Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).
Objective
To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.
Evidence acquisition
A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.
Evidence synthesis
Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.
Conclusions
Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.
Introduction
Delay of definitive therapy has an unfavourable impact on outcomes in different malignancies [1], [2], [3]. Because most malignant cells appear to grow exponentially with related systemic spread, we can reasonably assume that treatment delay of some tumours may risk missing the window of curability.
Prostate cancer (PCa) is generally considered a relatively slow-growing malignancy, with screening adding a considerable lead time [4], [5]. Delay between diagnosis and active therapy of PCa is often common. Unintended causes for this delay may include the need for pretreatment diagnostics or psychological and logistical reasons. Active surveillance (AS), as opposed to immediate definitive therapy, has garnered considerable support for several reasons in the treatment of low-risk disease. This strategy has introduced a new intended reason for delay in treatment [6], [7]. AS is designed to avoid unnecessary therapy in low-risk PCa, but identification of these tumours can be difficult and may miss the presence of occult higher risk disease.
We review the current medical literature to identify evidence whether treatment delay in PCa results in worse oncologic outcomes. Effects on functional outcome are not addressed.
Section snippets
Study selection
We conducted a systematic review of the electronic databases PubMed and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines [8]. Predefined search terms were used to identify articles describing the impact of a delay in treatment or extending the time interval between diagnosis and active curative therapy of PCa on pathologic, biochemical, and mortality outcomes. The literature search included papers published until 30 September 2012.
Search results
Our literature search identified 17 original articles that were included in the qualitative analysis [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Differences in study design, inclusion criteria, and outcome parameters between studies and the lack of study population details prevented combining data for quantitative analysis. Table 2 presents an overview of the 17 included studies. Four relevant studies were outdated by more recent
Conclusions
Among men with low-risk PCa, a treatment delay of several months or even years does not appear to compromise long-term oncologic results following definitive treatment. Limited data suggest that treatment delay may compromise oncologic outcomes in men with non–low-risk PCa. The overall quality of evidence of included studies was ≥3.
Curative treatment for low-risk PCa, if indicated at all, is not an urgent matter. This creates a window for additional risk stratification including initial AS.
Despite a largely successful ‘zero COVID’ policy in 2020, the COVID-19 pandemic disrupted routine cancer services in the city of Hong Kong. The aims of this study were to examine the trends in cancer incidence before and during the COVID-19 pandemic and estimate missed cancer diagnoses.
We used population-based data from the Hong Kong Cancer Registry 1983–2020 to examine the trends of age- and sex-standardised cancer incidence before and during the COVID-19 pandemic. We applied: (i) the annual average percentage change (AAPC) calculated using the Joinpoint regression model and (ii) the autoregressive integrated moving average (ARIMA) model to forecast cancer incidence rates in 2020. Missed cancer diagnoses in 2020 were estimated by comparing forecasted incidence rates to reported rates. A subgroup analysis was conducted by sex, age and cancer site.
The cancer incidence in Hong Kong declined by 4.4% from 2019 to 2020 (male 8.1%; female 1.1%) compared with the long-term AAPC of 0.5% from 2005 to 2019 (95% confidence interval 0.3, 0.7). The gap between the reported and forecasted incidence for 2020 ranged from 5.1 to 5.7% (male 8.5%, 9.8%; female 2.3%, 3.5%). We estimated 1525–1596 missed cancer diagnoses (ARIMA estimate –98, 3148; AAPC 514, 1729) in 2020. Most missed diagnoses were in males (ARIMA 1361 [327, 2394]; AAPC 1401 [1353, 1460]), with an estimated 479–557 missed cases of colorectal cancer (ARIMA 112, 837; AAPC 518, 597) and 256–352 missed cases of prostate cancer (AAPC 231, 280; ARIMA 110, 594).
The incidence of new cancer diagnoses declined in 2020 contrary to the long-term increase over the previous decades. Significantly lower diagnoses than expected were observed in males, particularly for colorectal and prostate cancers. Fewer reported cancer cases indicate missed diagnoses and could lead to delayed treatment that could impact future health outcomes.
