International Anal Neoplasia Society Scientific Meeting Amsterdam 2019

International Anal Neoplasia Society Scientific Meeting Amsterdam 2019 

Danni and Sarah from the mASCARA team are attending the IANS Scientific Meeting  in Amsterdam in November. The programme looks excellent, in particular we are looking forward to the updates on the SPANC and ANCHOR trials. 

We are also looking forward to making further mASCARA collaborations. If you are attending and would like to discuss mASCARA with us we will be delighted to meet you! Tweet us! @mascararegistry  

mASCARA team in Vienna!

Members of the mASCARA team are attending the European Society of Coloproctology Conference later this month in Vienna where we will be presenting our work on Anal Intraepithelial Neoplasia topical and ablative treatments.  

We are looking to make further collaborations for mASCARA, so if you have a passion for research into Anal SCC or AIN we would love to meet you! @mascararegistry 

Increases in Anal SCC incidence in England

The mASCARA team is very interested to learn from Public Health England that the incidence of Anal SCC in England has increased by 23% from 2013-2017 with female incidence increasing more rapidly than male incidence (29% compared to 14%).  This increasing trend has been identified all over the world. We hope that mASCARA will be able to help identify whether this is due to a change in patient demographics (such as more patients having immunosuppressive co-morbidities such as HIV) or if this is related to other factors.  

We’d love to hear your opinions! Tweet us! @mascararegistry 

mASCARA recruitment has begun

We are excited to announce that clinical center site recruitment has begin for mASCARA. We would love to collaborate with other research centers with an interest in being included in the first multinational Anal Squamous Cell Carcinoma data collaboration.

If you are interested in taking part – please tweet us @mascararegistry or contact us though the website contact from. We are looking forward to working with you.

Salvage surgery

After treatment with Chemoradiotherapy, recurring or persistent disease is treated with salvage surgery. This is usually Radical Abdominoperineal Resection but can also be Total pelvic Exenteration depending on presentation. Recurring disease occurs in up to 15% of patients diagnosed with Anal SCC. Salvage surgery is associated with a  high morbidity and mortality. Many patients with relapsing disease are unfortunately not suitable for high risk surgery.  

If suitable for salvage surgery it has been reported that 40-60% survive 5 years compared to a 5% 3 year survival rate if salvage surgery is not attempted.  

An abdominoperineal resection for recurrent and persistent disease is associated with  low post-operative mortality risk (3%) however, there is a risk of up to 70% of delayed wound healing, perineal hernias (15%) and up to 20% risk of significant cardiovascular or respiratory complications. 

The single most important factor in disease control and survival is achieving a complete (R0) resection. Unfortunately this is only being achieved in 9-16% of available case series in the literature.  

Most of the data reporting success rates of salvage surgery for persistent or recurrent disease is from small single centre case series that are limited by historical data, small sample sizes and patients being largely female and HIV negative. 

Ko et al (2019) has written a great systematic review this year which extensively summarised the findings of 28 retrospective salvage surgery case series. On meta-analysis they demonstrated that there was no significant difference in overall survival between patients receiving salvage surgery for persistent compared to recurrent disease. The median 5 years disease free survival was 44% and 23.5% of patients had a locoregional recurrence after salvage surgery. 14 studies reported HIV status and one study included only HIV positive patients. The authors reported that the included studies did not analyse HIV positive and HIV negative survival outcomes separately. Of 14 studies reporting HIV status, 12 reported less than 20% HIV prevalence in their patients undergoing salvage surgery.  

It is unclear whether the low numbers of HIV positive patients undergoing salvage surgery in the literature are appropriate for the population studied or whether HIV patients are less likely to undergo salvage surgery as either they are not fit for salvage surgery or that they are less likely to have recurrent/persistent disease in the first place.  

We hope that mASCARA, by including HIV outcomes and recurrence outcomes may add further information into this topic.  

