Treatment Options for Stage IV Colorectal Cancer (Oligometastatic Rectal Adenocarcinoma)

Patient Summary: A patient with stage IV low rectal adenocarcinoma (T3N0M0) initially had a 10 mm liver metastasis (oligometastatic disease). After chemotherapy, chemoradiotherapy to the rectum, and local ablation of the liver lesion, there is no current tumor in the rectum or liver. The remaining disease consists of several small lung nodules. The patient is RAS/RAF wild-type (WT), MMR-proficient (MSS), HER2-negative, with TP53 and APC mutations, low tumor mutational burden (TMB ~2.6), and is currently on FOLFIRI (irinotecan/5-FU) plus cetuximab (an anti-EGFR antibody). Below is a comprehensive overview of treatment strategies:

1. Standard-of-Care Treatments (U.S. & Europe)

Local Treatments for Oligometastatic Disease

For stage IV colorectal cancer with a few metastases (oligometastatic disease), aggressive local treatment can improve outcomes:

• Surgery (Metastasectomy): Surgical removal of metastases in the liver or lung can be curative in select cases. Five-year survival rates of 40–60% have been reported after resection of isolated lung metastases. Liver metastasectomy (or ablation) can yield 5-year survival ~30–50% in favorable cases. The patient’s liver metastasis was successfully ablated with no recurrence, consistent with this aggressive approach.
• Thermal Ablation & Stereotactic Radiation: For small or inoperable metastases, techniques like radiofrequency or microwave ablation and stereotactic ablative radiotherapy (SABR/SBRT) are standard. Guidelines support using thermal ablation for small metastatic lesions in the liver or lung when surgery isn’t feasible. In oligometastatic lungdisease, ablation or SBRT can be added to surgery depending on nodule size, number, and location. This aligns with the patient’s liver ablation and suggests a similar approach could be considered for accessible lung nodules.
• Chemoradiotherapy to Primary Tumor: For rectal primaries, standard care includes chemoradiation to control the local tumor. This was done for the patient (chemoradiotherapy) resulting in no rectal tumor recurrence. Typically, surgical resection of the rectal tumor would follow chemoradiation in a curative strategy. (In general, resection of an asymptomatic primary in widespread stage IV disease is not routine if it won’t improve survival​ pmc.ncbi.nlm.nih.gov , but in rectal cancer, local therapy is important to prevent obstruction or symptoms.)

Systemic Therapy (Chemotherapy and Targeted Agents)

First-Line Treatment: Stage IV colorectal cancer is initially treated with combination chemotherapy plus targeted therapy, tailored to molecular profile and tumor location:

• Combination Chemotherapy: Either FOLFOX (5-FU/leucovorin + oxaliplatin) or FOLFIRI (5-FU/leucovorin + irinotecan) are standard backbones. In fit patients, some may receive FOLFOXIRI (5-FU/leucovorin + oxaliplatin + irinotecan) for a more aggressive approach.
• Anti-EGFR Therapy: For RAS/RAF wild-type tumors, especially if left-sided (colon/rectum), adding an anti-EGFR monoclonal antibody (cetuximab or panitumumab) is a preferred first-line strategy. Trials have shown that FOLFIRI or FOLFOX with cetuximab improves response rates and survival in RAS WT patients with left-sided tumors. The patient’s current regimen (FOLFIRI + cetuximab) reflects this standard approach. (Note: In contrast, right-sided or RAS-mutant tumors benefit more from chemo + bevacizumab (anti-VEGF) in first-line.)
• Anti-VEGF Therapy: Bevacizumab (anti-VEGF antibody) can be combined with any chemotherapy backbone (FOLFOX, CAPOX, or FOLFIRI) in first-line or later lines. It’s often used if anti-EGFR is not indicated (e.g., RAS mutation or right-sided tumor) or even with triplet chemo in select cases. In the patient’s case (RAS WT), bevacizumab could have been an alternative to cetuximab; guidelines do not recommend combining EGFR and VEGF antibodies together.

