Precision Diagnosis of Colorectal Cancer and Refractory Colorectal Cancer | SYSUCC Prof. Ding Peirong & Prof. Han Kai | Panda Patient Education Live Replay
On December 9, 2024, we invited Prof. Ding Peirong and Prof. Han Kai from the Colorectal Department of Sun Yat-sen University Cancer Center to discuss the precision diagnosis and treatment of refractory colorectal cancer.
The discussion highlighted that colonoscopy with pathological biopsy is the gold standard for diagnosing colorectal cancer. Genetic testing can more accurately determine precise tumor subtypes, providing a basis for subsequent treatment, while also emphasizing the importance of early detection and effective treatment.
Prof. Han first shared insights on "early symptoms and diagnostic methods for bowel cancer," while Prof. Ding shared valuable clinical experience summarized from colorectal cancer treatment.
During the discussion, both professors shared their expertise in precision diagnosis and provided high-quality answers to representative questions from Panda support group members during the Q&A session.
Article Summary | Wang Yaoyao
Article Proofreading | Xiao He
Responsible Editor | Xian Ning
[ Conference Date: December 9, 2024 ]
Participants:
Prof. Ding Peirong
Director, Colorectal Department, Sun Yat-sen University Cancer Center
Prof. Han Kai
Associate Chief Physician, Colorectal Department, Sun Yat-sen University Cancer Center
Mr. Han Kai
Founder, Panda & Friends Patient Support Organization
Summary:
PART 1 Early Symptoms and Diagnostic Methods for Bowel Cancer | Han Kai
PART 2 Q&A on Refractory Colorectal Cancer | Ding Peirong
The following transcript uses the abbreviations: Xiao Han, Prof. Han, and Prof. Ding.
Xiao Han: High-quality examinations are the foundation of high-quality treatment. Confirming the subtype of colorectal cancer is crucial at the initial visit. Let's first invite Prof. Han to explain the precision diagnosis of colorectal cancer to our Panda group members.
Prof. Han's Sharing Section
01 Early Symptoms and Diagnostic Methods for Bowel Cancer
Patients with early-stage bowel cancer usually have no obvious symptoms. As the tumor grows, symptoms like black stools or abdominal pain may appear.
Right-sided colon tumors typically only cause symptoms when they are relatively large, mainly presenting as black stools, abdominal pain, anemia, or palpable masses. Early right-sided colon tumors are mostly discovered during routine check-ups.
Left-sided colon tumors typically present with pus and blood in the stool, abdominal pain, mucus in the stool, and a feeling of incomplete evacuation.
The reason right-sided colon tumors need to be larger to cause symptoms relates to intestinal physiology. The right colon is wider, and the stool here is mostly liquid from the small intestine. This liquid passes through a spacious area, so even a small tumor won't cause obvious symptoms. Symptoms usually only appear when the tumor grows large enough to cause partial obstruction.
In contrast, the left colon has a narrower lumen, so partial obstruction can occur even before the tumor becomes very large.
Pathological biopsy is required to confirm colorectal cancer, making it the most accurate diagnostic method. Pathological subtyping significantly impacts treatment plans, as different tumor types may require completely different approaches. Patients should be aware of early symptoms. (It is recommended that all patients undergo MSI/MMR testing upon initial diagnosis to determine if immunotherapy is needed and to preliminarily assess hereditary risks like Lynch syndrome based on MMR/MSI status.)
02 How to Choose Between Colonoscopy, CT, and MRI?
Diagnosing colorectal cancer requires a pathological biopsy, usually performed via colonoscopy. Most modern colonoscopies are done under sedation, so patients experience minimal pain.
For colorectal cancer detection, CT and MRI each have pros and cons, and the choice depends on tumor location and condition. Due to frequent peristalsis, the colon is primarily examined with CT, while MRI is used to confirm tumors in the rectum and pelvic sigmoid colon.
03 What Further Tests Are Needed After a Colorectal Cancer Diagnosis?
For all newly diagnosed colorectal cancers, MSI (Microsatellite Instability) or MMR (Mismatch Repair) testing is recommended. MMR testing primarily uses IHC (Immunohistochemistry), while MSI testing includes PCR and NGS (Next-Generation Sequencing).
For more advanced cases, testing for RAS/RAF genes, including HER2 amplification, is needed to explore more treatment options and targets, such as NTRK or RET fusion positivity. These genetic statuses correspond to different systemic treatment plans.