Superficially Invasive Squamous Cell Carcinomas (SISCCA’s) and the upcoming PLATO trial

Superficially Invasive Squamous Cell Carcinoma (SISCCA) is a term that is being increasing used in the literature, and it is defined by the LAST guidelines as  a completely excised Anal SCC (R0) that has an invasive depth less than 3mm from the basement membrane and has a maximum horizontal spread of less than 7mm.  

It is quite interesting that since the LAST guidelines in 2012, more study has gone into whether or not it is possible to spare chemoradiotherapy in this subgroup of patients with small T1 tumours that have already undergone a complete resection.  

Anecdotally, particularly in high HIV positive practices, many Anal SCC’s are identified incidentally after benign colorectal surgery in high risk patients.  There have been documented incidences in conference abstracts where no further treatment was given  after wide local excision only of SISCCA’s with good outcomes.   

Within the Colorectal community, organ sparing approaches such as minimally invasive excisions of rectal lesions are increasing in popularity. As they have larger patient numbers, evidence already exists that T1 rectal tumours can be excised and followed up sparing further operative treatment. The impact on patient quality of life after organ sparing treatment is significant.  

A very interesting paper by Chai et al (2018), is certainly worth a read, it reports the outcomes of treating 2243 T1 Anal SCC’s recorded on the American National Cancer Database.  Its demonstrates that there is no difference in survival outcomes between patients treated with chemoradiotherapy or wide local excision alone. However the use of the American Cancer Database is criticised by several authors in letters to the editor as it is not able to include data on position of tumour, chemoradiotherapy regimes used and recurrence rates. HIV status is also not included. 

In the meantime, The Association of Coloproctology of Great Britain and Ireland Guidelines in 2017, recommended that  SISCCA’s could receive wide local excision alone if technically possible. However, in the absence of peer reviewed research including recurrence and patient outcomes it looked to the ongoing PLATO Trial for further clarification.  

The Personalising Anal Cancer Radiotherapy Dose Trial (PLATO) opened for recruitment in 2017 and is set to release its results in 2028. It is including a study arm comparing the outcomes of T1N0M0 tumours receiving either wide local excision alone or IMRT and Chemotherapy.  

While we wait for the results of the PLATO trial, there remains a real need for further data on Anal SCC’s that includes data outcomes such as HIV status, recurrence data, AIN treatment and previous Genitourinary Dysplastic disease. By including these data outcomes in mASCARA we hope that it will be able to answer the research question that National Cancer Databases are unable to do.  

SPANC Trial

Study of the Prevention of Anal Cancer (SPANC) trial began enrolment in 2010 and its results are due to be reported soon.  

It is a clinical study following up homosexual men with and without HIV  after High Resolution Anoscopy (HRA)Screening  for three years. Currently there is insufficient evidence to recommend the wide spread use of HRA as a screening method for AIN. We look forward to the results of this study to see if they can add further evidence into the efficacy of HRA. 

ANCHOR Study

In 2014, the Anal Cancer HSIL Outcomes Research Study, a multicentre stage III Randomised Controlled Trial was launched in the USA.  

It is randomising HIV positive patients over 35 years of age with a new diagnosis of High Grade AIN to receive either topical treatments, ablative treatments or active monitoring.  

They are still recruiting and plan to publish their results in 2022.  

At the moment, there is very little evidence about the best treatment for AIN and whether or not treating AIN prevents the development of Anal SCC. We are looking forward to the results of this trial as we hope it will answer many  questions.  

Staging of Anal Squamous Cell Carcinoma

Up until fairly recently, we used to stage anal margin cancers (cancers up to 5cm away from the anal margin) differently to anal canal tumours, The rationale for this was that anal margin cancer were associated with a better prognosis, perhaps because they were more readily excised without risking sphincter function and also perhaps as patients more likely to notice the lesion sooner.  

This has changed in the most recent edition of the American Joint Committee TMN Staging where the two staging classifications have been merged together for better clarity.  The most recent classification is given below.  