Second-Line Treatment: If the cancer progresses on first-line therapy, second-line regimens typically switch the chemotherapy agents and often incorporate a different targeted drug:

• Patients previously on oxaliplatin (FOLFOX) are usually switched to an irinotecan-based regimen (FOLFIRI), and vice versa. Because our patient is on FOLFIRI now, a prior oxaliplatin-based regimen may have been used initially, or oxaliplatin could be introduced in a subsequent line.
• An anti-VEGF agent is generally used in the second-line if not used before, or continued if it was used (e.g., bevacizumab can be continued beyond first progression). Other VEGF pathway inhibitors for second-line include aflibercept (Zaltrap) or ramucirumab (Cyramza) often combined with FOLFIRI after initial FOLFOX. Guidelines recommend an angiogenesis inhibitor with chemo in second-line regardless of prior bevacizumab use.
• If the patient received an EGFR inhibitor first, second-line typically uses bevacizumab (or another anti-VEGF) with the new chemo regimen. Conversely, if bevacizumab was used first, and the tumor is RAS/RAF WT, an anti-EGFR might be introduced in second-line (particularly for left-sided tumors).

Later-Line (Third-Line and Beyond): Several standard options are available if disease progresses after two lines of therapy, assuming good performance status:

• Trifluridine–Tipiracil (TAS-102, brand Lonsurf) ± Bevacizumab: Trifluridine–tipiracil is an oral chemotherapy used in refractory metastatic CRC. The recent phase III SUNLIGHT trial showed that adding bevacizumab to TAS-102 significantly improved overall survival (median 10.8 vs 7.5 months) and response rate compared to TAS-102 alone. As a result, TAS-102 plus bevacizumab has become a new standard option after standard chemo failures. The FDA approved this combo in August 2023 for previously treated mCRC.
• Regorafenib: An oral multikinase inhibitor that modestly extends survival in chemo-refractory CRC. Regorafenib is recommended after failure of fluoropyrimidine, oxaliplatin, irinotecan, and biologics​ pmc.ncbi.nlm.nih.gov . It was shown in the CORRECT trial to improve survival vs placebo (median ~6.4 vs 5.0 months). Regorafenib is an option in both U.S. and Europe, although side effects need careful management.
• Fruquintinib: A newer oral VEGFR inhibitor that showed improved survival in heavily pre-treated mCRC. In the FRESCO-2 trial, fruquintinib significantly prolonged overall survival in patients who had exhausted standard therapies. It was approved by the FDA in 2023 for refractory metastatic CRC and is an additional option after prior oxaliplatin, irinotecan, fluoropyrimidine, anti-VEGF, and anti-EGFR (if RAS WT) treatments. Fruquintinib provides another targeted oral therapy with a manageable toxicity profile.
• HER2-Targeted Therapy (if HER2-positive): A small subset of metastatic CRC (~5% of RAS WT cases) have HER2 amplification. While this patient’s tumor is HER2–0, it’s notable that dual HER2 blockade is now standard for HER2-positive mCRC. The combination of tucatinib (TUKYSA) plus trastuzumab received FDA approval in 2023 for RAS WT, HER2-positive metastatic CRC after at least two prior lines​ pmc.ncbi.nlm.nih.gov . Other HER2-targeting combinations (like trastuzumab + lapatinib or pertuzumab) have shown activity in trials as well.
• BRAF-Targeted Therapy (if BRAF V600E mutant): About 5–10% of CRC cases have a BRAF V600E mutation (which portends a poor prognosis). For those, the FDA-approved regimen is encorafenib (BRAF inhibitor) plus cetuximab. This targeted combo improves survival versus chemotherapy in BRAF-mutant mCRC and is included in guidelines. (Our patient is BRAF WT, so this does not apply, but it’s a standard option for others.)
• Immunotherapy (if MSI-High/dMMR): Approximately 4–5% of metastatic CRCs are mismatch-repair deficient (MSI-high). For those patients, immune checkpoint inhibitors can be standard first-line therapy. Pembrolizumab (anti–PD-1) is approved for MSI-H CRC, yielding long-lasting responses in a subset of patients. Nivolumab alone or with ipilimumab (anti–CTLA-4) is also used in refractory MSI-H cases. However, for MSS (MMRp) tumors like our patient’s, single-agent immunotherapy has not shown benefit, so it is not part of standard care.

Notable Guidelines and Recommendations:

Leading oncology guidelines (e.g., ESMO and NCCN) emphasize biomarker-driven therapy selection in metastatic CRC. Key points include testing all mCRC for RAS/RAF mutations and MMR status up front. In RAS/RAF WT, left-sided tumors, chemo plus anti-EGFR therapy is strongly recommended in first-line, whereas right-sided or RAS-mutant tumors favor chemo ± bevacizumab. After first progression, switching chemo agents and continuing some form of targeted therapy (often bevacizumab or aflibercept) is advised. Third-line options (regorafenib, TAS-102 ± bevacizumab, fruquintinib) should be considered if the patient is fit. Aggressive local therapy for isolated metastases is encouraged when feasible, as it can prolong survival or occasionally achieve remission. All these strategies have been incorporated into the patient’s care (chemoradiation, combination chemotherapy, targeted therapy, and metastasis ablation), reflecting standard-of-care practice.

