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Clinicopathological details of 95 patients with squa- mous cell anal cancer undergoing primary chemoradiotherapy.
Source publication
Aim:
The purpose of this study was to examine factors related to treatment failure following chemoradiotherapy for squamous cancer and to compare the outcome of salvage surgery in one unit with national audit standards published by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) (ACPGBI position statement for management of...
Context in source publication
Similar publications
Relapsing or far advanced rectal and anal cancers remain difficult to treat and require interdisciplinary approaches. Due to modern standard protocols all patients receive irradiation and neoadjuvant chemotherapy—and in case of a relapse a second irradiation—rendering the surgical site prone to surgical site infections and oftentimes long lasting s...
Citations
... Salvage surgery, in the form of abdominoperineal resection, becomes a crucial consideration in cases of persistent or recurrent SCCA after initial CRT in order to achieve local control and improve survival. It is important to consider the morbidities of major surgery when considering this treatment modality [10]. The detection of elevated ctDNA levels or specific genetic alterations may serve as an indicator of treatment failure, prompting timely decisions regarding salvage surgery. ...
This systematic review investigates the potential of circulating tumour DNA (ctDNA) as a predictive biomarker in the management and prognosis of squamous cell carcinoma of the anal canal (SCCA). PubMed, EMBASE, and Cochrane Central Registry of Controlled Trials were searched until 7 January 2024. Selection criteria included research articles exploring ctDNA in the context of anal cancer treatment response, recurrence risk assessment, and consideration of salvage surgery. A total of eight studies were therefore included in the final review, examining a total of 628 patients. These studies focused on three main themes: SCCA diagnosis and staging, treatment response, and patient outcomes. Significant heterogeneity was observed in terms of patient cohort, study methodology, and ctDNA biomarkers. Four studies provided information on the sensitivity of ctDNA biomarkers in SCCA, with a range of 82–100%. Seven studies noted a correlation between pre-treatment ctDNA levels and SCCA disease burden, suggesting that ctDNA could play a role as a biomarker for the staging of SCCA. Across all seven studies with paired pre- and post-treatment ctDNA samples, a trend was seen towards decreasing ctDNA levels post-treatment, with specific identification of a ‘fast elimination’ group who achieve undetectable ctDNA levels prior to the end of treatment and may be less likely to experience treatment failure. Residual ctDNA detection post-treatment was associated with poorer patient prognosis. This systematic review identifies the broad potential of ctDNA as a useful and decisive tool in the management of SCCA. Further analysis of ctDNA biomarkers that include larger patient cohorts is required in order to clearly evaluate their potential role in clinical decision-making processes.
... Indeterminate TRG-3 scores changed most frequently (41%) to DWI-TRG-2, corresponding to excellent response. TRG-3 scores changed to DWI-TRG-4 in 9% of cases, indicating minimal response/residual disease, potentially allowing earlier consideration of salvage surgery, associated with favourable 5-year survival rates as high as 64% [16]. ...
Objectives:
A published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period.
Materials and methods:
This retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1-20 years' experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics.
Results:
Eighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28-0.58).
Conclusion:
DWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist's scoring confidence.
Clinical relevance statement:
Diffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists' confidence.
Key points:
Tumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma. Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%. Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.
... The 5-year survival rate after APR has been reported to be 60%-64%. 227,228 Following treatment of inguinal node recurrence, patients should have a DRE and inguinal node palpation every 3 to 6 months for 5 years. In addition, anoscopy every 6 to 12 months and annual chest, abdominal, and pelvic CT with contrast or chest CT without contrast and abdominal/pelvic MRI with contrast are recommended for 3 years. ...
This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.
... Data on SCC-AC recurrence are scarce. The most recently published study reported 17% of local recurrences, 11% of distant and 4% of both after a median follow-up of 4 years [32] . SCC-AC recurrence remains a substantial problem, especially in elderly patients or patients with an advanced stage at diagnosis [33] . ...
Background:
Little is known about the management of squamous cell carcinoma of the anal canal and its recurrence at a population level. The aim of this study was to draw a picture of management, recurrence and survival in squamous cell carcinoma of the anal canal.
Material and methods:
The 5-year probability of recurrences was estimated using the cumulative incidence function to consider competing risks of death. Net survival was estimated and a multivariate survival analysis was performed. The study was conducted using data of the Burgundy Digestive Cancer Registry. Overall, 273 squamous cell carcinomas of the anal canal registered between 1998 and 2014 were considered.
Results:
Overall, 80% of patients were treated with curative intent. Of these, 61% received chemoradiotherapy, 35% received radiotherapy and 4% received abdominoperineal resection alone. After these treatments, for cure the 5-year cumulative recurrence rate was 27% overall; it was 20% after chemoradiotherapy and 38% after radiotherapy. Five-year net survival was 71% overall; it was 81% after chemoradiotherapy and 55% after radiotherapy.