Delays in initiating and completing brachytherapy may have adverse oncologic outcomes for patients with cervical, uterine, and prostate cancer. The impact of the COVID-19 pandemic on brachytherapy in the United States has not been well-characterized.
We aim to evaluate how a positive COVID-19 test affected timeliness of treatment for patients undergoing brachytherapy for cervical, uterine, and prostate cancer.
We queried the National Cancer Database to identify patients diagnosed with cervical, uterine, and prostate cancer in 2019 and 2020 who received brachytherapy in their treatment. Patients who tested positive for COVID-19 between cancer diagnosis and start of radiation were compared to those who did not test positive for COVID-19. Time in days from cancer diagnosis to initiation of radiation was compared using two-sample t-tests with p < 0.05 signifying significant differences.
We identified 38,341 patients with cervical (n = 6,925), uterine (n = 18,587), and prostate cancer (n = 12,829). Rates of COVID-19 positivity were cervical cancer (n = 135; 2%), uterine cancer (n = 236; 1.3%), and prostate cancer (n = 141; 1%). Of those, 35% of cervical, 49% of uterine, and 43% of prostate cancer patients tested positive between their cancer diagnosis and initiation of radiation. Median days to radiation was significantly longer in these patients: 78 versus 51 for cervical cancer (p < 0.01), 150 versus 104 for uterine cancer (p < 0.01), and 154 versus 124 for prostate cancer (p < 0.01).
For patients with cervical, uterine, and prostate cancer diagnosed between 2019–2020, testing positive for COVID-19 after their cancer diagnosis was associated with a delay to initiation of radiation by 4–7 weeks.
In addition, there has also been a rapid increase in the number of patients with PCa in Japan.1 Definitive therapy delays can also have an unfavorable impact on outcomes in many malignancies.2–4 As most malignant cells appear to grow exponentially with related systemic spread, tumor treatment delays can risk missing the window of curability.
We evaluated the impact of the duration between the biopsy and surgery on the biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP).
We retrospectively evaluated 302 patients who underwent RARP in our institution from April 2010 to December 2017. Patients were categorized into 2 groups, an interval between biopsy and surgery of 180 days or less (Group A) and longer than 180 days (Group B). Factors retrospectively analyzed for the BCR for the interval between the biopsy and RARP included patient's characteristics, intraoperative and postoperative results. The Kaplan–Meier method and Cox proportional hazards regression model were used to evaluate the predictors of BCR.
The median follow-up was 42 months, with 24 patients developing BCR at a mean of 13.5 months after RARP. There was no difference in the rate of BCR in Group A and Group B. Multivariate analysis showed that BMI (<23.5 kg/m2, p = 0.034), worst GS of the biopsy (≥8, p = 0.007), and without lymph node dissection (p = 0.034) were significant predictors of BCR. Analysis of the interval from the biopsy showed that there was no significant difference between Group A and Group B, when tested according to the NCCN risk stratification (low risk: p = 0.871, intermediate risk: p = 0.205, high risk: p = 0.287).
The preoperative predictors of BCR included BMI (<23.5 kg/m2) and worst GS of the biopsy, and without lymph node dissection. A long duration from biopsy to RARP did not influence the probability of BCR, even in patients considered to be at a high risk.
Treatment delays in prostate cancer have been characterised, although not explicitly in men undergoing transperineal prostate biopsies. We aimed to determine if delays to radical prostatectomy correlate with adverse outcomes using a contemporary population-based cohort of men diagnosed by transperineal biopsies.
This study analysed men with prostate cancer of the International Society for Urological Pathology grade group ≥2, diagnosed by transperineal prostate biopsies who underwent prostatectomy, using the prospectively data from 1 January 2014 to 30 June 2018 Prostate Cancer Outcomes Registry-Victoria. Data were analysed according to stratified demographic and disease characteristics. Time intervals from biopsy (28, 60, 90, 120, and 270 days) were compared using odds ratios and regression analyses for proportion of upgrading, early biochemical recurrence, pT3 disease at prostatectomy, and positive surgical margins.