2. Experimental and Emerging Therapies (Clinical Trials & Novel Approaches)

For MSS metastatic CRC patients like this one (who don’t benefit from current immunotherapy), researchers are actively exploring new treatments. These include novel immunotherapy combinations, targeted agents for specific mutations, and other experimental strategies. Some promising avenues as of 2024–2025:

Emerging Immunotherapy Strategies for MSS CRC

Standard checkpoint inhibitors (pembrolizumab, nivolumab) alone have been ineffective in MSS colorectal cancer, but new combinations are showing activity by overcoming the immune-resistant tumor microenvironment:

• Dual Checkpoint Blockade (CTLA-4 + PD-1): A breakthrough came from a phase I trial of botensilimab (a novel CTLA-4 antibody) plus balstilimab (anti–PD-1). In MSS CRC patients refractory to chemo, this combo achieved disease control in 73% of patients without liver metastases, with nearly 23% having a major tumor response. (Notably, responses were minimal in patients with active liver mets, highlighting how liver tumors suppress immunotherapy.) Overall response rate (ORR) was ~17% and 12-month survival ~60% in the study. These results, published in Nature Medicine 2024, represent the first effective immunotherapy in MSS CRC and have led to an ongoing phase III trial.
• Checkpoint Inhibitors + Chemotherapy/Anti-VEGF: Another experimental approach is combining immunotherapy with standard chemo and bevacizumab to make “cold” tumors more “hot.” For example, the phase II POCHI trial tested pembrolizumab + CAPOX (capecitabine/oxaliplatin) + bevacizumab in previously untreated MSS mCRC patients selected for high tumor-infiltrating lymphocytes. The regimen achieved a 96% disease control rate, with 21% complete responses and 54% partial responses – remarkably high efficacy for MSS disease. While this approach is still investigative, it suggests that upfront chemo + anti-angiogenic therapy may synergize with immunotherapy in immunogenic MSS cases.
• Cancer Vaccines and Cellular Therapies: Therapeutic vaccines (aiming to stimulate the immune system against colorectal cancer antigens) and adoptive cell therapies are under study. For instance, personalized dendritic cell vaccines and CAR T-cell therapies targeting CRC-associated antigens (like CEA or EGFR) have shown some activity in early trials. CAR T-cells face challenges in solid tumors (poor T-cell trafficking and immunosuppressive microenvironment), and so far efficacy in CRC has been limited​. Researchers are trying to improve CAR T delivery and persistence in colorectal tumors wjgnet.com. These are experimental but could evolve with new engineering strategies.
• Other Immune Modulators: Trials are evaluating agents that modulate the tumor microenvironment to enable immunotherapy. Examples include inhibitors of MEK or IDO1, and agonists of STING or TLR pathways, combined with PD-1/L1 inhibitors. While early results have been mixed, this remains a hot research area. One small trial (CCTG CO.26) combining a PD-L1 inhibitor (durvalumab) with a CD73 inhibitor (oleclumab) showed only modest benefit in MSS CRC, highlighting the need for better strategies. Ongoing studies like COMMIT and MODUL are testing various immunotherapy combos in mCRC.

Novel Targeted Therapies and Trials

Beyond immunotherapy, researchers are targeting specific genetic or molecular features of colorectal cancer in clinical trials:

