Long-term Patterns of Failure and the Value of Blood Prognostic Markers in Anal Cancers Treated With Intensity-Modulated Radiation Therapy
Introduction
Anal cancers are rare and account for less than 1% of all cancers, but their incidence has been steadily rising in developed countries by almost 3% every year.1,2 Squamous cell carcinomas (SCC) are the predominant histological subtype of anal cancers and the majority of these are associated with the human papilloma virus (HPV).2 While radiation therapy (RT) with concurrent mitomycin-C (MMC) and 5-fluorouracil (5-FU)-based chemotherapy have remained the organ-sparing paradigm for these cancers since the 1980’s, RT delivery techniques have significantly evolved. Prior to circa 2010, RT was routinely delivered using a 3D-conformal technique (3DCRT), which employed large pelvic fields and often resulted in significant toxicity requiring treatment breaks. Modern intensity-modulated RT (IMRT) techniques using either static beams (static IMRT) or dynamic arcs (volumetric arc therapy, VMAT) are able to more tightly conform the high radiation dose regions around target volumes and thus spare neighboring organs at risk (OARs). Following a series of promising early results demonstrating increased treatment tolerability with IMRT, especially with reduced dermatological, gastrointestinal, and hematological toxicity,3, 4, 5, 6 static IMRT and VMAT have almost universally supplanted 3DCRT in the treatment of anal cancers.
However, geographic miss due to inadequate target volume coverage is a potential risk with these highly conformal techniques. This is particularly important because locoregional failure, rather than isolated relapse at distant sites, is the most common pattern of failure in patients with nonmetastatic anal cancers.7 To reduce inter-clinician variability in volume delineation as was observed during the early periods of IMRT adoption in anal cancers,6 several consensus guidelines have been developed with minor variations between them.8, 9, 10 Presently, there is a paucity of data on the long-term patterns of failure and the geographic relationship of locoregional recurrences with initial target volumes to confidently assess coverage of clinical and subclinical disease. Data on long-term outcomes of IMRT-treated anal cancers are also still evolving.3, 4, 5, 6,11, 12, 13
Furthermore, while anal cancers are generally considered radiosensitive, treatment resistance in a subgroup of patients is a well-recognized issue and there remains no reliable biomarkers of response.14 Cancer growth and suppression are now understood to be heavily influenced by a complex interplay between cancer cells and host factors, including the patient's immune status and response. In this context, various studies have suggested parameters taken from routine blood counts can be prognostic for outcomes in anal cancers, including pretreatment hemoglobin, total leukocyte and neutrophil counts, as well as inflammation-based indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic index of inflammation (SII) (defined as the platelet count multiplied by NLR).15, 16, 17, 18, 19, 20 However, the robustness of these parameters as independently prognostic alongside other known patient and tumor factors has not been widely verified.
As an update to our previously published experience in a large cohort of anal cancer patients treated with 3DCRT,21 we present a contemporary report describing our IMRT experience in a group of anal cancer patients homogenously treated using a standardized contouring protocol that is based on the Australian Gastrointestinal Trials Group guidelines.9 We analyzed the long-term outcomes in this patient cohort and focused on patterns of failure and the prognostic value of hematological parameters.
Section snippets
Patients
Hospital records of consecutive patients with nonmetastatic, pathologically confirmed SCC of the anus who received curative-intent IMRT at the Peter MacCallum Cancer Centre between 1 January 2010 and 1 February 2020 were retrospectively reviewed. All patients underwent a physical examination including a digital rectal examination, blood investigations, tumor biopsy, staging chest, abdominal and pelvic computed tomography (CT), whole body 18-fluorodeoxyglucose (FDG) positron emission tomography
Patient and Tumor Characteristics
Of the 173 patients identified during the study timeframe to have received curative-intent IMRT for SCC of the anus, 166 patients met eligibility criteria for inclusion in the study. Patients with no follow up data (4 patients) or who were treated according to the perianal skin SCC paradigm (3 patients) (employing different RT dose and volumes, and different chemotherapy regimens) were excluded. Patient, tumor and treatment characteristics are summarized in Table 1. Patients were predominantly
Discussion
Our study strengthens the emerging evidence surrounding the long-term efficacy and safety of IMRT for anal cancers, including the recently published long-term results of RTOG 0529.11,13,22,23 Importantly, our study also incorporates an analysis of the patterns of failure and hematological biomarkers on a large patient cohort that had uniform baseline staging with PET-CTs. Comparison with our previously published experience on 3DCRT-treated anal cancers allows direct evaluation of the effect of
Conclusion
We present herein long-term follow up data of a large cohort of anal cancer patients treated with IMRT, which affirms the effectiveness of IMRT in reducing toxicity and improving treatment tolerability without compromising tumor control. No evidence for geographic miss of sites-at-risk was identified within the pelvis and inguinal regions, in particular with the selective omission of external iliac and inguinal nodal irradiation in patients with early T1N0 anal cancers. This suggests that
Disclosure
The authors have stated that they have no conflicts of interest.
References (32)
- et al.
Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: toxicity and clinical outcome
Int J Radiat Oncol Biol Phys
(2005) - et al.
Intensity-modulated radiation therapy for anal malignancies: a preliminary toxicity and disease outcomes analysis
Int J Radiat Oncol Biol Phys
(2010) - et al.
RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal
Int J Radiat Oncol Biol Phys
(2013) - et al.
Squamous cell carcinoma of the anal canal: patterns and predictors of failure and implications for intensity-modulated radiation treatment planning
Int J Radiat Oncol Biol Phys
(2010) - et al.
Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas
Int J Radiat Oncol Biol Phys
(2009) - et al.
Australasian Gastrointestinal Trials Group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in anal cancer
Int J Radiat Oncol Biol Phys
(2012) - et al.
Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529
Adv Radiat Oncol
(2017) - et al.
Patterns and predictors of relapse following radical chemoradiation therapy delivered using intensity modulated radiation therapy with a simultaneous integrated boost in anal squamous cell carcinoma
Int J Radiat Oncol Biol Phys
(2020) - et al.
Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention
Lancet Oncol
(2015) - et al.
Leukocytosis and neutrophilia predicts outcome in anal cancer
Radiother Oncol
(2017)
External validation of leukocytosis and neutrophilia as a prognostic marker in anal carcinoma treated with definitive chemoradiation
Radiother Oncol
Twenty-five-year experience with radical chemoradiation for anal cancer
Int J Radiat Oncol Biol Phys
Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: clinical outcomes, patterns of relapse and predictors of failure
Radiother Oncol
NRG oncology/RTOG 0529: long-term outcomes of dose-painted intensity modulated radiation therapy, 5-Fluorouracil, and Mitomycin-C in anal canal cancer
Int J Radiat Oncol Biol Phys
Patterns of inguinal lymph node metastases in anal canal cancer and recommendations for elective clinical target volume (CTV) delineation
Radiother Oncol
Predictors of radiation therapy-related gastrointestinal toxicity from anal cancer dose-painted intensity modulated radiation therapy: secondary analysis of NRG oncology RTOG 0529
Int J Radiat Oncol Biol Phys
Cited by (3)
Long-term outcomes of definitive radiation with volumetric modulated arc therapy and concurrent chemotherapy for squamous cell carcinoma of the anus in a regional Australian cancer centre
2024, Journal of Medical Imaging and Radiation OncologyChanges in Tumor Immune Microenvironment after Radiotherapy Resistance in Colorectal Cancer: A Narrative Review
2023, Oncology Research and Treatment