Large-panel NGS (covering over 300 genes) can identify rare fusion genes or mutations with corresponding targeted therapies. Its tumor mutational burden (TMB) assessment can also provide clear evidence for immunotherapy in patients with pathogenic POLE/POLD1 mutations. When financially feasible, we highly recommend large-panel NGS for advanced patients.
In summary, in-depth molecular testing is key to precision diagnosis, and patients with MSI-H/dMMR subtypes may respond better to immunotherapy.
Prof. Han's Discussion Section
Xiao Han: For advanced MSI-H bowel cancer, dual immunotherapy as first-line treatment is already a consensus. However, for patients with locally advanced T4 colorectal cancer, should we use dual or single immunotherapy in clinical practice?
Prof. Han: Based on current experience, for locally advanced (T4a/T4b) patients with MSI-H/dMMR subtypes, PD-1 monotherapy generally yields good results. However, if tumor shrinkage is inadequate after four or eight cycles of monotherapy, we recommend considering dual immunotherapy combined with a CTLA-4 antibody, or combining it with a small-molecule TKI drug (e.g., fruquintinib, regorafenib). Considering cost, potential side effects, actual efficacy, and other factors, along with biotherapy department experience, we generally recommend follow-up imaging after 3 cycles of dual immunotherapy.
Xiao Han: For patients who have achieved CCR (Clinical Complete Response) or pCR (Pathological Complete Response), have any relapses been observed so far?
Prof. Han: No relapses have been observed. However, some Lynch syndrome patients may develop second primary tumors. We currently lack data on this specific subgroup.
Prof. Ding's Discussion Section
Xiao Han: Prof. Ding, your Tuesday clinic is currently suspended. When will it resume?
Prof. Ding: I currently have some administrative duties. Once these institutional arrangements are finalized, I will gradually resume the Tuesday clinic, increase appointment slots, and reduce the difficulty for patients to register.
Xiao Han: This year, we launched the Refractory Bowel Cancer Academy. Today, we'd like Prof. Ding to explain key considerations in bowel cancer treatment. What is refractory bowel cancer?
Prof. Ding: One type refers to cases beyond standard treatment protocols; another involves patients who, due to personal needs, are unwilling to follow conventional standard treatments. In English, it is precisely termed "Refractory Colorectal Cancer," referring to patients who have failed first, second, and third-line treatments for metastatic colorectal cancer. Launching the "Refractory Bowel Cancer Academy" aims to further identify and screen these patients, often relegated to "palliative care," to secure more opportunities for them. Currently, we are exploring curative opportunities for these patients through more detailed molecular subtyping, metastasis sites, and rare targets.
Xiao Han: Currently, the Panda group has several subgroups categorized by different metastasis sites and molecular subtypes.
Prof. Ding: This approach is highly forward-looking. In the traditional chemotherapy era, differences between metastasis sites were not as pronounced as they are in the current targeted and immunotherapy era. For immunotherapy, especially in colorectal liver metastases, immunotherapy for MSS (Microsatellite Stable) types is largely ineffective. However, we have extensive experience with extrahepatic metastases. After conventional chemotherapy and targeted therapy fail, using targeted-immunotherapy combinations, dual-target plus immunotherapy, or even adding low-dose chemotherapy can yield relatively high response rates. Moreover, once controlled, the duration of control is quite long, with some patients achieving long-term NED (No Evidence of Disease). Therefore, I believe further patient stratification is highly meaningful.
NED: No Evidence of Disease, generally referring to initially unresectable or advanced bowel cancer patients who, after conversion therapy and radical surgery, show no detectable tumors on imaging or endoscopy. Achieving NED is key to long-term survival for advanced patients.
Xiao Han: Immunotherapy has matured significantly this year. Which MSS patients do you think might benefit from it?
