Systemic Treatment and Adverse Event Management for Colorectal Cancer | Dr. Dong Qian, Liaoning Cancer Hospital | Panda Patient Education Live Replay
Throughout the diagnosis and treatment of colorectal cancer, every patient and family member encounters adverse reactions. Learning how to manage them scientifically is essential.
On December 19, 2024, the Panda Group invited Dr. Dong Qian, Director of the Second Department of Gastroenterology at Liaoning Cancer Hospital, for a live educational session on colorectal cancer diagnosis and treatment.
The discussion highlighted that bowel cancer diagnosis primarily relies on observing changes in abdominal bowel habits and stool characteristics. Initial staging is crucial. Chemotherapy adverse reactions include neutropenia, anemia, and thrombocytopenia. Immunotherapy shows significant efficacy for MSI-H/dMMR bowel cancer patients, improving treatment outcomes. However, immunotherapy adverse reactions are diverse, and clear predictive markers are currently lacking.
Additionally, post-surgical care, dietary adjustments, and how to assess adverse reactions were discussed. Dr. Dong also shared current clinical practices and advancements at Liaoning Cancer Hospital with Mr. Han Kai from the Panda Group.
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Article Summary | Wang Yaoyao
Article Proofreading | Xiao Han
Editor-in-Charge | Xian Ning
[ Meeting Date: December 19, 2024 ]
Participants:
Prof. Dong Qian
Chief Physician, Second Department of Gastroenterology, Liaoning Cancer Hospital
Mr. Han Kai
Founder, Panda and Friends Patient Mutual Aid Organization
Summary:
PART 1 Precision Diagnosis and Treatment & Adverse Reaction Management for Colorectal Cancer
PART 2 Doctor-Patient Interaction – Answering Patient Questions
Precision Treatment and Adverse Reaction Management for Colorectal Cancer
01 The Gold Standard for Bowel Cancer Diagnosis
Patients seeking medical attention generally fall into two categories: those with no obvious symptoms, often discovering polyps or early-stage cancers during routine check-ups; and those already experiencing symptoms, most notably changes in bowel habits, such as constipation, diarrhea, or alternating between the two, often accompanied by changes in stool consistency.
The pathology report is the gold standard for diagnosing colorectal cancer. All patients are advised to undergo a colonoscopy for tissue sampling and pathological biopsy. After bowel preparation, if the endoscopist identifies polypoid lesions or mucosal abnormalities during the procedure, tissue samples are taken, processed, and prepared into histological slides.
Pathologists then confirm the nature of the lesion based on cellular structure, morphology, and phenotypic characteristics. They determine whether it is cancer or another malignant condition and classify the tissue type.
HE Stained Slides: HE staining is a common histological staining method. Under a microscope, it reveals red and purple hues, allowing observation of tissue structure and cell morphology. Typically prepared from biopsy or post-surgical specimens to facilitate medical consultations.
Unstained Slides (White Slides): Required for MSI testing or genetic testing. If a consulting hospital requests unstained slides, specify the quantity (approx. 10 for MSI status, 20–25 for large-panel genetic testing) and thickness (usually 4–5μm) on the borrowing form. As these are prepared on demand, a preparation fee applies.
02 Pathological Classification of Colorectal Cancer
Pathological types include adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, medullary carcinoma, undifferentiated carcinoma, and carcinosarcoma. The most common type in the colorectum is "adenocarcinoma," accounting for about 95%, followed by mucinous adenocarcinoma and signet ring cell carcinoma. However, these two types tend to have poor adhesion, easily shedding into the bloodstream and causing peritoneal dissemination.
03 What is TNM Staging?
The intestine is a "tubular" structure, and lesions grow outward from the mucosal surface into the lumen.
The TNM staging system for colorectal cancer is specifically used to determine the extent of tumor spread during treatment, where:
T represents the size and extent of the primary tumor, indicating which layer of the bowel wall the tumor has invaded. A higher number signifies deeper invasion.
