How to Treat Esophageal Squamous Cell Carcinoma and Anal Squamous Cell Carcinoma? | Panda Patient Education Livestream Replay
In my view, Prof. Lu Zhihao from the Gastrointestinal Medical Oncology Department at Peking University Cancer Hospital is the foremost expert in the medical treatment of esophageal cancer, and he is also highly skilled in the comprehensive management of gastric and colorectal cancers. When my family sought treatment at Peking University Cancer Hospital, we visited Prof. Lu's clinic multiple times. We were drawn not only by his exceptional expertise but also by his deeply compassionate and uplifting bedside manner, which provides immense spiritual strength to patients.
As our Panda community surpasses 50,000 members, we are seeing a growing number of patients with relatively rare gastrointestinal tumors, such as esophageal and anal squamous cell carcinomas. Since our collective knowledge on squamous cell carcinoma treatment is still developing, we invited Prof. Lu to share his expertise and fill this gap.
Topics Covered in the Lecture:
1. What are the differences between squamous cell carcinoma and adenocarcinoma? What are their characteristics?
2. How is esophageal squamous cell carcinoma diagnosed, and what tests are required?
3. What are the treatment options for early-stage esophageal squamous cell carcinoma?
4. Which specialist should perform surgery for advanced esophageal cancer? Can all thoracic surgeons perform esophageal cancer surgery? Any recommendations?
5. What chemotherapy regimens are used for adjuvant therapy in esophageal squamous cell carcinoma?
6. What is the role of radiotherapy in esophageal squamous cell carcinoma?
7. What chemotherapy options are available for advanced esophageal squamous cell carcinoma?
8. What about immunotherapy for esophageal squamous cell carcinoma?
9. Is genetic testing necessary for esophageal squamous cell carcinoma? What targeted therapies are available?
10. Which domestic centers excel in the medical treatment of esophageal squamous cell carcinoma?
11. Can the chemotherapy regimens for advanced anal squamous cell carcinoma be used interchangeably with those for esophageal squamous cell carcinoma?
12. What is the treatment model for non-metastatic anal squamous cell carcinoma? What are the surgical indications?
13. Should anal squamous cell carcinoma undergo large-panel genetic sequencing? What targeted and immunotherapy options exist?
Article Summary | Da Congming, Tiantian
Proofreading | Han Kai
Editor-in-Charge | Xian Ning
[ Conference Date: September 9, 2024 ]
Esophageal Cancer Education
01 Differences in Esophageal Cancer Characteristics Between Western Countries and China
In Western countries, esophageal cancer is predominantly adenocarcinoma (over 70%), mainly occurring in the lower esophagus.
In China, it is predominantly squamous cell carcinoma (over 95%), mainly occurring in the middle thoracic esophagus, with most cases presenting at a locally advanced stage.
02 Clinical Manifestations of Esophageal Cancer
Early Symptoms:
Physical sensations are often subtle and easily overlooked, but may include "three sensations and one pain".
Three sensations: choking sensation when swallowing, feeling of food stagnation, and foreign body sensation in the esophagus.
One pain: burning, needle-like, or pulling/friction pain behind the sternum.
Advanced Stage Symptoms:
1. Progressive dysphagia (most typical);
2. Frequent expectoration of mucus-like sputum;
3. Gradual weight loss, dehydration, and weakness.
Late Stage Symptoms:
1. Cachexia: weight loss, hypoproteinemia, anemia, electrolyte imbalance;
2. Widespread systemic metastasis: abnormal liver function, jaundice, ascites, headaches, etc.
03 Hazards of Esophageal Cancer
1. Inability to eat leads to continuous weight loss, malnutrition, and anemia;
2. Causes persistent chest and back discomfort or pain, severely impacting quality of life;
3. In advanced stages, it may cause esophageal bleeding or perforation; massive hematemesis can be life-threatening.
04 Factors That May Lead to Esophageal Cancer
1. Unhealthy lifestyle habits
2. Excessive intake of nitrosamines
3. Fungal infections
4. Viral infections
5. Deficiency of certain trace elements
6. Vitamin deficiency
7. Long-term psychological stress and depression
8. Immunodeficiency and long-term use of immunosuppressants
05 Who Should Be Cautious?
Adults aged 40-45 and above.
