A 40-Year-Old Woman With Locally Advanced Rectal Cancer and a Solitary Liver Metastasis

CASE REPORT

Dr. Hajj: A 40-year-old-woman presented with changes in her bowel movements and bright red blood per rectum progressing over 4 years. Her family history was positive for a cousin with colon cancer diagnosed at age 52 and another cousin with prostate cancer.

Dr. Abou-Alfa: Dr. Ang, could you please comment on the family history?

Dr. Ang: The patient's young age and family history raise suspicion for a familial colon cancer, such as Lynch syndrome. The revised Amsterdam criteria for families with Lynch syndrome are as follows: 3 or more relatives with histologically proven hereditary nonpolyposis colorectal cancer (HNPCC; a colorectal cancer or cancer of the endometrium, small intestine, ureter, or renal pelvis); 2 or more successive generations affected; 1 or more relatives diagnosed before the age of 50 years; and 1 relative a first-degree relative of the other 2.¹ Familial adenomatous polyposis should be excluded in such cases as well.² Moreover, more relaxed criteria were defined in The Bethesda Criteria to better identify those families with germline mutations in the mismatched repair genes. Our patient did not meet the Amsterdam criteria. However, since she was younger than 50 years of age, she fulfilled the Bethesda criteria.³ At Memorial Sloan-Kettering Cancer Center (MSKCC), we prefer using the revised Bethesda criteria to screen for Lynch syndrome. Those criteria suggest that tumors be tested for microsatellite instability (MSI) in the following situations: colorectal cancer diagnosed in a patient who is less than 50 years of age; presence of synchronous colorectal, metachronous colorectal, or other Lynch-associated extracolonic cancers, regardless of age; colorectal cancer with the MSI-High (MSI-H) histology in a patient who is less than 60 years of age; colorectal cancer diagnosed in 1 or more first-degree relatives with a Lynch-related tumor, with 1 of the cancers being diagnosed under age 50 years; colorectal cancer diagnosed in 2 or more first- or second-degree relatives with Lynch-related cancers, regardless of age, plus signet ring cell-type colorectal cancer before age 45 or colorectal adenoma before age 40 years.

Dr. Shia: The Bethesda criteria are less restrictive than the Amsterdam criteria, but the specificity is low, since 75% and 80% of patients who meet the Bethesda criteria do not have Lynch syndrome.⁴ Histologically, Lynch-associated colorectal cancers tend to have features that would normally be regarded as poor risk but, in the context of Lynch syndrome, are actually associated with a favorable outcome. The features that are associated with Lynch syndrome include poor differentiation, a medullary growth pattern, tumor-infiltrating lymphocytes, a Crohn-like lymphocytic reaction, a mucinous component, and, occasionally, signet ring cell type. These tumors also tend to occur on the right side of the colon. Screening for Lynch syndrome is done through testing for mismatched repair proteins (MMR), MLH1, MSH2, PMS2, and MSH6⁵ or by PCR testing for MSI. Patients whose tumors show MMR deficiency (dMMR) are offered genetic testing to determine whether it is due to a germline mutation (ie, Lynch syndrome) or somatic mutation (ie, sporadic dMMR). If Lynch syndrome is present, it has implications for the patient and their relatives with respect to screening and surveillance for colonic and extracolonic malignancies. The presence of dMMR/MSI-H also influences therapeutic decision making in the setting of resected stage II colon cancer, as these patients do not appear to benefit from fluoropyrimidines⁶

Dr. Hajj: A colonoscopy revealed a mass just above the anorectal ring near the dentate line occupying 50% of the circumference, and the biopsy was positive for moderately differentiated adenocarcinoma, without mucinous component, signet ring cells, or lymphocytes. On endoscopic ultrasound, the rectal mass was staged as an uT3N1 tumor. A computed tomographic (CT) scan of the chest, abdomen, and pelvis, as well as positron emission tomography (PET) scan and liver magnetic resonance imaging (MRI) were performed.

Dr. Merhi: The liver MRI demonstrated a solitary liver lesion at the junction of segments 4A and 8, with imaging features suspicious for metastasis. The CT and PET scans demonstrated a suspicious rectal lesion, in addition to a solitary liver lesion suspicious for metastasis.

Dr. Abou-Alfa: Dr. Saltz, what is the best imaging modality for rectal cancer staging?

Dr. Saltz: This remains an area of controversy and a hot subject for debate. Either an MRI or endorectal ultrasound (ERUS) is recommended for optimal locoregional staging of rectal cancer. ERUS is accurate for assessing tumor depth and the regional lymph nodes, but is operator dependent. Pelvic MRI is more reproducible and can provide more detailed views to help determine whether tumor extension into the mesorectum, adjacent organ structures, and/or regional lymph nodes is present, but it should be used to complement and not replace a CT scan. The choice of which modality to use depends on local availability and expertise. Our patient had a solitary liver lesion, which is potentially curable. This is a classic case for a multidisciplinary conference, as there is no right or wrong answer. My approach would be to start with initial chemotherapy to assess its activity on the primary and the metastatic sites.