N indicates whether cancer cells are present in regional lymph nodes, broadly divided into two parts: local intestinal lymph nodes (pericolic/perirectal) and distant lymph nodes. If it spreads beyond the regional clearance area, it can be considered a distant organ (M category).
M indicates distant metastasis.
Therefore, as the values across these three TNM dimensions increase, it indicates a wider spread of the tumor and a more advanced stage.
04 Impact of Initial Staging on Treatment Strategies
For individual patients, after initial assessment, it is essential to determine the corresponding treatment goals and specific subsequent strategies based on the staging.
For mid-to-low rectal cancer, many patients face questions about sphincter preservation. For those initially diagnosed with peritoneal metastasis, treatment strategies and goals differ significantly. If neoadjuvant therapy can convert the patient to a disease-free state, that yields the greatest benefit.
If achieving NED (No Evidence of Disease) is not possible, we will still "deploy our forces strategically," striving to shrink tumors during second-line therapy to achieve organ preservation and prolong survival.
Some patients do not understand why initial tests take so long before treatment begins. This underscores the importance of understanding the initial status confirmation.
Accurate staging and diagnosis, combined with good patient compliance, will yield twice the results with half the effort in subsequent treatment.
05 What Does Systemic Treatment for Colorectal Cancer Include?
Systemic treatment for colorectal cancer is divided into chemotherapy, targeted therapy, and immunotherapy.
The adverse reactions of chemotherapy mainly stem from its mechanism of killing rapidly proliferating and metabolizing cells. It is non-selective, affecting both healthy and cancerous cells.
In the human body, tissues with rapid proliferation and metabolism include the gastrointestinal and oral mucosa, and hair follicles. This leads to adverse reactions like nausea, vomiting, and hair loss.
Targeted therapy intervenes at specific molecular targets on cancer cells, such as EGFR/KRAS/HER-2/NTRK/CKIT. However, it can only be used if "there is a target to hit."
Immunotherapy utilizes the patient's immune system to recognize and attack cancer cells. This is a highly active field in recent years, having changed outcomes in many tumor types. Its efficacy in colorectal cancer is particularly notable.
06 How to Choose Systemic Treatment?
Through molecular marker testing, all diagnosed colorectal cancer patients should undergo microsatellite instability (MSI) or mismatch repair protein (MMR) testing. If dMMR/MSI-H is identified, immunotherapy can be considered.
Currently, the accuracy of these methods exceeds 90%, and combining two different testing methods increases accuracy further. Immunotherapy can significantly improve prognosis for these patients, thereby increasing the clinical cure rate for colorectal cancer.
However, these testing methods have limitations. For example, immunohistochemistry testing for the four proteins (PMS2, MLH1, MSH2, MSH6) can yield false positives or negatives. We have encountered cases where all four proteins were negative or mismatched. In such cases, testing or sampling issues should be considered, and retesting is recommended.
If no such specific genetic alterations are present, and the patient has multiple metastases with advanced staging, we also recommend a large-panel genetic test. For instance, patients with POLE mutations tend to respond better to immunotherapy.
In terms of patient proportion, MSI-H and dMMR patients account for about 15% to 20% overall. By stage, early-to-mid stage patients make up about 15% of the total, while late-stage patients account for about 5%.
Besides molecular testing, MSI status can also be partially inferred from patient age, condition, family history, and baseline imaging. If a patient has a very large local tumor but no distant metastasis, the probability of MSI-H is relatively high.
For MSS/pMMR patients, the genetic status is roughly 40% wild-type and 60% mutated. Treatment drugs are then selected based on the tumor location (left vs. right side).
07 What is Chemotherapy? & Common Drugs
The most commonly used chemotherapy drugs include platinum-based agents, such as oxaliplatin; fluorouracil-based agents, such as intravenous pump-controlled fluorouracil. Oral medications include capecitabine, and TAS-102 (trifluridine/tipiracil) for third-line treatment. Additionally, topoisomerase inhibitors, such as irinotecan, serve as cornerstone drugs in bowel cancer treatment.
08 Adverse Reactions of Chemotherapy
Common chemotherapy adverse reactions include hair loss, gastrointestinal mucosal irritation, and hematopoietic tissue abnormalities.