Prof. Ding: First, regarding metastasis sites, extrahepatic metastases like lung metastases, and some peritoneal metastases, show decent response rates. Second, based on genetic subtyping (dMMR/MSI-H, pathogenic POLE/POLD1 variants, ARID1A mutations). Third, looking at TMB levels. Besides TMB-H, we further screen about 10% of TMB-L patients who fall into the TMB-Median range (around 7, 8, or 9). If these patients also have the extrahepatic metastasis features mentioned earlier, their chances of benefiting from immunotherapy are higher. Additionally, colorectal cancer typically doesn't use the CPS indicator, but in special cases—such as standard treatment failure with extrahepatic metastasis and high CPS, or MSS/MSI-L with BRAF V600E mutation but high CPS—we may add a PD-1 antibody to the standard BRAF inhibitor (e.g., encorafenib) plus EGFR inhibitor (e.g., cetuximab) and chemotherapy (e.g., FOLFOX, FOLFIRI). We've also found that certain imaging features are indicative. If the primary tumor is particularly large, the likelihood of benefiting from immunotherapy is higher. Among about 200 T4b large tumors, postoperative analysis showed roughly half were MSI-H, offering these patients a chance to benefit from immunotherapy. If a large tumor tests negative for MSI-H/dMMR, it is highly likely to be caused by a pathogenic POLE/POLD1 variant. An MSS tumor that appears large and expansively growing on imaging may also benefit from immunotherapy. We should gradually shift away from the mindset of immediately removing large tumors. Recently, using AI to read immune microenvironment features from HE-stained slides to predict immunotherapy efficacy has also shown progress.
ARID1A Mutation: ARID1A mutations are associated with increased immunogenicity in colorectal cancer, especially in microsatellite stable (MSS) tumors. These mutations lead to higher tumor mutational burden and increased expression of immune checkpoint molecules (like PD-L1, CTLA4, and PDCD1). This immunogenic profile is characterized by enhanced infiltration of cytotoxic T lymphocytes and other immune cells, which are crucial for PD-1 inhibitor efficacy. In MSS colorectal cancer patients, ARID1A mutations correlate with a more active immune microenvironment, making these tumors more susceptible to immune checkpoint blockade therapy. ARID1A-mutated tumors exhibit higher levels of neoantigens and immune-related gene expression, predicting their response to PD-1-based immunotherapy. [1],[2]
Xiao Han: For refractory bowel cancer with multi-organ metastasis detected at initial diagnosis, what should generally be noted? How should comprehensive pre-treatment assessment and decision-making be conducted?
Prof. Ding: First and second-line treatments should follow guideline-standardized protocols. Only in special cases, such as MSS/MSI-L with BRAF V600E mutation, do guidelines recommend first-line triple therapy (mFOLFOXIRI) plus bevacizumab. However, among young bowel cancer patients in our country, the proportion of BRAF V600E mutations is relatively high, and their condition differs from older patients. For young BRAF V600E-positive patients, I lean more toward the BREAKWATER study regimen: doublet mFOLFOX combined with anti-BRAF and anti-EGFR, which has shown good disease control rates in my practice. A comprehensive assessment must consider age, molecular subtype, tumor microenvironment, severity of metastases, treatment tolerance, and primary tumor status. We often encounter advanced patients with insufficient initial assessments, such as those who only had a 30-40 gene NGS at diagnosis. While this may not greatly impact first-line treatment, it leaves subsequent decisions on aggressive therapies after progression inadequately informed. We sometimes see patients who undergo multiple cytoreductive surgeries for peritoneal metastasis, only to develop new lesions 2-3 months post-op. Following conventional logic, they would enter third-line treatment and try various options. We must remind patients to ensure their initial assessment is thorough. Many visiting my clinic are advised to undergo more detailed testing, like large-panel NGS, which can identify rare targets and TMB information. This is crucial, as 5-10% of MSS patients have TMB levels near 10, and ARID1A mutations occur in 3-5%, collectively enabling better decision-making. I've treated patients who underwent multiple peritoneal cytoreductive surgeries at major hospitals, only to have new abdominal lesions recur. When asked if another surgery was possible, I suspected insufficient initial assessment despite excellent surgeons. A new large-panel NGS revealed a TMB of 200, indicating a POLE pathogenic mutation-driven bowel cancer, completely changing the treatment landscape (immunotherapy became an option). This patient has been disease-free for three years, which is not uncommon. For refractory bowel cancer, patients should not lose hope due to initial disease status or numerous metastases. The initial biological behavior often presents as widespread metastasis. However, what's more important is whether certain drugs can reverse or alter this biological behavior and control it. If suitable drugs can control it, the original biological behavior becomes secondary.
Xiao Han: For some heavier patients, immunotherapy drugs might not fully match the required dosage. Would reducing the dose affect treatment?
