With the application and promotion of cervical cancer screening technology, the diagnosis and treatment of precancerous lesions and early-stage cervical cancer have significantly reduced the mortality rate of cervical cancer, but advanced cervical cancer still accounts for a large proportion of cases in developing countries. However, advanced cervical cancer still accounts for a large proportion of cervical cancer in developing countries. The difficulty of treating advanced cervical cancer often leads to local uncontrolled cancer or recurrence, which still has a high mortality rate and should be taken seriously.
Late stage cervical cancer and recurrent cervical cancer are the main reasons affecting 5-year survival rate recurrence mortality.
The 5-year survival rate: 30%-50% for stage III and 5%-15% for stage IV (2004, Downs). 11,150 new cases of cervical cancer and 3670 deaths in the United States in 2007; recurrence rate after treatment for cervical invasive cancer: 35% (2002, Disaia et al.).
I. General concept
Recurrent cancer: refers to the recurrence of cancer tumor after radical treatment. The cancer tumor reappears in the original treatment area, and its pathological type is the same as the original cancer tumor.
According to recurrence site
1.Pelvic recurrent cancer: central recurrent cancer (vagina, cervix, bladder, rectum); pelvic sidewall recurrence (pelvic side, pelvic floor, lymph).
2.Distant recurrence of cancer: lung, bone, etc., abdominal para-aortic lymph nodes (recurrence of cervical cancer generally refers to pelvic recurrence).
Recurrence after surgery: recurrence after radical cervical cancer surgery means no residual cancer foci after surgery, and recurrence is when cancer foci appear 1 year after surgery, 25% of which are located in the upper vaginal segment or stump); recurrence within 1 year is uncontrolled. Recurrence after radiotherapy: It refers to the recurrence of primary invasive cancer foci in the cervix, vagina and parametrium that disappeared after radical radiotherapy and reappeared six months later. If the primary tumor or site still persists or new lesions appear within 3 months after the end of radiotherapy, it is uncontrolled after radiotherapy.
The recurrence sites after radiotherapy are mostly found in the upper part of the cervix, uterine body or vagina (about 27%), parametrium (43%), distant metastasis 16%, and the middle and lower part of the vagina 6%.
Clinical manifestations and signs
It depends on the site of uncontrolled or recurrent cancer, the size of the cancer foci and the extent and degree of involvement of surrounding tissues. Early stage may be asymptomatic (10%-20%). Symptoms: vaginal water or bleeding (central recurrence is common); pain, lower abdomen or leg and hip, lower limbs (pelvic side recurrence or metastasis, bone metastasis is common about 80%).
Other: lung and brain metastases, corresponding signs and symptoms of advanced peripheral organ involvement. Symptoms and signs of urological and digestive system involvement, retroperitoneal lymph node metastasis and recurrence are often without any symptoms and signs.
Auxiliary examinations and diagnosis
(A) Auxiliary tests
1.Serum marker test
Serological markers mainly used for cervical cancer surveillance and their detection: including squamous cell carcinoma antigen (SCC), tissue peptide antigen (TPA), other CA125, CEA, CyFR21-1.
(1) SCC-Ag is one of the 14 subcomponents of tumor antigen TA-4 isolated from cervical squamous cell carcinoma and is found in high concentration in the cytoplasm of cancer cells. Serum levels are mostly in the normal range, and SCC levels released into and out of serum levels are not related to local conditions (57%-65% of patients with primary squamous cervical cancer have ↑ serum levels). SCC-Ag is also elevated in patients with squamous carcinomas (head and neck, esophagus, lung, vulva, uterus, vagina and lung adenocarcinoma), skin diseases, eczema and psoriasis.
SCC correlated with squamous carcinoma differentiation, with a positive rate of 78% for highly differentiated SCC, 67% for moderately differentiated, and 38% for poorly differentiated.
SCC levels: pre-treatment correlated with stage, tumor size, depth of cervical infiltration, vascular involvement, and lymphatic metastasis (controversial as to whether this is an independent prognostic factor).
Postoperative dynamic monitoring of SCC-positive patients: the rate of agreement with the patient’s condition and disease course is 72%, and it decreases normally after effective treatment; if it increases, the survival rate is lower and treatment (or postoperative adjuvant therapy) should be performed.
SCC and recurrent cancer: 70%-92% of recurrent cases have SCC ↑, appearing 4-12 months earlier than clinical (1-20 months), which is an important indicator for postoperative follow-up monitoring of intermediate and advanced SCC. Positive predictive value 97%, sensitivity 70%, 8 weeks after treatment did not decline normal field, 92% suggest residual cancer foci.