We often see white blood cells and neutrophils drop within a week after chemotherapy. Platelets and red blood cells, due to their longer lifespan (around 120 days), show abnormalities later.
Most of these toxicities are reversible. Clinically, we grade adverse reactions based on patient symptoms and their impact on daily life.
Neutropenia: When neutrophils drop below 1000–500/mm³, it is Grade 3. Fever, cough, and infection may occur. Seek medical attention promptly and disinfect the room.
Anemia: Hemoglobin below 8.0 g/dL is Grade 3. Dizziness and nausea may occur. Iron supplementation is necessary.
Thrombocytopenia: Platelets below 50,000–25,000/mm³ is Grade 3. Subcutaneous bleeding spots may appear. Avoid strenuous exercise.
Diarrhea: Increased bowel movements (4–6 times/day) is Grade 2. Stop medication temporarily and avoid dairy and high-energy foods.
Nausea, Vomiting, Fatigue: Severe vomiting requires intravenous fluids. Drink warm beverages to prevent dehydration. Rest for systemic fatigue, and exercise when physically able. These are generally Grade 2.
The management of these adverse reactions relies on early detection and early intervention. Gastrointestinal reactions can be prevented with antiemetics. Other reactions may require rescue therapy. Early treatment minimizes the impact on patients.
09 Targeted Therapy & Common Drugs
The most common targeted therapy is anti-EGFR therapy, including cetuximab and cetuximab-β. For wild-type left-sided patients, it is combined with chemotherapy, though adverse reactions may be higher.
Another type is anti-angiogenic therapy, such as bevacizumab. There are currently no effective screening markers for anti-angiogenic drugs; they can be used regardless of KRAS/NRAS/BRAF mutation status.
Third-line VEGF inhibitors like fruquintinib and regorafenib are oral medications acting on intracellular signaling pathways in tumor cells. They are small-molecule multi-target tyrosine kinase inhibitors (TKIs).
10 Relationship Between Targeted Therapy and Tumor Location
The left and right sides of the colon are typically divided at the "splenic flexure" of the transverse colon.
The "right side" includes the ascending colon and transverse colon, while the "left side" includes the descending colon, sigmoid colon, and rectum below the splenic flexure.
Embryological and molecular biological differences between the two lead to variations in tumor malignant behavior.
Left-sided patients generally have a better prognosis. RAS wild-type patients benefit more from cetuximab.
11 Adverse Reaction Management for Targeted Therapy
EGFR stands for "Epidermal Growth Factor Receptor." Adverse reactions from anti-EGFR drugs mainly manifest as facial rashes (acne, pimples). Management requires appropriate medications, along with sun protection and moisturizing.
Anti-VEGF drugs typically cause hypertension. We usually use sartans (ARBs) and may add calcium channel blockers for further management.
12 Immunotherapy: Immune Checkpoint Inhibitors
Tumors arise due to "immune escape," where cancer cells "disguise" themselves to evade immune detection.
Immunotherapy removes this "disguise," helping the patient's immune system re-mark and effectively kill tumor cells. It also enhances the tumor-killing ability of immune T cells. For MSI-H/dMMR bowel cancer patients, the effect is particularly excellent. Early-to-mid stage patients can even achieve "drug-induced cure," which is highly significant for organ preservation, especially in rectal cancer.
According to a Phase III clinical study, in advanced MSI-H/dMMR colorectal cancer patients, some with concurrent BRAF/RAS mutations used PD-1 monotherapy or PD-1 combined with CTLA-4 inhibitors (to reduce primary resistance from gene mutations), showing significant efficacy.
Monotherapy often takes longer to work, but once effective, it provides long-lasting action. Dual immunotherapy can activate T cells through synergistic effects, further improving efficacy.
13 Adverse Reactions of Immunotherapy
Immunotherapy has systemic effects, and biomarkers/predictive indicators are not yet clear, making its adverse reactions unpredictable.
For patients who respond well to immunotherapy, the enhanced immune cell activity against tumors sometimes attacks normal tissues, increasing the probability of adverse reactions.