Prof. Ding: I don't think the impact would be significant. Based on past experience, some patients who reduced drug dosages due to financial burdens still achieved remarkable treatment outcomes. When objective conditions are limited, compromises can be made. If you find a large tumor and genetic testing shows it's not MSI-H/dMMR, the second possibility is a POLE/POLD1 mutation. Especially for large tumors with local leakage, abdominal wall penetration, or infection, one should consider that some surgeons without systematic training might immediately opt for resection. Patients should ask more questions, such as whether genetic testing is needed, and consult other patients. Second opinions are popular abroad, and I see this trend gradually emerging domestically.
Xiao Han: Which groups have a higher risk of primary resistance to immunotherapy? For example, those with peritoneal metastasis, liver metastasis, high tumor burden, or late-stage disease?
Prof. Ding: Multiple studies indicate that liver and peritoneal metastases (especially with malignant ascites), mucinous adenocarcinoma, and signet ring cell carcinoma have molecular characteristics that impair effector T-cell function, carrying a higher risk of primary resistance to immunotherapy, especially monotherapy. Low TMB levels [3], MSI/MMR discordance, multi-organ metastasis, and the patient's inflammatory state also increase resistance risk. Dual immunotherapy can somewhat reverse primary resistance. The inflammatory state is particularly important. Inflammatory cells secrete numerous adverse cytokines that prevent immune cells capable of killing tumor cells from infiltrating. [4]
MSI and MMR Discordance: Biologically, dMMR and MSI-H should co-occur, as should pMMR and MSS/MSI-L. Discordance refers to cases like dMMR but MSS, or pMMR but MSI-H.
Xiao Han: Some patients mention poor treatment outcomes for mucinous adenocarcinoma. What are your treatment strategies for this tumor type?
Prof. Ding: First, we must consider the tumor's molecular subtype. For MSI-H mucinous adenocarcinoma patients where immunotherapy or chemotherapy is ineffective, if cytoreductive surgery is feasible, patients are likely to benefit, and our experience shows most have a decent prognosis. For MSS mucinous adenocarcinoma patients progressing on conventional chemo/targeted therapy, we cannot yet conclude they will benefit from surgery. However, if the PCI index is low (e.g., below 15, or 10-15), we will thoroughly discuss it in an MDT meeting. Surgery can be considered, though benefits vary significantly among patients.
Xiao Han: The significance of the Refractory Bowel Cancer Academy is twofold: sharing successful cases and encouraging more practitioners to proactively manage challenging patients, thereby advancing the entire field.
Prof. Ding: In the new normal, many municipal hospitals can handle routine surgeries, so our frontline teams encounter more refractory bowel cancer patients. We need to focus more on complex surgeries and managing subsequent complications. The academy's original intention is to make colleagues aware of this, encouraging them to actively manage refractory cases, especially sharing rare experiences like brain or bone metastases, which is invaluable.
Xiao Han: Some of our MSI-H patients tested positive for MRD (Minimal Residual Disease) post-surgery. How should this be handled?
Prof. Ding: That's an excellent question. Based on our team's experience, many stage II MSI-H patients with positive MRD, or even consecutive positives during follow-up, are likely false positives upon further testing and long-term monitoring. Regarding metastasis sites, lung and peritoneal metastases have a higher probability of false-negative MRD results (the peritoneal blood barrier may be one reason), which requires vigilance.
Xiao Han: Are there any recent updates on the Lynch syndrome vaccine?
Prof. Ding: A Phase I trial in 2019 showed promising results, but there's no latest news yet. Some newer teams are also developing this vaccine. With mRNA technology, vaccine development cycles have shortened significantly, allowing newer teams to potentially catch up quickly.
Xiao Han: Should dMMR patients with T4bN0M0 (high-risk stage II) choose chemotherapy or immunotherapy post-surgery?
Prof. Ding: We currently have a Phase II clinical trial on two cycles of adjuvant immunotherapy for high-risk stage II patients. Choosing two cycles is based on prior experience and European trials. For these patients, standard treatment is chemotherapy. Without neoadjuvant therapy, direct surgery carries a 20-30% recurrence risk. Direct immunotherapy is more suitable for patients eager to try it actively, though more data is still needed.
Xiao Han: An FAP group admin asks: Are you conducting experiments using ki67 and p53 immunohistochemistry on adenomas to observe the carcinogenesis process?
Prof. Ding: FAP is currently a major concern for patients. We do have such plans and are exploring surgical and adjuvant treatment methods, with clinical trials under application. We feel a greater pressure and responsibility to address this. Prof. Han can share more.
