Long-term Patterns of Failure and the Value of Blood Prognostic Markers in Anal Cancers Treated With Intensity-Modulated Radiation Therapy

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Abstract

Background

To analyze the long-term outcomes and prognostic value of hematological parameters in anal cancer patients receiving intensity-modulated radiation therapy (IMRT).

Materials

Hospital records of consecutive patients with anal squamous cell carcinoma who received curative-intent IMRT according to a standardized contouring protocol between 2010 and 2020 were reviewed. Locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Coverage of locoregional recurrences by the initial IMRT volumes were assessed. The prognostic value of pretreatment blood counts for PFS and OS were determined using Cox regression analysis.

Results

A total of 166 patients were analyzed with a median follow-up of 3.3 years. Forty-six percent and 54% of patients had Stage I-II and IIIA-B cancers, respectively. The 5-year LRFS, DMFS, PFS and OS were 81%, 89%, 65% and 76% respectively. Grade ≥ 3 toxicity occurred in 5% of patients. Of all patients who relapsed, 70% had only locoregional recurrence as first site of failure. Ninety percent of locoregional recurrences were in-field. Hemoglobin, neutrophil and platelet counts were associated with PFS on univariable analysis, but only cancer stage and p16 status remained prognostic on multivariable analysis. Patients with more advanced cancer stages also had higher baseline neutrophil counts. Performance status and neutrophil counts were prognostic for OS on multivariable analysis.

Conclusion

This study affirms the long-term efficacy and safety of IMRT. Treatment resistance, rather than radiation geographic miss, is a major issue underpinning locoregional recurrences. Pretreatment blood counts were not validated to be independently prognostic for disease recurrence.

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.

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