For patients with MSI-H, POLE mutations, etc., skin toxicity, thyroid toxicity, and liver/kidney toxicity are common and require close monitoring.
14 Adverse Reaction Management to Monitor Closely at Home
Constipation: For gastrointestinal cancer patients, constipation can lead to bowel obstruction.
Diarrhea: Clean the perianal area, apply oily ointment, and avoid direct contact between stool and skin.
Sleep Disorders: Besides medication, try exercise, massage, foot baths, and music.
Nausea & Vomiting: Mild cases: take medication. Severe cases: seek medical help. If vomiting causes missed doses, take the next dose as scheduled the following day.
Oral Mucositis: Use concentrated tinidazole or gallic acid mouthwash, and supplement vitamins.
Doctor-Patient Interaction – Answering Patient Questions
Xiao Han: Regarding adjuvant therapy: For a T2N0 patient with vascular tumor emboli (Stage I), what adjuvant treatment would you recommend?
Prof. Dong Qian: For advanced patients, decisions are usually straightforward. For early-stage patients, whether gastric or bowel cancer, I am very cautious. Especially for mid-to-low rectal cancer, I usually ask them to bring imaging and pathology reports. Through repeated imaging confirmation and pathology slide consultation, we further determine if postoperative adjuvant therapy is needed. Especially for some T3/T4a patients, I ask pathologists to stain elastic fibers to see if the surface elastic fibers are ruptured, using these indicators to comprehensively judge the stage. I also recommend MRD (minimal residual disease) testing. Patient descriptions sometimes deviate from reality, so my diagnosis for these early postoperative patients is very cautious.
Xiao Han: If lymph node metastasis or high-risk factors are found after rectal cancer surgery, is radiotherapy needed? How do you advise these patients?
Prof. Dong Qian: It depends on the location. For mid-to-low T3, MRI is crucial. T3a, b, and c have differences. Assuming high-quality total mesorectal excision (TME) surgery, if the patient can tolerate it, I still recommend radiotherapy. Postoperatively, we usually ask patients to bring surgical records, as intraoperative findings often differ from pathology reports. It must be combined with imaging.
Xiao Han: Dr. Dong shared a lot today. Let's summarize a few key points. First, complete initial tests. Some hospitals have long imaging wait times. If rectal cancer requires an MRI, how long is the wait at your hospital now?
Prof. Dong Qian: For first-time visits, MRI can usually be done within 2-3 days. We prioritize first-diagnosis patients. Liaoning Province now promotes mutual recognition of imaging. At Liaoning Cancer Hospital, we can clearly view scans by scanning a QR code. I ask patients to copy the imaging onto a disc or USB drive and bring a laptop so I can review the frame-by-frame images and give a conclusion as quickly as possible.
Xiao Han: Besides ensuring imaging quality, patients and families must confirm one thing: the doctor actually reviewed the scans. Some medical oncologists don't look at scans and base treatment solely on lab reports, which is not recommended. If you want an accurate assessment at another hospital at key decision points, prepare the imaging to save the oncologist's time.
Xiao Han: For the same stage, are there any special changes in chemotherapy regimens for mucinous adenocarcinoma patients?
Prof. Dong Qian: Mucinous adenocarcinoma can be understood as having a high tendency to shed into the blood or tissue fluid, leading to peritoneal or abdominal cavity implantation. Especially for gastric mucinous adenocarcinoma, PET-CT sometimes has poor sensitivity; imaging may show nothing, but open surgery reveals widespread dissemination. With advances in imaging and MDT, doctors' predictive abilities have improved. These tumors appear relatively low-density and diffuse on imaging, prone to pelvic and peritoneal metastasis. CA19-9 levels might be relatively higher. However, there is no special difference in medication.
Xiao Han: Mucinous adenocarcinoma is a "relative underperformer," but that doesn't mean we stop treating it. Appendiceal mucinous adenocarcinoma typically tends to cause peritoneal metastasis.