Although this is based on the previous staging classification, the 5 year survival associated with each clinical stage is as follows: Stage 1 86%, Stage 2: 77%, Stage 3: 66%, Stage 4: 37%.  

The literature suggests that approximately half of patients present with Stage 1 or Stage 2 disease.  

American Joint Committee on Cancer recommended TMN staging 8th Edition of Anal Squamous Cell Carcinomas of Anal margin and Anal Canal.  

TMN Anal Squamous Cell Carcinomas: Combined Anal Canal and Anal Margin (within 5cm)
T1 Tumour less than 2 cm N0 No regional lymph nodes M0 No distant metastases
T2 Tumour less than 5 cm but greater than 2cm N1a Metastases in inguinal, mesorectal and/or internal iliac lymph nodes M1 Distant Metastases
T3 Tumour greater than 5 cm N1b Metastases in external iliac lymph nodes
T4 Tumour of any size that invades adjacent organs N1c Metastases in external iliac and in inguinal, mesorectal and/or internal iliac lymph nodes

Classification of TMN staging 8th Edition for Anal Squamous Cell Carcinomas. 

Classificationof staging
Stage I T1 N0 M0
Stage IIA T2 N0 M0
Stage IIB T3 N0 M0
Stage IIIA T1/T2 N1 M0
Stage IIIB T4 N0 M0
Stage IIIC T3/T4 N1 M0
Stage IV Any T Any N M1

Guidelines for Anal SCC and Anal Intraepithelial Neoplasia

Although there are extensive guidelines on Anal SCC, the most recent being: American Society of Colon and Rectal SurgeonsAssociation of Coloproctology in Great Britain and Ireland and the joint guidelines of the European Society of Medical and Surgical Oncology, there is little consensus on the best practice in the treatment of AIN. Recommendations for the treatment and surveillance of AIN  are often based on poor clinical evidence with much discrepancy.  

The guidelines have also significantly changed since they were compared and contrasted in this great paper by Alam et al (2016). In the UK, The ACPGBI guidelines in 2011 were encouraging of High Resolution Anoscopy (HRA) in high volumes centres and gave a preference for 5% imiquimod as a treatment for AIN3 and 1% Cidofovir in female patients with Genitourinary Intraepithelial Neoplasia. They also recommended Photodynamic therapy and Ablative therapies such as electrocautery and Laser treatment as possible treatment modalities. Anal mapping was also advocated after a diagnosis of AIN. 

This is quite different to the ACPGBI guidelines in 2017  which downgraded the importance of anal mapping due to futility and patient experience, were less enthusiastic about the benefits of HRA and, with the exception of HIV positive MSM where they suggested electrocautery may be the optimal treatment, they did not recommend a particular AIN treatment modality. They also had a new recommendation that all high grade AIN patients should be discussed at a specialist Anal SCC MDT.  

The 2008 ASCRS guidelines recommended the treatment of AIN in all stages by either 5% Imiquimod, 5% Fluorouracil, targeted surgical destruction or Photodynamic therapy. There were no recommendations on High Resolution Anoscopy. The current ASCRS 2018 guidelines restricts ablative treatments to High Grade AIN only and recommends HRA in high risk populations when experienced practitioners are available. Unlike in the UK, ASCRS 2018 guidelines recommend the use of cytology for the diagnosis of AIN but recommends adding in HPV serology and p16 status.  

Overall,  there are 7 guidelines available for review in the literature, from 5 different countries between 2011 – 2018. Most recommend that screening could be beneficial to high risk populations, however there is insufficient evidence to suggest screening prevents malignancy.  Guidelines from European countries recommend surgical excision (where possible) as the first line treatment, this conflicts with USA guidelines which prefer ablative or topical treatments. Except for one UK guideline that recommends the use of Imiquimod in lesions too large for surgical resection, no guideline expressed a strong preference for a specific AIN treatment.