Long-term smokers and drinkers, those who frequently consume very hot drinks/food or hard/rough foods, individuals with long-term exposure to carcinogens, patients with esophageal precancerous lesions, those with insufficient fruit and vegetable intake, and families in high-incidence areas.
06 How Esophageal Cancer is Diagnosed
Gastroscopy (Endoscopic Ultrasound): Direct visualization, allows biopsy (pathology is the gold standard), high detection rate for early cancer.
CT Scan: Assesses depth of invasion, lymph node metastasis, surgical feasibility, and treatment efficacy.
PET-CT: Detects distant metastases outside the chest. Differentiates between uncontrolled tumor, recurrence, and scar tissue after chemoradiotherapy.
Ultrasound: Observes abdominal organs and lymph node metastasis in the abdomen and neck.
MRI: Evaluates local conditions and treatment efficacy.
07 Endoscopic Treatment for Early Esophageal Cancer
Follow-up endoscopies are recommended at 3, 6, and 12 months post-resection. If no recurrence is found, annual follow-ups are advised, combined with relevant imaging and tumor markers.
08 Key Considerations for Resectable Advanced Esophageal Cancer
Resectable advanced esophageal cancer: Surgery is the first choice.
1. Tumors <3 cm in the cervical segment, <5 cm in the upper thoracic segment, and <7 cm in the lower thoracic segment have a higher chance of successful resection;
2. The resection margin should be 5-8 cm away from the tumor;
3. Concurrent chemoradiotherapy is preferred for cervical esophageal cancer;
4. At least 15 lymph nodes should be dissected, with two-field or three-field lymphadenectomy.
09 Key Considerations for Unresectable Locally Advanced Esophageal Cancer
Unresectable locally advanced esophageal cancer is primarily treated with radiotherapy (definitive concurrent chemoradiotherapy or chemotherapy followed by radiotherapy).
Radiotherapy effectively alleviates clinical symptoms, reduces bleeding, relieves pain and dysphagia, and improves quality of life, with an efficacy rate of 60-70%.
10 Treatment for Advanced Esophageal Cancer
First-line treatment for advanced esophageal squamous cell carcinoma was historically chemotherapy-based, with immunotherapy mainly used in second-line or later settings before 2020.
Since 2020, numerous first-line studies have been published.
Chemotherapy drugs include: Paclitaxel, cisplatin, fluorouracil, docetaxel, irinotecan, etc.
Targeted therapy: Cetuximab, nimotuzumab, apatinib, anlotinib, afatinib, etc.
Immunotherapy: Pembrolizumab (K drug), nivolumab (O drug), camrelizumab, tislelizumab, sintilimab, toripalimab, etc.
11 Symptoms and Management of Complications
1. Perforation: Chest pain, cough, fever, etc. Progressively worsening severe retrosternal or back pain is the main sign of perforation. Treatment: Early closure of the fistula, fasting, infection control, acid suppression, and adequate nutritional support.
2. Bleeding: Small, chronic bleeding is often asymptomatic. Acute massive bleeding presents with hematemesis, dizziness, palpitations, cold sweats, fatigue, dry mouth, and syncope. Treatment: Conservative management under close observation (hemostasis + blood transfusion); surgery if conservative treatment fails.
12 Targeted Therapy for Esophageal Cancer
Nimotuzumab combined with first-line chemotherapy has a response rate of 50-60% and is currently in Phase III trials;
Cetuximab combined with first-line chemotherapy has a response rate of 40-60%, with Phase II trials completed;
Apatinib/Anlotinib: Second-line monotherapy response rate is 8-28%, with risks of bleeding and perforation;
Afatinib: After screening at Peking University Cancer Hospital, second/third-line monotherapy response rate reaches 40%.