Prof. Han: Traditionally, FAP patients have loss-of-function APC gene mutations, which trigger familial adenomatous polyposis. Research found that APC gene truncations can act as functional oncogenes, driving disease progression via oxidative phosphorylation. At the cellular level, inhibitors like metformin have been shown to suppress APC-driven adenoma-to-carcinoma progression, but human trials are pending, remaining at the research data stage. For preventing polyp malignant transformation in pMMR tumors, agents like sulindac or aspirin are mostly recommended, though efficacy remains inconclusive.
Xiao Han: For FAP patients, total colectomy is like amputation because it causes secondary issues.
Prof. Ding: The overall prognosis for FAP patients is decent. The biggest challenge isn't metastasis, but subsequent complications and duodenal tumors, which are also troublesome. Additionally, FAP patients often face financial strain due to their condition, so the economic toxicity of new drugs must be considered.
Xiao Han: We have a Lynch group member whose tumor relapsed due to progestin. For young female patients who achieve CCR after immunotherapy, how soon can they consider pregnancy?
Prof. Ding: From a treatment impact perspective alone, if they haven't undergone radiotherapy or chemotherapy, I generally recommend waiting about a year on average. A significant impact comes from immunotherapy-induced hormonal changes, such as thyroid or adrenal cortical function alterations, which can affect pregnancy. Thyroid function, in particular, greatly impacts fetal neurological development. Based on individual cases, the overall impact on fertility is relatively small. For some Lynch/MSI-H patients with multi-organ metastases including reproductive organs, long-term prognosis varies individually.
Xiao Han: For Lynch syndrome patients, is immunotherapy effective for ureteral involvement?
Prof. Ding: Overall, urothelial tissues respond well to immunotherapy, so ureters and bladders generally show good responses. Conventional chemoradiotherapy shrinks tumors from the inside out, whereas immunotherapy shrinks them from the outside in. Given enough time, complete tumor regression is entirely possible.
Xiao Han: Some group members want to know about first-line treatment for advanced HER2-amplified bowel cancer at your center. What is the regimen?
Prof. Ding: Dual-target therapy alone (e.g., trastuzumab plus pertuzumab) is insufficient. Dual-target plus chemotherapy is our standard approach. However, because the tumor immune microenvironment in HER2 bowel cancer is relatively poor, adding immunotherapy to dual-target plus chemotherapy isn't very effective. If TMB is high, I lean toward immunotherapy. Whether to use anti-HER2 dual-target plus doublet chemotherapy in the first line depends on specific conditions. For high tumor burden, I prefer this aggressive approach; for lower burden, I might not. The risk of recurrence in HER2 lung or peritoneal metastases remains high. Through our team's sequential cytoreductive surgeries, we've found some patients achieve better prognoses and potentially longer survival.
Xiao Han: For MSS/MSI-L patients with BRAF V600E mutation presenting with peritoneal metastasis at diagnosis, what is your first-line treatment?
Prof. Ding: Two chemotherapy drugs plus dual-target therapy can achieve nearly a 95% disease control rate (DCR) in first-line treatment. Even if obstruction occurs, we can relieve it through certain interventions and proceed with subsequent treatment once the patient's condition improves. We have treated many such BRAF mutation patients and have considerable experience.
Xiao Han: For some stage III bowel cancer patients with MSS/MSI-L and BRAF V600E mutation, the prognosis and recurrence risk are very high. Do you think targeted therapy could be moved forward to preoperative adjuvant treatment?
Prof. Ding: Some centers in Japan are doing this, and I believe it's entirely reasonable. It can salvage some patients, improving efficacy by about 10-20% compared to traditional doublet chemotherapy.
References:
1. Mehrvarz Sarshekeh A, Alshenaifi J, Roszik J, et al. ARID1A Mutation May Define an Immunologically Active Subgroup in Patients with Microsatellite Stable Colorectal Cancer. Clin Cancer Res. 2021;27(6):1663-1670. doi:10.1158/1078-0432.CCR-20-2404
2. Tokunaga R, Xiu J, Goldberg RM, et al. The impact of ARID1A mutation on molecular characteristics in colorectal cancer. Eur J Cancer. 2020;140:119-129. doi:10.1016/j.ejca.2020.09.006
3. Schrock AB, Ouyang C, Sandhu J, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019;30(7):1096-1103. doi:10.1093/annonc/mdz134
4. Sui Q, Zhang X, Chen C, et al. Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer. Nat Commun. 2022;13(1):7316. Published 2022 Nov 28. doi:10.1038/s41467-022-35096-6
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