The purpose of this study is to see whether avoiding preventative radiation to the groin in patients with normal sentinel node biopsy and PET-CT, is at least as effective treating cancer as giving preventative radiation to the groin for patients with anal canal cancer.

The investigators also want to know if avoiding radiation to the groin will cause fewer side effects and better quality of life

Radiotherapy (RT) with concurrent 5-fluorouracil and mitomycin-C (5FU/MMC) combination is the treatment of choice for non-metastatic locally advanced anal squamous cell carcinoma (ASCC). While, locally advanced AC treatment involves elective inguinal lymph node irradiation along with concurrent chemotherapy with significant improvement of locoregional control and colostomy free survival, many oncologists believe that routine, elective irradiation of bilateral inguinal areas of patients with limited disease (T1-T3) without lymph node involvement may be overtreatment and the larger radiation target that includes entire pelvis and bilateral inguinal region causes significant acute and late toxicities.

SLNB is the standard procedure currently used for breast cancer staging. The most significant observation was that when the SLN is negative, no further ALND or adjuvant axillary radiation is need for those patients. The SLNB had shown a better diagnostic accuracy (31% vs.25%) and higher sensitivity (85% vs.75%) than FDG-PET imaging to detect inguinal lymph node metastasis. Given better diagnostic accuracy and high sensitivity of SLNB, this technique could be used precisely to define target population who could be spared of prophylactic inguinal irradiation.

The investigators hypothesize that patients with early clinical stage node negative anal cancer (T1-T3N0) have low risk of subclinical inguinal lymph node involvement that can be detected by a combination of PET imaging and SLNB. Hence, any early stage AC patients with node negative disease confirmed by PET imaging and SLNB have relatively low risk of nodal failure and so inguinal radiation could be avoided. This approach would limit over treatment of early stage patients, reduce acute and late toxicities. This will be tested in a phase II study with close follow up of study patients so that inguinal relapse if any occur will be salvaged successfully. If this treatment approach is successful, it could be practice changing with improvement of H-QOL of patient.

Inclusion Criteria:

1. Participants capable of giving informed consent.
2. Patients must be 18 years of age or older.
3. Patient should have histologically proven primary squamous cell carcinoma.
4. Patients must have early AC, Stage T1-3 N0 M0.
5. No inguinal nodal involvement confirmed by PET imaging and SLNB.
6. No history of prior malignancy other than non-melanoma skin cancer or other malignancy with disease free survival ≥ 5 years.
7. Performance status ECOG 0-2 / Zubrod performance status ≥70.
8. Patient should be eligible for concomitant chemotherapy (e.g. adequate hepatic, renal and bone marrow function).
9. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause.
10. Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly (Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard).
11. Females must not breastfeed during study treatment.
12. Male patients should agree to not donate sperm during study treatment.
13. Absence of any condition hampering compliance with study protocols and follow-up schedule; those conditions should be reviewed with the patient prior to trial registration.

Exclusion Criteria:

1. T1N0 patients going for primary surgery
2. Prior radiation therapy to the pelvis.
3. Pregnancy or lactation.
4. Prior surgical treatment for anal cancer other than biopsy.
5. Prior surgical or chemotherapy treatment for anal cancer.
6. Evidence of distant metastases.
7. Comorbid medical conditions precluding radical treatment at the discretion of Oncologist.
8. Histology other than squamous cell carcinoma or variants.