13 Immunotherapy for Esophageal Cancer
14 Precision Medicine for Esophageal Cancer
1. Confirm diagnosis with stained slides; use unstained slides for immunohistochemistry and genetic testing (4-6μm, 10-20 slides)
2. EGFR immunohistochemistry
3. HER2 immunohistochemistry
4. PD-L1 immunohistochemistry
5. NGS genetic testing
15 Future Directions for Esophageal Cancer
Ongoing Clinical Trials at Peking University Cancer Hospital:
Perioperative: Nimotuzumab + immunotherapy + chemotherapy
First-line trials: Pembrolizumab + chemotherapy + lenvatinib; immunotherapy + chemotherapy + radiotherapy
Second-line trials: EGFR-HER3-ADC, B7H3-ADC, immunotherapy + apatinib + chidamide, CDK inhibitor + pyrotinib, etc.
Post-second-line: Esophageal cancer mRNA therapeutic vaccines, CAR-T, PRMT5 inhibitors, etc.
16 Esophageal Cancer Q&A
Xiao Han: Is it meaningful to take afatinib for EGFR 3+ in gastric cancer? Should genetic testing be done to check for EGFR amplification?
Prof. Lu Zhihao: The correlation between EGFR immunohistochemistry in gastric adenocarcinoma and afatinib efficacy is not very strong. We do not routinely recommend taking it just for EGFR 3+, but if there is gene amplification, it can be tried. There have been similar cases where afatinib showed excellent efficacy.
Xiao Han: If there is EGFR amplification, would afatinib work better compared to cetuximab or nimotuzumab?
Prof. Lu Zhihao: Yes, afatinib alone is sufficient. However, cetuximab and nimotuzumab require combination with chemotherapy. As monoclonal antibodies, their efficacy as monotherapy is relatively weaker compared to small-molecule drugs.
Xiao Han: From experience, how do they compare in terms of PFS (progression-free survival)?
Prof. Lu Zhihao: Previous research on cetuximab plus chemotherapy showed that with EGFR amplification, survival can exceed 17 months, which is similar to chemotherapy plus immunotherapy. If amplified, chemotherapy plus cetuximab plus immunotherapy yields even better results.
Xiao Han: I've heard that with EGFR amplification, immunotherapy might cause hyperprogression.
Prof. Lu Zhihao: Hyperprogression markers exist in lung cancer data. In gastric and esophageal cancers, using immunotherapy alone for EGFR amplification shows poor results, slightly better than chemotherapy alone but with minimal benefit, and worse than in non-amplified cases. Adding cetuximab or nimotuzumab at this point may yield very good results.
Xiao Han: For a patient post-ESD for esophageal cancer with pathology showing submucosal invasion of 200 microns and negative margins, is further treatment needed?
Prof. Lu Zhihao: In such cases, adjuvant radiotherapy might be considered. Precise evaluation and multidisciplinary consultation are required, taking into account overall physical condition and age.
Xiao Han: After radiotherapy for esophageal squamous cell carcinoma, some patients develop strictures causing choking when eating. How should this be managed?
Prof. Lu Zhihao: There are two scenarios: one is post-radiotherapy edema. If strictures persist long after radiotherapy, it may be due to a scar-prone constitution, making treatment challenging. If radiotherapy was recent, dilation can be attempted, but local handling must be very careful as the esophagus becomes fragile and inelastic, prone to tearing (balloon dilation carries risks). Dilation is generally not recommended immediately post-radiotherapy. If enough time has passed and elasticity recovers, it can be attempted. If severely impacting life, a feeding tube or gastrostomy can be placed to maintain nutrition.
Xiao Han: A patient with locally advanced disease plans surgery. Since esophageal surgery is major and post-op recovery is tougher than for colorectal cancer, with poor tolerance for post-op chemo, is it better to prioritize neoadjuvant chemoradiotherapy?