• KRAS Inhibitors: About half of CRC patients have RAS mutations, which historically made them ineligible for EGFR inhibitors. New KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have been approved in lung cancer and are being tested in KRAS G12C-mutant CRC. Early trials show modest activity, and combining these drugs with EGFR inhibitors may improve efficacy in CRC. While our patient’s tumor is RAS wild-type, the development of RAS inhibitors could benefit those who acquire RAS mutations over time or were mutant from the start.
• c-MET and Other Pathways: Some CRC tumors develop resistance via MET amplification or other bypass pathways. Trials are investigating MET inhibitors (like cabozantinib or tepotinib) in metastatic CRC, especially after anti-EGFR therapy. There are also studies targeting the Wnt/β-catenin pathway (frequently dysregulated via APC mutation) – for example, porcupine inhibitors that block Wnt ligand secretion. These are experimental and not yet standard, but are relevant given the patient’s APC mutation.
• Oncolytic Virotherapy: Oncolytic viruses are engineered to infect and kill cancer cells and stimulate immunity. Multiple oncolytic viruses (adenovirus, reovirus, vaccinia, etc.) have been tested in CRC. A phase II trial combining an oncolytic reovirus (pelareorep) with FOLFOX/bevacizumab showed an improved response rate, though overall survival was not significantly prolong Other early trials of oncolytic herpes and vaccinia viruses in refractory CRC reported good safety but only occasional tumor responses​. No oncolytic virus is yet FDA-approved for CRC, but research is ongoing using viruses in combination with chemotherapy or immunotherapy​.
• Precision Medicine Trials: Given the patient’s TP53 mutation (common in CRC), one area of research is drugs targeting mutant p53 or related pathways. Agents like APR-246 (eprenetapopt) aim to restore normal function to mutant p53 – mostly explored in blood cancers, but conceptually could apply to CRC. Another approach is targeting tumor metabolic vulnerabilities; for instance, trials of IDH1 inhibitors in IDH-mutant CRC (rare) or PARP inhibitors in tumors with DNA repair defects. While none of these are standard, patients may consider molecular tumor boards or sequencing-driven trials (often listed on clinicaltrials.gov) to find experimental therapies matching their tumor’s profile.

Notable Clinical Trials (2024–2025): Patients seeking experimental options can explore trials such as:

• Agenus “ALIGN” Trial: Phase III trial of botensilimab + balstilimab vs standard chemo in refractory MSS mCRC (building on the phase I results).
• POCHI/ATOMIC Trials: Ongoing studies integrating checkpoint inhibitors with chemotherapy in first-line MSS CRC, to confirm if subsets benefit as in early data.
• EGFR Rechallenge Trials: For RAS WT patients who responded to anti-EGFR then progressed, trials like CRICKET and CHRONOS study re-introduction of cetuximab/panitumumab after a “drug holiday” or after clearance of emerging RAS mutations. These address the fact that resistant tumor clones can fade over time, potentially restoring sensitivity to EGFR inhibitors.
• Personalized Vaccine Trials: E.g., Moderna’s mRNA vaccine for KRAS-mutant CRC (in combination with immunotherapy) – an exploratory approach to “teach” the immune system to recognize tumor mutations.
• Adoptive Cell Therapy Trials: e.g., trials of tumor-infiltrating lymphocyte (TIL) therapy in CRC or CEA-targeted CAR-T cells. While still in early phases, these are offered at some large centers for investigational use.

Staying updated through resources like the NIH clinical trials database or major cancer center websites can identify appropriate trials. It’s advisable for an oligometastatic MSS CRC patient to consult academic centers for trial eligibility, especially as standard options become exhausted.

3. Complementary and Integrative Therapies

Many stage IV cancer patients explore complementary therapies to support quality of life and alleviate symptoms alongside conventional treatment. It’s important to note that these do not replace standard oncology care, but may be used in addition to it (with the oncology team’s guidance). Based on reputable sources, some approaches include:

• Diet and Nutrition: Eating a well-balanced diet helps maintain strength during treatment. Some patients adopt anti-inflammatory or high-protein diets; however, no special “cancer diet” has proven to cure cancer. Maintaining adequate calories and managing side effects (like nausea or bowel changes) is key. Nutritional counseling is often offered. There is some evidence that vitamin D sufficiency may be beneficial – for example, a phase II trial (“SUNSHINE”) suggested high-dose vitamin D might slightly delay progression in metastatic CRC (though the difference was not statistically significant)​ pubmed.ncbi.nlm.nih.gov. Patients should discuss with doctors before taking high-dose supplements.
• Herbal Supplements and Vitamins: Curcumin (from turmeric) has been studied for its anti-cancer properties. A phase II clinical trial found that adding curcumin to FOLFOX chemotherapy was safe and tolerable for metastatic CRC patients​ pubmed.ncbi.nlm.nih.gov , and hinted at improved progression-free and overall survival (though larger trials are needed). Other compounds like green tea extracts (EGCG), resveratrol, and medicinal mushrooms (PSK) are under study for potential benefits​. IMPORTANT: Patients must inform their oncologist about any supplements, as some can interfere with treatment or be harmful. For instance, high-dose antioxidants might reduce chemotherapy effectiveness, and St. John’s Wort can alter drug levels.
• Mind-Body Practices: Stress reduction and mental health are vital. Yoga, meditation, tai chi, and mindfulnessprograms can help patients cope with anxiety and fatigue. These practices are low-risk and have been associated with improved quality of life. Many cancer centers offer guided meditation or yoga classes for patients.
• Acupuncture: This traditional Chinese medicine technique can be used to manage symptoms. Clinical studies have shown acupuncture may reduce chemotherapy-induced nausea and vomiting and help with pain or neuropathy in cancer patients. It has also been studied in postoperative recovery; one trial in colorectal surgery patients showed acupuncture shortened post-surgery ileus (bowel inactivity), speeding up recovery. Major centers like MSKCC have integrative medicine services that include acupuncture for symptom control.
• Massage Therapy and Relaxation: Gentle massage can help with pain relief and stress. Similarly, music therapy, art therapy, or even simply breathing exercises can alleviate anxiety and improve mood during the long course of treatment.
• Exercise: Light to moderate exercise as tolerated (e.g. walking) is encouraged. Studies suggest exercise can improve fatigue and even outcomes in cancer patients. Even with lung nodules, if the patient is physically able, staying active under guidance can be beneficial.
• Supportive Care: Beyond “alternative” therapies, standard supportive/palliative care measures are crucial. This includes effective pain management, nutritional support (possibly appetite stimulants if needed), and psychosocial support (support groups or counseling). Palliative care teams can work alongside oncology to manage symptoms and maintain quality of life.