(2) CA125 is a marker of cervical adenocarcinoma, and the lymphatic status is assessed preoperatively in combination with SCC-A. CA125 is significantly ↑ in patients with advanced adenocarcinoma and ↑ in patients with advanced adenosquamous carcinoma, such as CA125, SCC and CFA.
2.Cytology and colposcopy
Early diagnosis of cervical cancer recurrence has greater clinical value and should be used especially for central recurrence. If it is routinely used in follow-up, it can improve the early diagnosis rate (46.7%-86.7%, Zhang Wenhua et al.). For recurrence after radiotherapy to local recurrence, the accuracy is limited by the change of local epithelium of vagina after radiotherapy, such as atrophy and necrosis, so it is less used, and suspicious cases should be biopsied directly.
3.Imaging examination
Routine chest X-ray, abdominal and pelvic CT or MRI, B-ultrasound, isotope bone scan, intravenous pyelogram, etc.
PET-CT examination: It is an important basis for recurrence and metastasis inside and outside the pelvis, and also has important guiding value for treatment planning and monitoring of treatment effect.
(B) Diagnosis
Confirmation of diagnosis is pathological histological diagnosis.
1, in case of central recurrence, direct multi-point biopsy, or ECC, and endoscopic biopsy should be performed under the guidance of colposcopy.
2. for parametrial or pelvic sidewall recurrence, puncture biopsy should be performed under ultrasound guidance (or under CT localization).
3, lung and bone metastases, etc., according to imaging and laboratory dynamic monitoring for clinical diagnosis.
Emphasis should be placed on differentiation from the following (mainly referring to recurrence after radiotherapy).
1, local reaction of radiotherapy and uncontrolled recurrence differentiation Long healing time after radiotherapy, local inflammatory necrosis makes pathological examination difficult to confirm the diagnosis.
2.Parametrial recurrence and parametrial fibrosis Clinical examination of different signs, dynamic observation, FNA to assist diagnosis (high false negative rate).
Emphasis on follow-up and the role of SCC-Ag testing in the auxiliary diagnosis The literature reports that 20%-76% of cervical radiotherapy and postoperative recurrences are asymptomatic at the time of diagnosis. The diagnosis is mainly based on SCC-Ag↑ and imaging examination to further confirm the diagnosis.
IV. Treatment
(I) Treatment principles
1.Comprehensive assessment
The first treatment method, the time from the first treatment, the scope and location of recurrent tumor, the general status of the patient and the economic situation.
2.Treatment principles
(1) Radiation therapy (simultaneous radiotherapy) is preferred for pelvic recurrence and retroperitoneal lymph node recurrence after radical surgery, and the 5-year survival rate can reach 33%. If the cancer is central recurrence, surgery is optional.
(2) Recurrence after radiotherapy. The recurrence in the original irradiated field is treated with radiotherapy or radiochemotherapy; the recurrence in the original irradiated field and the central recurrence is treated with surgery; if the cancer cannot be removed surgically, the efficacy of re-radiation is poor and the complications are high, which is controversial.
(3) Advanced or cervical cancer is treated with concurrent radiotherapy, or palliative treatment with radiotherapy or chemotherapy alone.
(2) Treatment methods
1.Radiation therapy
The radiotherapy for recurrent cancer should be mainly external irradiation, or intracavitary or interstitial radiotherapy can be used according to the location, size and response of recurrence. The general tumor dose (DT) is 40-45Gy, and it is better to use 3D conformal radiotherapy (intensity modulated conformal radiotherapy), because it can make the high dose irradiation area consistent with the shape of the tumor target area in 3D direction and meet the target area dose requirements (clinical target area CTV, planned target area PTV, tumor target area GTV), and because of improving the tumor irradiation dose in the target area, the local control rate reduces the irradiation dose to normal tissues and reduces the damage and complications. It reduces the damage and complications due to the increased tumor irradiation dose in the target area and the local control rate. The dose (GTV) can reach 60-70 Gy (conventional full pelvic dose of 40-50 Gy + local conformal intensity modulation of 25-30 Gy) with 200-300 cGy/session, 3-5 times/week.
Concurrent radiochemotherapy has been widely used in the treatment of advanced cervical cancer, and the 5-year tumor-free survival rate for advanced cervical cancer has reached 40%-59.7% (overall remission rate up to 90%), which is significantly higher than that of radiotherapy alone (30%) and palliative chemotherapy (0%). It has become the conventional treatment for advanced cervical cancer.
Postoperative vaginal stump recurrence: Intracavitary radiotherapy can be added after the completion of external radiotherapy to improve the local control rate of the tumor. It has been reported (Ito et al., 1997) that CR 83% and 10-year survival rate 63%.
For recurrence in the original irradiated area: i.e. recurrence in the irradiated area after radiotherapy, if treated with re-radiation therapy has poor efficacy and complications up to 30%-50%, which has serious impact on patients’ quality of life. Therefore, it is only used for a few strictly selected patients with recurrence of cancer in the hind limbs.
