Case BackgroundIn accordance with our institutional review board (IRB) approved protocol to retrospectively review patients treated with radiation for rectal cancer, we present the case of a 69-year-old man with no significant medical history who was diagnosed with a palpable 3 cm rectal moderately differentiated adenocarcinoma, microsatellite stable, magnetic resonance imaging (MRI) staged T2N0, 3 cm from the anal verge (Figure 1). Prior to diagnosis, he had only noticed intermittent low volume bright red blood per rectum which was not associated with any changes in the caliber of his stool, pain, nor diarrhea. A former smoker (2-year pack history > 10 years prior to diagnosis), he was otherwise healthy except for hypertension and a remote history of a quadruple bypass; he had an excellent Karnofsky Peformance Status (KPS) of 90%. The patient was offered radical oncologic resection for which sphincter-preservation was not feasible, necessitating an abdominoperineal resection (APR). To avoid a permanent colostomy, the patient elected to pursue a definitive chemoradiation (CRT) strategy with subsequent transanal local excision (LE) or non-operative management (NOM) depending on tumor response.

Figure 1Endoscopic visualization of tumor at diagnosis prior to any treatment. Arrow indicates the dentate line.

The patient was simulated in the prone position on a belly board and planned for 45 Gy at 1.8 Gy per fraction to the pelvis followed by at least a 5.4 Gy boost at 1.8 Gy per fraction with helical 3D conformal radiation therapy (Figure 2A, 2B). Diagnostic MRI images were fused to the treatment planning CT to facilitate delineation of the gross tumor volume (Figure 2C). As per Radiation Therapy Oncology Group (RTOG) consensus contouring guidelines, the clinical target volume was delineated to include the internal iliac nodes, presacral nodes, and mesorectal nodes. (23) The anal canal was included in the RT field since the tumor was within 6cm of the anal verge. (14) Although this was a low lying tumor, elective irradiation of the inguinal nodes was not indicated.1Elective groin irradiation is not indicated for patients with adenocarcinoma of the rectum extending to the anal canal. An interval MRI was planned at 30.6 Gy to assess tumor response and tailor the final radiation boost/volume planning. As a radiation sensitizer, the patient received 5-flurouracil (5-FU) in the oral capecitabine formulation.At a dose of 10.8 Gy, he experienced Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 diarrhea and fecal urgency, which increased in severity to Grade 3 diarrhea along with mild perianal erythema at 19.8 Gy. 2Definition and delineation of the clinical target volume for rectal cancer. After 16 fractions (28.8 Gy), the patient developed urinary hesitancy, severe tenesmus and complained of intermittent lower abdominal spasms. Medications including tamsulosin for the urinary symptoms and dicyclomine for the spasms were administered with a 3-day treatment break from CRT. At 30.6 Gy, an interval rectal protocoled MRI with diffusion weighted imaging showed no viable tumor, however, severe proctocolitis and perirectal edema were present (Figure 3). Despite another treatment break, his symptoms worsened requiring hospital admission. Chemoradiation was discontinued given the intolerance to therapy as well an absence of radiographically measurable viable tumor. With supportive care, the patient's symptoms resolved over the subsequent weeks. Approximately 6 weeks following discontinuation of CRT, flexible sigmoidoscopy demonstrated a flat, white scar with no apparent residual disease, endoscopically consistent with a clinical complete response (Figure 4).

Figure 3MRI after chemoradiation demonstrates no residual mass (mrT0N0) with proctocolitis and perirectal edema.

Figure 4Endoscopic view approximately 6 weeks after discontinuation of chemoradiation secondary to severe acute toxicity. The arrow points to a flat, white scar with telangiectasia consistent with an endoscopic clinical complete response.

Since the patient was strongly averse to an APR and demonstrated radiographic and endoscopic findings consistent with a complete clinical response (cCR), he was observed under a high intensity surveillance protocol, despite incomplete CRT3Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management.. However, interval endoscopic examination approximately 6 months from last fraction of radiation demonstrated a nodule, consistent with a local regrowth (Figure 5). Re-staging showed no distant disease, and immediate resection was advised. The patient inquired whether pursuing additional radiation was an option, rather than pursuing an APR. The patient was referred for genetic counseling and a broad genetic testing panel was ordered which included a total of 72 genes associated with hereditary colorectal cancer as well as sensitivity to ionizing radiation (Table 1), including the Fanconi anemia complementation group.4The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists.. The results revealed a heterozygous germline pathogenic variant FANCD2 c.707_708del (p.Ile236Argfs*19). Given his increased sensitivity to radiotherapy, definitive surgery was recommended for curative intent treatment. APR was thus performed with final pathology ypT2N0, AJCC Tumor Regression Grade 1 (near complete response). Since his surgery, the patient has been doing well. No further therapy was required given his pathological findings and he entered into surveillance. At his last colonoscopy through his stoma, 26 months from diagnosis, he was found to have no evidence of disease with a serum carcinoembryonic antigen (CEA) of 1.9 ng/dl.