Conclusions and relevance:
Chemoradiotherapy was highly effective in routine practice. We confirm that it is difficult to distinguish between persistent active disease and local inflammation due to radiotherapy. Squamous cell carcinoma of the anal canal recurrences remains a substantial problem, highlighting the interest of prolonged surveillance. Aggressive management of recurrences may be beneficial.
... Despite generally excellent outcomes after primary chemoradiation and the ability to avoid surgery in the majority of patients, studies show persistent disease in 10-15% [108][109][110] of patients and recurrent disease in 10-30% of patients [111]. Harris et al. [112] sought factors related to treatment failure following chemoradiation and found that only T4 disease at presentation was associated with the eventual need for salvage surgery. Gunderson et al. [113] found increasing risk of locoregional failure at 5 years in patients with T2N0 disease (17% chance of locoregional failure at 5 years), T3N0 (18%), T2N1-3 (26%), T4N0 (37%), T3N1-3 (44%), and finally patients with T4N1-3 disease (60%) [113]. ...
... In 2018, Bignell et al. showed that APE with reconstruction of the perineal defect using vertical rectus abdominis myocutaneous flap is feasible with excellent oncologic outcomes and represents an advance from typical APE afforded by flap that allows both extensive resection and reduction in wound complications [118]. Although their 29-patient cohort demonstrated 5yrOS of 67%, consistent with other recent reports [112,126,130], they demonstrated a low local rerecurrence rate of 7%, with only one with positive margins (3%) (rate of re-recurrence including regional and distant rerecurrences was 31%) [118]. The authors suggest the benefit of myocutaneous reconstruction, which allows for a wide perineal excision without concern for closure. ...
Purpose of Review
Although uncommon, locally recurrent rectal cancer (LRRC) and locally recurrent anal cancer (LRAC) after definitive chemoradiation can confer high morbidity and mortality. Although surgery is critical for management, recent studies show promising results with other locally directed and/or systemic treatment approaches. Here we review the literature to examine recent advances in management of this patient population.
Recent Findings
For LRRC, studies demonstrate success with newer surgical approaches and redefine contraindications for surgery. The roles of brachytherapy, repeat external beam irradiation, and induction chemotherapy are under investigation. Advances in LRAC show that surgery remains a core element of treatment after primary chemoradiation failure. Recent reports of overall survival are promising.
Summary
Surgery remains the mainstay of treatment for LRRC and LRAC, and overall survival is improving. Benefits of newer surgical, radiotherapeutic, and other treatment approaches are being elucidated. These findings pave the way for further improvements in cancer-specific outcomes and quality of life.
... Additionally, Kim et al. [29] recently showed a continuous improvement of CSS over time by means of conditional disease-specific survival. OS rate in our cohort compares favorably with the literature [17,19,[30][31][32][33][34] although it is difficult to compare results because most studies and investigations examine and evaluate data of patients who either suffer from anal canal cancer only (exclusion of anal margin cancer) [19,30,31] or who exclusively received chemoradiation [17,19,31,34]. The tendency towards a lower survival rate in anal canal cancer in our cohort can be explained with the higher age and higher tumor stages in this group. ...
... Additionally, Kim et al. [29] recently showed a continuous improvement of CSS over time by means of conditional disease-specific survival. OS rate in our cohort compares favorably with the literature [17,19,[30][31][32][33][34] although it is difficult to compare results because most studies and investigations examine and evaluate data of patients who either suffer from anal canal cancer only (exclusion of anal margin cancer) [19,30,31] or who exclusively received chemoradiation [17,19,31,34]. The tendency towards a lower survival rate in anal canal cancer in our cohort can be explained with the higher age and higher tumor stages in this group. ...
... Five-year OS following chemoradiotherapy in curative intend was 73.6% in our patient cohort. This is in line with the results of other studies which range from 62.1 to 89% [15,17,19,30,[33][34][35]. Hardt et al. [35] presented a 5-year OS after chemoradiotherapy of 79%; however, this study is limited because of a short follow-up. ...
Purpose
Therapy of anal cancer follows national and international guidelines that are mainly derived from randomized trials. This study aimed to analyze long-term results of stage-dependent treatment of anal cancer in a non-selected patient cohort.
Patients and method
All consecutive patients treated for anal cancer between 2000 and 2015 were retrieved from a prospective database. Risk-dependent screening for human immunodeficiency virus showed no infection. Main outcome measure was overall survival with respect to tumor site and treatment. Secondary endpoints were cause-specific survival, stoma free survival, and the rate of salvage operations.
Results
In total, 106 patients were treated for anal cancer. Of those, 69 (65.1%) suffered from anal canal cancer and 37 (34.9%) from anal margin cancer. Three patients with synchronous distant metastases were excluded from analysis. The majority of patients (n = 79, 76.7%) were treated by chemoradiotherapy in curative intention. Twenty-two patients underwent local surgery. Five-year overall survival was 73.1% and cause-specific survival at 5 years was 87.4%. Overall, 14 patients (13.6%) needed salvage surgery. Their 5-year cause-specific survival was 57.7%. A permanent ostomy was avoided in 77.7%.