Important Note: Always discuss complementary methods with the oncology team before starting them. Many integrative therapies can help with symptom relief (for example, acupuncture for nausea, or yoga for fatigue), but none have proven to cure advanced colorectal cancer on their own. The medical team can help ensure that any supplements or therapies chosen won’t conflict with treatment. When used appropriately, complementary therapies can improve comfort and well-being during what is often an intensive treatment journey.

4. Prognosis and Expected Outcomes

Prognosis in stage IV colorectal cancer is quite variable and depends on the extent of disease, biology of the tumor, and the treatments used. General statistics provide a baseline, but individual factors often lead to outcomes that are better (or worse) than the average:

• Overall Survival Statistics: Historically, the 5-year relative survival for metastatic (distant stage) colorectal cancer is around 14%–18%. This means roughly 1 in 6 patients are alive 5 years after a stage IV diagnosis, although not necessarily disease-free. Median survival without treatment is ~6–12 months, but with modern combination chemotherapy this improved to ~2–3 years in many cases. In fact, as of the late 2010s, median overall survival for mCRC patients in clinical trials has exceeded 30 months (2.5 years) with aggressive treatment, reflecting progress in therapies.
• Oligometastatic Disease Prognosis: Patients with only a few metastatic sites that are treatable (as in this patient’s case) often have a better outlook than diffuse metastases. If all metastases can be ablated or resected and no new disease appears, long-term survival is achievable and some patients may even be cured. For example, surgical series in lung-only oligometastases report 5-year survival up to ~50%. The fact that our patient currently has no active disease in rectum or liver is a very positive sign. The remaining lung nodules, if limited in number, could potentially be managed with local therapies (surgery or SBRT) or controlled on systemic therapy. Achieving “no evidence of disease” (NED) status through combined modality treatment offers the best chance at prolonged survival or cure, even in stage IV.
• Molecular Factors: This patient’s tumor is RAS and BRAF wild-type, which generally confers a better prognosis and allows use of EGFR-targeted therapy. RAS mutations are associated with shorter survival and limited therapy options (no anti-EGFR benefit)​
  pubmed.ncbi.nlm.nih.gov. BRAF V600E mutation predicts a particularly poor prognosis (median survival often <12 months with standard therapy), though targeted therapy has improved that somewhat. Being MSS (microsatellite-stable) is the norm in metastatic CRC (~95% cases) and means immunotherapy is less effective – a negative factor compared to MSI-high cases that can sometimes get durable remission on PD-1 inhibitors. However, MSS status is so common that prognosis is usually assessed more on tumor burden and biology. The TP53 and APC mutations are very common in CRC and on their own do not drastically change prognosis; they mainly indicate the cancer is “conventional” colorectal adenocarcinoma (not a special subtype). Low TMB reflects fewer mutation-based neoantigens, consistent with the lack of immunotherapy response.
• Tumor Location: Left-sided colon and rectal cancers tend to have slightly better outcomes than right-sided. A meta-analysis found that left-sided mCRC had a survival advantage over right-sided, possibly due to differences in biology and treatment responsiveness. Our patient’s rectal primary (left side) and RAS WT status mean he could fully benefit from EGFR inhibitors, which have been shown to improve survival especially in left-sided tumors.
• Treatment Response: How well the cancer responds to initial therapy is one of the strongest prognostic indicators. In this case, after chemotherapy and targeted therapy, the primary tumor and liver metastasis are controlled (no recurrence), indicating a good response. Only small lung nodules remain, implying the bulk of disease was addressed. Patients who achieve major responses or complete remission of lesions with chemo ± targeted therapy have longer median survival. Depth of response and being able to render the patient NED (via therapy and ablations) correlate with improved outcomes.
• Expected Outcomes with Current Treatment: On FOLFIRI + cetuximab (a typical second-line regimen if FOLFOX was first-line), one would expect disease control in a significant fraction of patients. Clinical trials (e.g., CRYSTAL and others) showed cetuximab + chemo can prolong survival in RAS WT mCRC to ~29–30 months on average. If the lung nodules shrink or stabilize on this regimen, the patient could potentially proceed to local ablation of those as well, which might put them in a no-evidence-of-disease state. In oligometastatic cases where all lesions are cleared, some studies document survival beyond 5 years in 20–30% of patients, and occasional cures. If systemic therapy controls but doesn’t eliminate the lung lesions, the disease becomes more of a chronic condition – managed by successive lines of therapy. Many patients go through multiple chemo lines over several years. Quality of life and treatment breaks are balanced with disease control.
• Role of Maintenance and Holidays: Patients who respond may go on lighter “maintenance” therapy (like 5-FU or capecitabine ± bevacizumab) to give a break from intensive chemo, resuming full chemo upon progression. This strategy can maintain quality of life without compromising survival in many cases.
• Emerging Therapies Impact: As discussed, experimental options might provide new hope if standard therapies are exhausted. For instance, if immunotherapy combos (like botensilimab/balstilimab) prove successful in trials, they could significantly improve outcomes for MSS patients. It’s possible that in a few years, the prognosis for MSS stage IV CRC will improve if these novel treatments become available.