Prof. Lu Zhihao: Neoadjuvant therapy before esophageal surgery is currently standard. Previously, after concurrent chemoradiotherapy, surgery was performed without further treatment. Now, if complete pathological response isn't achieved post-surgery, adjuvant immunotherapy is used, which is highly endorsed internationally. In China, we often prefer neoadjuvant chemotherapy plus immunotherapy first, as it shows excellent tumor shrinkage and better control of distant metastases. Surgeons also prefer it as it doesn't increase surgical difficulty like radiotherapy does. Typically, 2-3 cycles are given pre-op, with a total of 4 perioperative cycles. If only 2 are given pre-op, 2 more are given post-op. If recovery is poor, single-agent immunotherapy is maintained for one year.
Xiao Han: If neoadjuvant therapy works well but doesn't achieve pCR, what should be done post-op?
Prof. Lu Zhihao: Standard clinical practice is to maintain immunotherapy for one year.
Xiao Han: A special case: liver transplant 5 years ago, diagnosed with MSI-H gastric cancer last year, used O drug for 14 months. Recently experiencing pyloric bleeding. Local doctors deem surgery high-risk and suggest conservative treatment, switching to cadonilimab. Is switching appropriate?
Prof. Lu Zhihao: Is the tumor growing? Is the bleeding due to progression? If progressing, cadonilimab must be used cautiously due to high post-liver transplant risks. If the tumor is progressing, surgical resection remains the best option.
Xiao Han: A 54-year-old esophageal cancer patient received 3 cycles of neoadjuvant chemo-immunotherapy, 22 fractions of half-dose radiotherapy, and underwent radical surgery. Post-op pathology is Tis. Now 45 days post-op with poor recovery. Is single-agent immunotherapy for one year recommended?
Prof. Lu Zhihao: Yes, single-agent immunotherapy for one year is recommended. No further chemotherapy is needed.
Anal Cancer Education
Anal cancer is relatively rare, accounting for 3-3.5% of rectal and anal cancers. It is more common in women and middle-aged/elderly individuals, though there is a trend toward younger onset.
The main symptom is anal pain, especially pronounced after bowel movements, which may be accompanied by anal itching with a foul odor, hematochezia, etc.
01 Risk Factors for Anal Cancer
Primarily viral infections such as HPV (especially HPV16 and HPV18). Other factors include immunosuppression, unsafe sexual practices, and smoking.
02 Diagnostic Principles for Anal Cancer
03 Staging of Anal Cancer
It is crucial to note that the TN staging for anal cancer differs from colorectal cancer. For anal cancer, tumor size determines the T stage. Inguinal, internal iliac, external iliac, and mesorectal lymph nodes are all considered regional lymph nodes for anal cancer.
Tx: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ, Bowen's disease, high-grade squamous intraepithelial lesion (HSIL), anal intraepithelial neoplasia II-III (AIN II-III)
T1: Tumor maximum diameter ≤2 cm
T2: Tumor maximum diameter >2 cm, ≤5 cm
T3: Tumor maximum diameter >5 cm
T4: Tumor invades adjacent organs, such as vagina, urethra, or bladder
Note: Direct invasion of the rectal wall, perianal skin, subcutaneous tissue, or sphincter is not classified as T4.
Regional Lymph Nodes (N)
Nx: Regional lymph node metastasis cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis present
N1a: Metastasis to inguinal, mesorectal, and/or internal iliac lymph nodes
N1b: Metastasis to external iliac lymph nodes
N1c: Metastasis to external iliac lymph nodes and any N1a lymph nodes
04 Treatment Principles for Anal Cancer
05 Surgical Principles for Anal Cancer
06 Chemotherapy Drugs for Anal Cancer
In the figure above:
Carboplatin, paclitaxel, Folfcis (fluorouracil + leucovorin + cisplatin), docetaxel, DCF (docetaxel + cisplatin + fluorouracil).
According to the 2024 NCCN guidelines:
The preferred regimen is carboplatin combined with paclitaxel; other options include Folfcis, mFolfox6, 5FU+DDP, DCF, etc.
END
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