In total, 2008 men were analysed. There were 306 (16.7%) men with upgrading, 151 (8.4%) with biochemical recurrence, 1068 (54.1%) with pT3 disease, and 464 (23.1%) with positive surgical margins (percentages excluded patients with missing data). All adverse outcomes studied were significantly associated with higher prostate-specific antigen and grade at diagnosis. Delays of 120–270 days did not adversely alter the incidence of Gleason upgrading, pT3, or recurrence. Delays (most frequent 60–89 days, 28%) were associated with positive surgical margins but not monotonically. Regression modelling demonstrated no increased likelihood of most adverse outcomes for up to 270 days.
Men with prostate cancer of grade group ≥2 diagnosed through transperineal biopsy may wait up to 270 days for a prostatectomy without a greater likelihood of upgrading, pT3 disease, positive surgical margins, or biochemical recurrence.
Meta-analysis, retrospective reviews, and trials were selected for all cancer types: breast, colorectal, lung, prostate, head and neck, ovarian, uterine, renal cell carcinoma, bladder, lymphoma, and leukemia; a selection is presented on Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2021.100134.21,27-55 The level of increase in the risk of cancer death associated with 1 week to 6 months of delay (depending on the studies) was investigated. With the exception of studies in indolent lymphomas and low-risk prostate cancer,15-18 the majority of other studies reported an increased risk of death ranging from 0.5% per week of delay to 169% per 12 weeks of delay depending on cancer types and across studies21,27-55 (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2021.100134). Comparisons of the different proportions and numbers were conducted using the chi-square test or the nonparametric Mann–Whitney U test.
The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France.
The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses.
A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years.
In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years.
The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic.
We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65 years of age.
We analyzed data from 332 outpatients’ case files between 9th of March and 30th of April 2020. The median age was 75 years (range: 65–101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period.
Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.
La prise en charge des patients âgés atteints de cancer fut très difficile pour les cliniciens durant la première vague de la pandémie COVID-19. En effet, ils ont dû faire face à un dilemme : ne pas surexposer les patients aux risques d’infection tout en maintenant leur prise en charge carcinologique.
Nous avons analysé les données de prise en charge de 9 hôpitaux. L’objectif principal était d’évaluer la prévalence des adaptations de prise en charge des patients âgés durant la pandémie. L’objectif secondaire était d’évaluer l’incidence des hospitalisations liées à l’infection de la COVID-19. Les données collectées provenaient de la prise en charge de patients âgés de plus de 65 ans.
Nous avons analysé les données de 332 patients ambulatoires entre le 9 mars et le 30 avril 2020. L’âge médian était de 75 ans (intervalle : 65–101) et 53 % étaient des hommes. Compte tenu de la pandémie, plus de la moitié des patients ont eu une adaptation thérapeutique, définie par une intervention chirurgicale décalée ou annulée, un schéma d’irradiation adapté, adaptation du traitement systémique ou l’utilisation de la télémédecine. Parmi les patients présentant une maladie localisée et ceux présentant une maladie métastatique, 60 % et 53 % respectivement ont eu une adaptation thérapeutique liée à la pandémie. L’utilisation des GCSF a été rapportée chez 83 % des patients en nette augmentation compte tenu de la pandémie. Soixante-neuf pour cent des cliniciens ont utilisé la télémédecine. Lors de l’analyse finale, seul un patient a été hospitalisé pour cause d’une infection de la COVID-19, aucun décès n’a été rapporté.
Notre étude fut la 1re à rapporter l’adaptation thérapeutique durant cette pandémie chez les sujets âgés. Durant cette crise sanitaire, notre objectif est de protéger nos patients et notamment les plus vulnérables, face à l’infection avec les gestes barrières et le confinement tout en garantissant la continuité des soins du cancer. Nous avons constaté la capacité d’adaptation des cliniciens avec un faible taux d’incidence d’infection grave chez les patients âgés ambulatoires.
