Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 6/2020
Following clinical evaluation of rectal cancer, the cancer is referred to as Stage IV rectal cancer if the final evaluation shows that the cancer has spread to distant locations in the body, which may include the liver, lungs, bones, or other sites.
Certain patients with stage IV rectal cancer can be cured of their cancer and others derive meaningful palliative benefit from treatment. Patients with stage IV rectal cancer can be broadly divided into two groups: those with cancer that may be possible to remove with surgery and those with more extensive widespread cancer.
Treatment of Extensive Stage IV Rectal Cancer
While some patients have a single site of metastatic cancer that can be treated with curative intent, the majority of patients with stage IV rectal cancer have more widespread cancer that cannot be completely removed with surgery.
If the cancer is extensive but not causing symptoms, treatment may consist of chemotherapy, precision cancer medicines, and immunotherapy or some combination that is often determined by genomic - biomarker testing of the cancer. Some individuals are only treated with precision cancer medicines or immunotherapy and can avoid chemotherapy all together. Individuals with cancer that has metastasized to one or two sites may also be treated with surgery or radiation directed to those sites. Treatment planning and selection is based on
- Genomic biomarker testing
- Location of the primary cancer
- Patient preference
Fluorouracil chemotherapy (5-FU) based chemotherapy has been the standard treatment for stage IV rectal cancer patients who don't have a targetable cancer driving mutations that can be treated with a precision cancer medicine. 5FU is typically administered with leucovorin (LV), a drug that is similar in structure and function to the essential vitamin folic acid. Leucovorin enhances the anticancer effects of fluorouracil by helping the chemotherapy drug bind to and stay inside the cell for a greater period of time, producing longer lasting anticancer effects.
The addition of other drugs to 5-FU/LV and an oral alternative has been found to provide additional benefit to 5-FU alone and standard chemotherapy treatment for advanced colon cancer now includes any of the following regimens for individuals that do not have a cancer driving mutation or targetable biomarker.
- FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
- CAPEOX (Xeloda (capecitabine) + Eloxatin)
- FOLFIRI (LV/5-fluorouracil + Camptosar (irinotecan)
- FOLFOXIRI (LV/5-fluorouracil + Camptosar + Eloxatin)
These treatment regimens are typically paired with Avastin® (bevacizumab) and are the standard initial treatment for most patients and improve survival. (2) These regimens can be associated with significant side effects including diarrhea, fatigue and damage to the nerves (neuropathy).
Colon Cancer Mutations Targeted by Precision Cancer Medicines
Genetic Mutations: Not all rectal cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing should be performed to test for genetic mutations or the proteins they produce on ALL patients. By testing an individual’s cancer for specific unique genomic- biomarkers doctors can offer a personalized treatment approach utilizing precision medicines. Rectal cancer mutations are being identified and new medicines developed to target these mutations on an ongoing basis.
Precision Cancer Medicines
Individuals with the following biomarkers may have their colon cancer treated differently using targeted precision cancer medicines.
Epidermal growth factor receptors(EGFR) occurs in rectal cancers and can be targeted with Erbitux® (cetuximab) andVectibix (panitumumab) which are precision cancer medicine called monoclonal antibodies that work by binding to EGFR and when combined with chemotherapy can improve outcomes in patients that test positive for EGFR and do not have a RAS mutation.(4,5,6,)
BRAFV600: Patients with mutant BRAF gene have historically had a poorer prognosis but their prognosis is significantly improved with the development of precision cancer medicines that target the V600E BRAF mutation. Treatment with a combination of precision medicines has been shown to double survival time for patients with recurrent cancer and doctors are now evaluating the use of these medications as initial therapy for BRAF positive cancers.(3) BEACON Trial results…
Microsatellite Instability High (MSI-H): MSI-H is a DNA abnormality found in some rectal cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-High rectal cancer can be more effectively treated with the precision cancer immunotherapy drugs called "checkpoint inhibitors." Keytruda, and Opdivo have both been demonstrated to improve treatment of individuals with MSI-High disease. (7,8)
Study suggests Jakafi not associated with increase in significant secondary malignancies.
Study suggests Jakafi not associated with increase in significant secondary malignancies.
