drawn inform the evaluations of the impact of delayed adjuvant therapy initiation on the survival of patients with cervical cancer were consistent. Noh et al. [43] reported that wait-time intervals for definitive concurrent chemoradiation had a significant influence on the OS of patients with cervical cancer when the cutoff wait-time interval was 14 days (as a categorical variable: HR = 1.53, p = 0.018; and as a continuous variable: HR = 1.023/per day, p = 0.007). Similarly, the delayed initiation of adjuvant radiotherapy also impaired the OS of patients with early-stage cervical cancer [22]. Thus, delayed time to treatment may have had a greater impact on the postoperative adjuvant therapy prior to the initial treatment. Robust evidence derived from comprehensive analyses in the future (such as uniform cutoffs of intervals, longer follow-ups, and multicenter datasets) should be considered to help clinicians improve their therapeutic plans for patients with cervical cancer.

Although some of the cancers and stages mentioned in the current study showed better OS and CSS patterns in the intermediate treatment delay group, the results need to be interpreted carefully and evaluated further. A relatively prolonged time from diagnosis to treatment might not impair the prognosis of most patients with cancer after adjusting for numerous confounders, revealing that cancer-specific characteristics are more pivotal prognostic factors than wait-time intervals between diagnosis and treatment.

Accumulative evidence suggests that a multi-level social network is associated with improved survival among patients with cancer. To date, many scholars believe that the connection between marital status and cancer survival reflects social support. Spouses motivate patients to seek regular medical care, which can lead to an earlier diagnosis and treatment of a disease. Patients with cancer receive encouragement from their spouses to continue to follow up with their treatment and to seek support from other survivors of cancer [46‐49], and previous studies have examined the association of marital status with breast cancer risk and survival [49‐51]. In an earlier study, researchers showed that unmarried women were at increased risk for death from breast cancer, which might be attributed to their decreased social support and social networks [52]. According to a report by Parise et al., the survival patterns of married white women and female Asian/Pacific Islanders with triple-negative breast cancer improved after adjusting for confounders such as age, stage, tumor grade, and treatment [53].

In the present study, married patients also had shorter wait-time intervals from diagnosis to treatment, regardless of their cancer stage and subtype. Furthermore, a significantly higher probability of long-term OS was found in married patients with stage I NSCLC (Additional file 1: Table S4), breast cancer (Additional file 1: Table S5), differentiated thyroid cancer (Additional file 1: Table S6), and colorectal cancer (Additional file 1: Table S7), compared with single or divorced patients. However, this effect was not observed in patients with early-stage cervical cancer (Additional file 1: Table S8). The insurance data in our study was missing; therefore, the median household income was used as a reference for an indirect measure of insurance status. Similar to the findings of marital status, early-stage patients with high incomes (> $75,000/year) showed significantly better survival outcomes, compared with low-income patients (< $35,000/year), especially patients with NSCLC, breast cancer, and colorectal cancer. The underlying mechanisms in the associations between socioeconomic status and cancer outcomes, as well as its clinical influence, need further exploration. Nevertheless, our results showed that appropriate psychosocial care and support helped female patients cope with their cancer diagnosis and treatment, especially low-income, divorced, and unmarried subpopulations.

The present study has strengths that should be mentioned. First, it was conducted using a nationwide large-scale database. Our results partially confirmed the conclusions of previous studies in the field of breast cancer, NSCLC, and colorectal cancer, and our study provides new findings on cervical and thyroid cancers among female patients. Second, we focused on cancers with the highest incidence rates among females worldwide to help researchers understand the impact of wait-time intervals on the prognosis of patients with early-stage cancers, especially female-specific or predominate cancers.

To date, most of the evidence supporting the association between the time to treatment initiation and survival is based on data from cancer registries from developed countries. Thus, future research should be conducted in the middle- or low-income countries, where patients with cancer are more vulnerable to disease progression due to treatment delays. Careful scrutiny and comprehensive evaluations of the time from diagnosis to the initiation of treatment within institutions are likely to have far-reaching effects, which could help public health administrators make tailored decisions on treatment deferral in resource-limited regions due to pandemics and facilitate the process of global health missions.

The present study has several limitations that need to be addressed. First, this is a retrospective observational study with selection bias, unbalanced baseline characteristics, and other potential confounders. Second, information about the patient’s characteristics, including lifestyle, educational level, insurance status, Charlson-Deyo comorbidity index, mental health, and medical knowledge, which might have affected their prognosis [15, 28, 54], were not available in the SEER database. Third, we only included cancers with the highest incidence rates in females for the analysis. Thus, future studies should include more cancer subtypes to reach more comprehensive and robust conclusions for clinical decision-making. Furthermore, a detailed record of the reasons for the treatment delays was unavailable in the present database. This information is crucial for research on this important topic and for reducing the progression of cancers due to treatment delays.

Our findings indicate that prolonged delays in treatment initiation (within 6 months) have a limited negative impact on the survival of patients with early-stage NCSLC, infiltrating breast cancer, DTC, colorectal cancer, and cervical cancer. Whether these results can be used as evidence supporting a more comprehensive pre-treatment evaluation needs further exploration and validation, and patients' preferences and anxiety levels should be considered.