Prof. Dong Qian: Many patients are diagnosed with cancer after appendicitis surgery. For subsequent treatment, if open surgery is possible, avoid laparoscopy. I've encountered a few laparoscopic cases where metastasis recurred along the CO2 insufflation path.
Xiao Han: A patient had Stage III colon cancer surgery. Six months later, ovarian metastasis occurred and was removed. The surgeon recommended genetic testing. Is postoperative ovarian metastasis common? Please advise.
Prof. Dong Qian: For such patients, we communicate with surgeons to place an intraperitoneal port (similar to a venous port on the abdominal wall). We administer drugs both intraperitoneally and intravenously, such as oxaliplatin and bevacizumab. If no port is placed, a catheter can be left for intraperitoneal perfusion, as these patients are highly likely to experience recurrence.
Xiao Han: Ovarian metastasis patients usually progress to peritoneal metastasis next. We actually have a small subgroup for this in the Panda patient group.
Prof. Dong Qian: We encountered a rather "extreme" case. A young patient with hepatocellular carcinoma failed systemic therapy after three years. With no more treatment options and two-thirds of the abdominal cavity occupied by the ovaries, surgery was performed despite an albumin level of only 16. This salvage surgery changed our gynecological team's perspective: even if survival time isn't extended, improving quality of life is meaningful.
Xiao Han: Ovarian metastatic lesions often have different genetic profiles compared to the primary tumor. Do you recommend testing the primary or the metastatic site?
Prof. Dong Qian: Our hospital currently charges for one test regardless of multiple lesion samples. Ovarian metastasis is particularly difficult to treat and exhibits significant heterogeneity. Patients can negotiate with the hospital to test as many as possible if feasible.
Xiao Han: For T4N2M1 rectal cancer with liver metastasis, if the liver cannot reach NED status, does removing the primary tumor help overall survival?
Prof. Dong Qian: It may not extend survival, but for obstructive patients, cytoreductive surgery during an appropriate window can significantly improve their living condition. If the intestinal tumor doesn't shrink well later, as a palliative cytoreductive option, a stoma might be better.
Xiao Han: If liver metastasis is inoperable, the main issue likely lies in the liver. If the intestinal lesion isn't severely narrowed, it can be addressed later. Additionally, for colorectal liver metastasis patients with decent baseline health and wild-type genes, conversion therapy should still be pursued.
Prof. Dong Qian: A case presented at a conference this year involved third-line treatment for colorectal liver metastasis, followed by liver transplantation, achieving a PFS of 16.8 months. This over-one-year survival deeply impacted me. It suggests we should strive for cytoreduction in these patients. The liver acts like a sieve, trapping escaped tumors in a fixed location. Does this indicate that colorectal liver metastasis has macroscopically selected specific biological behaviors in patients? This is a new thought for me.
Xiao Han: I attended a colorectal liver metastasis academic conference in Guangzhou. Prof. Adam's liver transplant data drew widespread attention, but selecting beneficiaries amid liver shortage remains under study. First, screening for genetically suitable populations based on drug response is key. Cytoreductive surgery for wild-type colorectal liver metastasis usually has significant value. Tumor biology greatly influences treatment quality.
Xiao Han: Is CTC testing meaningful for rectal cancer?
Prof. Dong Qian: Some hospitals still have the equipment and perform it, but with the development of MRD, the significance of CTC testing is not particularly high.
Xiao Han: We covered a lot today. I recommend many group members watch the replay for the foundational science popularization part.
CTC (Circulating Tumor Cells) refers to tumor cells that detach from the tumor tissue and enter the bloodstream, acting as "seeds" for metastasis. CTC testing is a "liquid biopsy" technique. By analyzing the quantity and characteristics of CTCs in peripheral blood, it can be used for early cancer detection, efficacy monitoring, and prognosis assessment.
Prof. Dong Qian: Every discussion feels highly rewarding. Director Xiao Han's perspective, bridging professional and lay understanding, offers new angles. You've absorbed insights from many experts and integrated your own understanding.
Xiao Han: The Panda Group relies heavily on expert support. Thank you again, Dr. Dong.
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