Figure 5Retroflexed endoscopic view showing a mucosal irregularity with superficial ulceration, which is delineated by the arrow. Blue tattoo is noted just distal.

DiscussionIncreased risk of radiation toxicity may be associated with co-morbidities such as diabetes, hypertension, and collagen/vascular disorders5Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.. However, a small proportion of patients possess genetic abnormalities resulting in heightened radiosensitivity and are treatment-limiting. (Table 1). Early toxicity can be associated with genetic alterations in DNA damage response genes, with genetic causes estimated to account for up to 80% of observed cases of severe acute toxicity5Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.. The majority of patients are unaware of a pre-existing genetic mutation, and for those experiencing severe and acute toxicity, genetic testing can be performed to identify potential causes of radiosensitivity. Referral to specialized genetic services such as genetic counselors can help identify appropriate genetic testing options, interpret test results, and educate patients regarding the impact results may hold for their families. Genetic results may assist in guiding additional treatment considerations, provide insight regarding additional primary cancer risk, and provide information regarding increased cancer risk for family members.For this case, genetic testing revealed a FANCD2 variant. Fanconi anemia (FA) is an autosomal recessive disease known to affect about 1 in 136,000 individuals 6Multifaceted Fanconi Anemia Signaling.. The FA pathway comprises of at least 17 known Fanconi anemia genes (Table 1),6Multifaceted Fanconi Anemia Signaling., with FANCA pathogenic variants being the most common cause of FA (66%)7Clinical radiation sensitivity with DNA repair disorders: an overview.. Fanconi anemia genes are involved in DNA repair and are implicated in carcinogenesis as well as toxicity to anti-neoplastic therapies (radiation toxicity and chemotherapy). This patient carried a pathogenic heterozygous FANCD2 variant that resulted in loss of protein function. FANCD2 has a prominent role in the FA pathway. In response to DNA damage, FANCD2 undergoes monoubiquitination and localizes to the damage sites serving as a molecular platform for recruitment of other DNA repair proteins, as shown in Figure 68Niraj J. Färkkilä A. D'Andrea A.D. The Fanconi Anemia Pathway in Cancer.. Loss of FANCD2 can impair the ability to repair single or double-stranded DNA breaks7Clinical radiation sensitivity with DNA repair disorders: an overview. following radiation exposure9Gastrointestinal radiation injury: symptoms, risk factors and mechanisms. but the influence of heterozygous FANCD2 loss on severe, early onset radiation toxicity has not yet been fully elucidated. A prior case report described acute hypersensitivity to chemoradiation in a patient heterozygous for a FANCA mutation, proposing that FA heterozygotes may have an increased risk for chemoradiation toxicities10Hypersensitivity to chemoradiation in FANCA carrier with cervical carcinoma-A case report and review of the literature..

Figure 6A simplified cartoon of the FA pathway and role of FANCD2. Radiation induced damage can cause DNA conformational changes that activate the FA pathway. The FANCI and FANCD2 complex undergoes monoubiquitination, localizes to DNA damage sites, and recruits other DNA repair proteins.

Figure 2ADose-Volume Histogram for the treatment plan for this patient.

Figure 2BDose-Volume Histogram statistics for the patient's treatment plan.

Figure 2CAxial, Coronal, and Sagittal views of radiation treatment plan for this patient.

Additionally, the patient was treated with 5-fluorouracil (5-FU) which sensitizes to radiation therapy11Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer.. Fluoropyrimidines have effectively been used in gastrointestinal malignancies as radiosensitizing agents with a number of proposed mechanisms of action to include downregulation of NAD+-dependent deacetylase sirtuin-712Lawrence T.S. Blackstock A.W. McGinn C. The mechanism of action of radiosensitization of conventional chemotherapeutic agents.. Given that the patient's FA mutation is known to induce sensitivity to radiation in the homozygous setting, this heterozygous FANCD2 mutation may have contributed to the patient's treatment-limiting toxicity. Further research into FA mutation-carriers may determine whether they are at increased risk for severe radiation toxicity which could also be exacerbated by the concurrent administration of 5-FU. Consistent with our patient's presentation, patients possessing a heterozygous FA genetic mutation (that is, carriers of FA) do not possess the characteristic phenotypic manifestations associated with the syndrome (e.g. small or absent distal radius or thumb, short stature, endocrine anomalies, and diabetes with hyperinsulinemia). If early radiation toxicity is identified, additional treatment should be withheld and alternative approaches considered, as was done in this case7Clinical radiation sensitivity with DNA repair disorders: an overview..