In summary, the patient described has a relatively favorable profile for a stage IV CRC case: limited metastatic sites, successful control of the primary and liver lesion, and molecular features allowing multiple therapy options. With current treatments, long-term control is possible. Five-year survival in such a scenario may substantially exceed the general 13–18% statistic for stage IV, especially if the lung nodules can be managed. Each treatment strategy – whether aggressive local therapy or switching systemic lines – offers a chance to extend survival. It’s important to maintain realistic optimism: while cures in stage IV are rare, a subset of patients achieve very prolonged remission. Ongoing follow-up with scans is critical to detect any recurrence early. And as time goes on, new therapies (from clinical trials or emerging approvals) may further improve the outlook. The care plan should remain dynamic, integrating standard therapies, clinical trial options, and supportive care to optimize both longevity and quality of life for the patient.

References:

• Cervantes A. et al. ESMO Clinical Practice Guideline for metastatic colorectal cancer, Ann Oncol. 2023.
• NCCN Clinical Practice Guidelines in Oncology – Colon/Rectal Cancer, Version 2024 (key recommendations for first-line and subsequent therapies).
• American Cancer Society – Colorectal Cancer Survival Rates (2025 update); ACS Treatment Guidelines.
• FDA Approval alerts – e.g., Trifluridine/Tipiracil + Bevacizumab (SUNLIGHT trial) and Tucatinib + Trastuzumab for HER2-positive CRC​
  pmc.ncbi.nlm.nih.gov
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• Grothey A. et al. CORRECT trial (regorafenib in mCRC), Lancet 2013. Li J. et al. FRESCO-2 trial (fruquintinib in refractory mCRC), Ann Oncol. 2022.
• Huang Y. et al. Curcumin with FOLFOX in mCRC, J Nutr 2019 (phase II trial)​
  pubmed.ncbi.nlm.nih.gov
  . Ng K. et al. SUNSHINE trial (Vitamin D in mCRC), JAMA 2019​
  pubmed.ncbi.nlm.nih.gov
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• Dana-Farber Cancer Institute – News release June 2024 on botensilimab + balstilimab (MSS CRC immunotherapy); Nature Medicine 2024.
• OncLive 2024 – Report on pembrolizumab + chemo/bev (POCHI trial) in MSS CRC.
• World J Gastrointest Surg. 2023 – “Current and emerging therapeutic approaches for CRC” (review of oncolytic viruses, CAR-T, etc.)​
  wjgnet.com
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• The ASCO Post – Integrative therapies in colorectal cancer, 2019. Bowel Cancer UK – Complementary therapy guidance.