Conclusions
Treatment of anal cancer results in low rates of salvage surgery and permanent ostomies, when therapy was determined by a multidisciplinary team following national and international guidelines.
... Given that the majority of patients in our cohort are year OS and DFS of 51% and 47% respectively. The OS of our cohort sits midway within the range quoted in the literature of 23-78%.112,118,124,125,[234][235][236][237] ...
Anal SCC is a rare disease that has increased significantly in both incidence and mortality over the last fourty years. Definitive chemoradiotherapy is the primary modality of treatment, offering a 5-year overall survival rate of 65%. For patients with locally persistent or recurrent disease, salvage surgery is an option with a 5-year overall survival of 50%. However, for those patients with un-resectable locoregional or metastatic disease, there are limited treatment options, and patients face a dismal outcome. Progress in identifying new treatment options for patients with anal cancer has been hampered by a deficiency in understanding the underpinnings of the disease and a lack of appropriate preclinical models.
This thesis has focussed on addressing both of these deficiencies in addition to assessing the success of salvage surgery at a quaternary centre in Australia. Firstly, an attempt has been made to further our understanding of the biology of Anal SCC. This was undertaken by exploring the immune and genomic landscape of ASCC, to identify potential prognostic and therapeutic biomarkers. This has provided insight into the prognostic power of assessing the CD8+ immune infiltrate in Anal SCC. It has also identified PI3K aberrations as a frequent genomic event that may serve as a future therapeutic target.
Secondly, it has led to the establishment of both human and mouse preclinical models of this disease. This includes the world’s first panel of human anal SCC cells lines and a syngeneic mouse model. Both of these pre-clinical models have been validated and characterised, with features closely resembling the human disease. These models can now act as a platform to further explore and facilitate investigation into potential new therapeutic options in this disease.
... The 5-year survival rate after APR has been reported to be 60%-64%. 141,142 After treatment of inguinal node recurrence, patients should have a DRE and inguinal node palpation every 3-6 months for 5 years. In addition, anoscopy every 6-12 months and annual chest, abdominal, and pelvic CT with contrast imaging are recommended for 3 years. ...
The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care.
... In the past 20 years, six Phase III randomized controlled trials (RCTs) [4][5][6][7][8][9] determined the effectiveness of chemoradiotherapy as primary treatment in patients with ASCC, and it is now the primary treatment for 75-80% of patients [10]. Locoregional failure occurs in 18-25% of patients and requires radical salvage surgery involving multidisciplinary approaches [11,12]. Overall, treatment-related morbidity is thought to be considerable, but generally is poorly quantified. ...
Aim
Six phase III randomised trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core set of outcomes (COS). As the first stage of COS development, we undertook a systematic review to summarise the outcomes reported in studies evaluating chemoradiotherapy for ASCC.
Method
Systematic literature searches identified studies evaluating radiotherapy or chemoradiotherapy for ASCC. Outcomes and accompanying definitions were extracted verbatim and categorised into domains.
Results
From 5170 abstracts, we identified 95 eligible studies, reporting 1192 outcomes and 533 unique terms. We collapsed these terms into 86 standardised outcomes and five domains: survival; disease activity; life impact (including quality‐of‐life, QoL); delivery of care; and toxicity. The most commonly reported domains were survival and disease activity, reported in 74 (86%) and 54 (62%) studies, respectively. No outcome was reported in every publication. Over half (43/86) of the standardised outcome terms were reported in less than 5 studies, and 21 (25%) were reported in a single study only. There was wide variation in definitions of disease‐free, colostomy‐free, and progression‐free survival (PFS). Anal continence was reported in only 35 (41%) studies.
Conclusion
Outcomes reported in studies evaluating chemoradiotherapy for ASCC were heterogenous and definitions varied widely. Outcomes likely to be important to patients such as ano‐rectal function, toxicity and QoL have been neglected. A COS for future trials will address these issues.
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... Following radical CRT, regression is recognised to be slow, and may take up to 6 months. presented with recurrence at a median of 10 (10-36) months [125]. ...
In this review, a summary of our current understanding of squamous cell carcinoma of the anus (SCCA) and the advances in our knowledge of SCCA regarding screening, prevention, the role of the immune system, current treatment and the potential for novel targets are discussed. The present standard of care in terms of treatment is 5-fluorouracil (5-FU) and mitomycin C (MMC) concurrently with radiation, which results in a high level of disease control for small early cancers. Preservation of the anal sphincter is achieved in the majority, although anorectal function is often impaired. Although evidence from prospective studies to support a change in the treatment strategy is lacking, patients with HPV-negative SCCA appear to be less responsive to chemoradiation (CRT) and relapse more frequently. In contrast, HPV-positive tumours usually fare better, but oncological outcomes are modified by smoking and immune incompetence. There is current interest in escalating the radiotherapy dose for larger, more advanced tumours, and de-escalating treatment for HPV-positive tumours. The use of novel immunological treatments to target the underlying different molecular pathways of HPV-positive cancers is exciting.