In retrospect, given the pathological findings, the patient had likely experienced a complete response of gross disease at 30.6 Gy but still had residual microscopic disease remaining. It may have been possible to pursue a boost dose of RT to the site of small volume initial disease to a microscopic disease dose of 45-50.4 Gy once the patient's acute symptoms had resolved. This would have decreased the volume irradiated, significantly limiting the extent of rectal/small bowel mucosa exposed to further dose and potential complications. It is not clear, however, whether the patient could have tolerated such focused RT and whether increasing the dose would have resulted in a durable cCR.

This case raises the question of how best to optimize the radiation dose for the individual patient and remains an active area of investigation. In the TIMING trial for locally advanced rectal cancer with higher doses of RT to the 54 Gy range, the pathologic complete response (pCR) rate was highest (38%) when the CRT was delivered followed by 6 cycles of FOLFOX chemotherapy13Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.. This is far higher than the 8% pCR rate reported in the landmark German Rectal Cancer trial, for which 50.4 Gy CRT alone was delivered14Preoperative versus postoperative chemoradiotherapy for rectal cancer.. The substantial increase in tumor regression, as reflected by higher pCR rates, suggests neoadjuvant systemic chemotherapy administered sequentially to CRT expands the proportion of patients that may be considered for a rectal organ preservation approach. In patients with early stage rectal cancer, neoadjuvant CRT results in significant tumor response, with low reported local recurrence rates following either transanal excision or NOM.15Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial. In the Phase 2 ACOSOG Z6041, 49% of clinical T2N0 patients treated with neoadjuvant CRT had a ypT0 or ypTis tumor determined by local excision, with 4% (3 of 79 patients) of the study population experiencing local recurrence at 3 years, resulting in 91% of the patients preserving the rectum at the end of follow-up.16Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial. Both the CARTS and GRECCAR-2 studies similarly reported good long-term local recurrence oncologic outcomes for early stage rectal cancers treated with neoadjuvant CRT and organ preserving transanal local excision15Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.,17Long-term Oncological and Functional Outcomes of Chemoradiotherapy Followed by Organ-Sparing Transanal Endoscopic Microsurgery for Distal Rectal Cancer: The CARTS Study.. With MRI guided radiation therapy, it may become possible in the future to assess tumor response with more sophisticated tools during therapy, such as radiomic measurements, such that the boost dose can be better optimized to enhance response18Magnetic Resonance Guided Radiotherapy for Rectal Cancer: Expanding Opportunities for Non-Operative Management..As we approach wider adoption of total neoadjuvant therapy (TNT) with improved response rates, more patients may achieve cCR and be interested in a NOM approach. Such a strategy necessitates careful consideration of the volume irradiated to the highest doses since long term function, particularly of the anorectum, is important for continence19The dose-response of the anal sphincter region–an analysis of data from the MRC RT01 trial.. This is significant since the majority of patients choosing such an approach may do so to avoid APR; by consensus contouring guidelines, inclusion of the anal canal (AC) would be indicated since the primary tumor would lie within 5-6 cm of the anal verge20Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas.. This would mean that the full circumference of the AC would receive 45 Gy so that the boost dose should be precisely targeted to minimize the volume of the anal sphincters receiving the highest doses to maximize an organ preservation approach.Biomarkers to measure tumor radiation sensitivity have been reported21Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform., 22A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation., 23Prediction of radiation sensitivity using a gene expression classifier. and are becoming closer to clinical practice integration so they may soon have a role as well in personalization of radiation therapy. One such test, the Radiation Sensitivity Index (RSI), measures the expression profiles of multiple somatic genes from the tumor DNA such that the genomically adjusted radiation dose (GARD) can be predicted24A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study.. Future tools such as this may have a role in prospectively identifying those patients with the highest likelihood of achieving a cCR so that optimizing cure without increasing long term morbidity may be possible.Article InfoPublication HistoryPublication stageIn Press Journal Pre-ProofFootnotes

Conflict of Interest:

J. Kevin Hicks: Research funding from OneOme; consultant for Quest Diagnostics.

No other authors have any disclosures pursuant to this manuscript.

Funding: None

Data Availability Statement: Research data are not pertinent to this study.

Acknowledgements: There are no acknowledgements.

Identification

DOI: https://doi.org/10.1016/j.adro.2021.100717

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© 2021 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

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