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HER 2: Human epidermal growth factor receptor 2 (HER 2) targeted therapies can dramatically improve outcomes and all colo-rectal cancers should be tested for HER 2 at the time of diagnosis. This is important because patients over expressing HER2 do not benefit from treatment with the commonly used EGFR inhibitors and these medications should be avoided. Patients can benefit from treatment with one of several different precision cancer medicine combinations that target HER2 like Herceptin (trastuzumab), Tykerb (lapatinib) and Tucatinib. (9) - Learn more about HER2 directed therapy in colon cancer.
NTRK: neurotrophic tropomyosin receptor kinases (NTRKs genes, which encode for TRKs can become abnormally fused to other genes, resulting in growth signals that can lead to cancer and be targeted with specific medications.
Cancer driving mutations and biomarkers that can be used to develop new precision cancer medicines are being continuously identified and incorporated into genomic testing panels and all patients should discuss the role of genomic biomarker testing with their doctor.
Treatment of Metastatic Rectal Cancer to a Single Site
Rectal cancer may spread (metastasize) to the liver, lung or other locations in the body. When the site of metastasis is a single organ, such as the liver or lungs, patients may benefit from local treatment directed at that single site of metastasis and are still potentially curable.
Highly selected patients with isolated areas of rectal cancer can be cured if the primary cancer in the rectum and the isolated area of cancer outside the rectum can be surgically removed. Treatment begins with with systemic therapy as described above. If the cancer in the rectum responds to treatment and decreases in size potentially curative surgery can be considered at that time.
Treatment of the liver: The most common site of metastasis for patients with rectal cancer is the liver. When it’s possible to completely surgically remove all liver metastases, surgery is the preferred treatment. Some patients may have both the liver and the rectum treated in a single operation, and others may have two operations: one to treat the rectum and one to treat the liver. Chemotherapy or chemotherapy plus radiation therapy may be used before and/or after surgery.
Although surgery offers some patients the chance for a cure, a majority of patients with liver metastases are not candidates for surgery because of the size or location of their tumors or their general health. Some of these patients may become candidates for surgery if initial treatment with systemic shrinks the tumors sufficiently. If the tumors continue to be impossible to remove surgically, other liver-directed therapies may be considered. These other therapies include radiofrequency ablation (use of heat to kill cancer cells), cryotherapy (use of cold to kill cancer cells), delivery of chemotherapy directly to the liver, and radiation therapy. Relatively little information is available from clinical trials about the risks and benefits of these other approaches, but they may benefit selected patients. (10)
Strategies to Improve Treatment
While some progress has been made in the treatment of Stage IV rectal cancer many patients still succumb to cancer and better treatment strategies are clearly needed. Future progress in the treatment of rectal cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of rectal cancer.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack colon cancer cells with specific abnormalities, leaving normal cells largely unharmed. Development of precision medicines are for the treatment of rectal cancer is ongoing and these novel medicines are first utilized patients with recurrent cancers and once proven effective they become available through clinical trials for treatment of earlier stage disease. All patients need to make sure their cancer undergoes genomic profiling. This can also be accomplished with a tissue sample and in blood using a "liquid biopsy" if tissue is not available.
New Approaches to Treating Liver Metastases: Researchers continue to explore news ways to treat cancer that has spread to the liver. One approach that is being evaluated is radioembolization This strategy uses radioactive microspheres (small spheres containing radioactive material). The small spheres are injected into vasculature of the liver, where they tend to get lodged in the vasculature responsible for providing blood and nourishment to the cancer cells. While lodged in place, the radioactive substance spontaneously emits radiation to the surrounding cancerous area while minimizing radiation exposure to the healthy portions of the liver.2 Researchers are also exploring alternatives to radiofrequency ablation for the destruction of liver tumors, as well as new approaches to delivering chemotherapy to the liver.
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research.
- Venook A, Niedzwiecki D, lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
- Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 33, 2015 (suppl 3; abstr 657).
- Cunningham D, Humblet Y, Siena S, et al. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer. New England Journal of Medicine 2004;351:337-345.
- Hriesik C, Ramanathan R, Hughes S. Update for Surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum. Journal of the American College of Surgeons2007; 205: 468-478.
- FDA Approves First-Line Use of Vectibix® (Panitumumab) Plus FOLFOX for Patients with Wild-Type KRAS Metastatic Colorectal Cancer
- FDA approves first cancer treatment for any solid tumor with a specific genetic feature
- FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer
- Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncology. Published online April 20, 2016.
- Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.
- Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy. Journal of Clinical Oncology. 2010;28:3687-94.