2.Chemotherapy
Chemotherapy has been emphasized for the treatment of advanced or recurrent cervical cancer, and is mostly used for simultaneous radiotherapy or as neoadjuvant chemotherapy. Neoadjuvant chemotherapy is not only used for Ib2-II2 and some IIb patients with locally advanced disease, but also has a 72% local tumor efficiency for stage III-IVa cervical cancer, but does not improve the 5-year survival rate and reduce the distant metastasis rate.
Chemotherapy drugs and regimens: platinum-based combination regimens are the most effective drugs, such as Bleomycin, 5-Fu, MMC, VCR, IFO, Taxol, Docetaxel, Gemcitabine, etc. in combination with platinum (Taxol+DDP, efficiency S.Ca. 57.7%, adenocarcinoma 81%, 2005).
3.Surgical treatment
(1) Surgical treatment of recurrent cervical cancer of central type (selection and precautions for pelvic organ clearance)
Pelvic Exenteration Brunschuig first described this procedure in 1948 and has been used as a surgical treatment for advanced and recurrent cervical cancer.
Indications.
(i) recurrent cervical cancer after radiotherapy (central recurrence, 25% recurrent cancer).
(ii) Treatment of primary or metastatic pelvic cancer: vaginal cancer, vulvar cancer, rectal cancer.
③ for radical surgery (only in fistula-forming as palliative).
Features.
① wide scope of surgery.
②Complicated preoperative and postoperative management.
③ patient tolerance requires high skills, teamwork, high recurrence rate of intraoperative and postoperative complications, and psychological status affecting treatment. The patient’s age is over 50 years old and there are many individual variations, which is a problem that should be solved by senior gynecologic cancer specialists in oncology treatment centers.
Histological examination to confirm the diagnosis: FNA, biopsy (pelvic and para-aortic lymph nodes, oblique muscle lymph node biopsy in case of distant metastasis).
Surgical procedure.
① total pelvic organ removal.
② anterior pelvic organ removal.
(iii) posterior pelvic organ removal.
Preoperative preparation.
Comprehensive examination, bowel preparation, antibiotic administration.
(2) Treatment of recurrence of cervical cancer in the pelvic sidewall (CORT and LEER procedures)
Recurrence of cervical cancer in the pelvic lateral wall.
(1) For the few patients who have not received post-surgical radiotherapy, radiotherapy or chemotherapy can be used to relieve symptoms.
② Treatment of pelvic lateral wall recurrence after 95% of patients who have received adjuvant pelvic radiotherapy is extremely difficult.
Diagnosis.
Postoperative or post-CT swelling of the lower extremities, lumbosacral, pelvic or lower extremity pain, and one or more of the triad of hydronephrosis symptoms.
Examination: pelvic sidewall mass (triad) or imaging (MRI) for tumor involvement of the pelvic sidewall.
Biopsy: Histological type consistent with the primary cancer is required for the diagnosis of pelvic sidewall recurrence.
Treatment: Complete resection of the lateral pelvic lesion is often not possible to preserve the blood vessels and nerves that affect the function of the lower limbs.
Combination of surgery and radiation therapy is used to treat recurrence of tumor after radiation therapy, so that the tumor site can receive high dose of local radiation again.
Laterally extended endopelvic resection (LEER) refers to the surgical excision of the muscular part of the pelvic wall (pelvic floor side) near the recurrence site (internal pelvic muscle, pubococcygeus muscle, iliococcygeus muscle, etc.) and removal of the wall branch of the internal iliac vessels.
Complications (severe) 25%, operative death <5%, prolonged postoperative tumor-free survival and improved quality of life.
Survival rate (strictly controlled indications): 5yr. SR 40%-50% (Hockel, 1999,20003).
Technically demanding: management of bleeding (abdominal aortic block), ligation of internal iliac arteries and veins.
V. Prognosis
The prognosis for advanced and recurrent cervical cancer is extremely poor, with a 5-year survival rate of 30%-50% for stage III, 5%-15% for stage IV, and about 10% for both local recurrence and distant metastases (Kastrtis et al., 2005), with 60% dying within 2 years. Only central recurrence with purely para-aortic lymphatic metastasis can prolong survival with aggressive treatment (surgery or concurrent radiotherapy). How to improve the outcome of patients with advanced recurrent cancer remains an important clinical and research issue in gynecologic oncology.
In conclusion, the diagnosis and treatment of advanced or recurrent cervical cancer is one of the important issues facing gynecologic oncologists at present or in the long term, and is a key issue in reducing the mortality rate of cervical cancer. We hope that obstetrics and gynecology specialists and experts will work together to make better achievements.