Dr. Shamseddine: I agree with Dr. Saltz. At AUB (American University of Beirut), we regularly discuss such cases in our tumor board meetings. Our practice is to start with FOLFOX chemotherapy. After assessing the chemosensitivity of the tumor, we decide on whether to proceed with chemoradiation and surgery.

Dr. Sidani: I concur with Dr. Shamseddine. In the event of a good response to chemotherapy, we would refer the patient to chemoradiation before taking him to surgery and then attempt rectal tumor resection and liver metastasectomy.

Dr. Geara: I add that, in case of a good response to chemotherapy, I would recommend pelvic radiation treatment to improve the patient's quality of life.

Dr. Goodman: This patient had a very low tumor at the anorectal ring. Even if she had a very good response to induction chemotherapy, sphincter-preserving surgery would not be possible without prior chemoradiation. However, the downside of preoperative chemoradiation in a 40-year-old woman would be premature menopause. We are currently addressing this side effect in our young patients by performing a robotically assisted ovarian transposition outside of the radiation field.⁷ The other problem is the ability of the patient to carry a pregnancy to term because of radiation-induced uterine fibrosis.⁸ We discussed with the patient the possibility of egg retrieval and using a surrogate mother. In patients with localized disease, the standard paradigm for rectal cancer management consists of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy.⁹ However, this approach involves a delay of approximately 16 weeks before effective systemic chemotherapy is administered, raising the concern that metastatic disease may develop in the interim, especially in patients with overt metastatic disease. We therefore favor starting with induction chemotherapy before concurrent chemoradiation. To date, no study has been conducted to determine the outcomes of combined treatment approaches in patients with locally advanced rectal cancer and synchronous resectable metastases. Chau et al¹⁰ were the first to evaluate neoadjuvant capecitabine plus oxaliplatin before chemoradiation and total mesorectal resection in patients with newly diagnosed, MRI-defined, poor-risk rectal cancer. MRI criteria for poor-risk rectal cancer were tumors within 1 mm of the mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below the levators, tumors extending ≥5 mm into the perirectal fat, T4 tumors, and T1–4N2 tumors. Neoadjuvant chemotherapy resulted in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection. Overall survival was not assessed in this study. The same group also showed that neoadjuvant systemic fluorouracil and mitomycin C as a prelude to synchronous chemoradiation can be administered with negligible risk of disease progression and produces considerable symptomatic response with associated tumor regression.¹¹ An ongoing randomized study, the PROSPECT trial (www.clinicatrials.gov, NCT01515787), is evaluating neoadjuvant FOLFOX followed by the selective use of chemoradiation, depending on response to FOLFOX, before proceeding to surgery. Chemotherapy is also less well tolerated after surgery. From our experience, induction chemotherapy before chemoradiation for patients with locally advanced disease and resectable metastases is associated with acceptable toxicity, substantial tumor regression, and promising clinical outcomes in patients with high-risk, locally advanced rectal cancer with synchronous, resectable metastatic disease; however, this remains an area of controversy. Future prospective studies are warranted, to evaluate different treatment sequencing.

Dr. Abou-Alfa: Dr. Saltz, did this patient receive neoadjuvant therapy? If not, what was the form of treatment?

Dr. Saltz: Yes, this patient did receive neoadjuvant therapy. It is important to note that preoperative systemic therapy for metastatic colorectal cancer falls into 1 of 2 categories: neoadjuvant therapy, given in the context of disease that is completely resectable up front (as in this patient), and conversion to resectability therapy, given with the intent of trying to render unresectable disease resectable. If preoperative chemotherapy is given with neoadjuvant intent, FOLFOX alone is effective and significantly improves disease-free survival in patients who undergo surgery for their liver metastases.¹² If conversion therapy is being given, adding cetuximab or panitumumab, if the tumor is KRAS wild-type,^13–14 or irinotecan (ie, FOLFOXIRI) may achieve a greater response, although toxicity profiles must be considered.¹⁵ Bevacizumab has not been shown to improve response rates when added to FOLFOX or CAPOX.¹⁶

Dr. Hajj: The patient completed a course of induction chemotherapy with an excellent clinical response on physical examination and imaging. She subsequently received preoperative concurrent chemoradiation treatment, and her examination showed complete clinical response. She therefore underwent a low anterior resection and partial hepatectomy, with a pathologic complete response. On the patient's last follow-up, 2.5 years out from treatment, she had no evidence of disease and had undergone egg retrieval with fertilization and use of a surrogate mother.

Dr. Abou-Alfa: To conclude, there remain several controversial aspects to the management of locally advanced rectal cancer, some of which were discussed today. The role of preoperative chemoradiation in a patient with stage IV rectal cancer after induction chemotherapy is especially important in cases of high-risk, bulky primary tumors or low-lying disease. However, to date, there are no prospective studies showing that this intense approach is tolerable for patients with stage IV disease or that it would improve local control or survival. In our practice, we are seeing reasonable local and distant control in these patients with high-risk primary disease and synchronous primaries, and the sequencing of therapy does not appear to reduce the ability to achieve either distant or local control. It is important to mention that in a young patient with oligometastatic rectal cancer, one may consider a curative intent with induction chemotherapy, followed by definitive chemoradiation and surgery, including metastasectomy, in the absence of progression of the disease after completion of the induction treatment.