Abstract
OBJECTIVE To investigate the short-term and long-term therapeutic efficacy of preoperative intra-arterial infusion chemo-embolization on stage IB2-IIB uterine cervix cancer (UCC).
METHODS A total of 143 patients with Stage IB2-IIB UCC were divided into a clinical trial group and a control group. The patients in the clinical trial group (n = 86) were treated with a combined therapy, i.e., preoperative intra-arterial infusion chemo-embolization, surgical therapy and postoperative radiotherapy, and those in the control group (n = 57) were given surgical therapy and post-operative radiotherapy. The adverse effects, changes in local lesion and pathological examinations of the cancer, and the state during the surgery were observed after the intra-arterial infusion chemo-embolization. The survival rate and recurrence rate between the two groups were compared.
RESULTS The total effective rate of the intra-arterial infusion chemo-embolization on Stage IB2-IIB UCC was 93.02%. The treatment could reduce tumor size, bring about retro-conversions of the clinical stage of the tumors and pathological grade of the cancer cells, and decrease the quantity of intra-operative blood loss as well as the operating time. It could significantly improve the 5-year survival rate (P< 0.05), and reduce the 2 and 5-year tumor recurrence rates (P < 0.05). Moreover, its side effects were little.
CONCLUSION Preoperative intra-arterial infusion chemo-embolization can create conditions for radical operation, lower the postoperative recurrence rate, and improve the prognosis in the patients with UCC. It is an effective therapy in treating UCC.
keywords
- intra-arterial infusion chemo-embolization
- uterine cervix cancer
- clinical effectiveness
- prognosis
- recurrence
Introduction
Uterine cervix cancer (UCC) is one of the most common malignant gynecological tumors which badly threaten women’s health, and its prognosis is related to treatment methods. Over the past few years, with the development of interventional therapy (IVT), the IVT has played an important role in treating the intermediated-advanced UCC. A combined therapy including preoperative intra-arterial infusion chemo-embolization (interventional therapy), surgery and radiotherapy on Stage IB2-IIB UCC has achieved a satisfactory therapeutic effect in our hospital.
Materials and Methods
General data
A total of 143 patients with Stage IB2-IIB UCC (based on FIGO staging standard[1]), admitted to our hospital from January 1997 to January 2002, were included in our study. The diagnosis of all patients was confirmed by pathological examination. These patients were divided into two groups, i.e. the clinical trial group and the control group, see Table 1. Statistical analysis showed that there was no significant difference in general data between the two groups (P > 0.05). No contraindications of chemotherapy, surgery and radiotherapy were found in any of the patients.
Therapeutic methods
Trial group
A combined therapy including preoperative intra-arterial infusion chemo-embolization, surgery and radiation therapy was conducted in trial groups. Selding’s technique was usually used in the pre-operative intra-arterial infusion plus chemo-embolization (i.e. interventional therapy, IVT), that is, to conduct an intubation by femoral arteriopuncture, and put the 6F or RIM catheter into the internal iliac artery for an arteriography. Based on findings of the arteriography, the character, position, nutrient vessels and the bleeding arteriolae of the lesion were determined. Then ultra-selective insertion of the catheter into the uterine artery was conducted, with the infusion of drugs (MFP regimen: mitomycin 10 mg, 5-FU 1,000 mg, cisplatinum 70 mg/m2 and iodinated oil) for chemoembolization. After the procedure, the catheter was pulled out and the pricking point oppressed for 10 min, allowing any active bleeding to cease. The dressings were removed 12 h after a pressure dressing was applied. An 8 mg of i.v. drop infusion of ondansetron was carried out, 30 min ahead of the chemo-embolization, to prevent vomiting caused by the chemotherapeutic agents. After the surgical procedure, the patient was instructed to lie absolutely prostrate in bed for 8 h, with a 3-day i.v. drop infusion of antibiotics to prevent an infection, and also with a 3-day i.v. drop infusion of sodium thiosulfate to neutralize poison and to hydrate urine in order to prevent an impairment of the kidney. Radical hysterectomy plus pelvic lymphadenectomy was conducted 21 to 28 d after the IVT. Two to 4 weeks after the surgery, radiotherapy was performed in the patients with a lymphatic metastasis of the pelvic cavity and parametrial infiltration or invasion of the vagina, with irradiation of the total pelvic cavity and a total dose of 45~50 Gy.
Control group
No IVT was conducted in this group. After completion of the preoperative preparation, a radical hysterectomy plus pelvic lymphadenectomy was performed. The patients with a lymphatic metastasis of the pelvic cavity, and a parametrial infiltration or invasion of the vagina underwent radiotherapy 2 to 4 weeks after surgery, receiving total pelvic cavity irradiation with a total dose of 45~50 Gy.
Evaluation of the therapeutic
Short-term efficacy of the IVT
The effectiveness was assessed based on the degree of the tumor regression after the interventional therapy. Complete remission (CR): complete regression of the local lump; partial remission (PR): a 50% or more diminution of the local lump; no change (NC): no change of the local tumor size; progression of disease (PD): increase of the local tumor size or emergence of new tumors during the treatment; both CR and PR indicate an efficacy. The patients’ conditions in the two groups were compared, and pathological manifestations were observed following the IVT.
Long-term efficacy of the IVT
Follow-up was conducted in all the patients. Recurrence of the tumors was observed by clinical examinations, B ultrasound and chest X-ray examination etc., and the 2-year and the 5-year survival rates of the patients were analyzed.
Statistical analysis
Statistical software SPSS 13.0 was used for the χ2 and t tests.
Results
Short-term efficacy of the IVT on Stage IB2-IIB UCC
The effectiveness of IVT on UCC
In the 86 patient trial group, CR was achieved in 30 (34.88%), PR in 50 (58.14%), NC in 6 (6.98%), and PD in 0. The total effective rate was 93.02%.
Adverse effects of IVT
Adverse reactions occurred after the patients were subjected to the intra-arterial infusion chemo-embolization as follows: i) abdominal pain: a slight to moderate pain in the abdomen was present in all the 86 patients, among which the symptom occurred immediately after surgery in 6, and was present 6 to 8 h after surgery in the others, with a remission within 3 to 7 d. ii) gastrointestinal reaction: nausea and vomiting occurred in all 86 patients, between 1 to 3 times a day with a duration of 1 to 2 days. iii) syndrome of the chemo-embolization: there was red swelling of the skin on the buttocks, fever and ecchymosis in the iliac region. Red turgescent buttocks were found in 6 of the patients, and the ecchymosis in the iliac region in 3. All the 9 patients were palliated, without receiving any special treatment. No obvious bone marrow depression, impairment of the hepatic and renal function or nerve lesions were found in any of the 86 patients.
Local change of the lesion by vaginoscopy after IVT
Vaginoscopy was conducted to observe local change of the lesion 10 to 14 days after IVT in 86 patients. Complete extinction of the local cervical tumor was observed in 30 of these patients. It was shown that there was severe cervical hypertrophy and erosion, and several rodent ulcers were seen at the cervical os, where the fornix was thoroughly exposed, or deepened and widened. A 7/8 to 9/10 reduction of the local tumor occurred in 50 patients, with the fornix deepened and widened, and softening of the parametrial tissues in some of the cases.
Intra-operative situation of the patients from the two groups during radical hysterectomy and pelvic lymphadenectomy
Radical hysterectomy and pelvic lymphadenectomy was conducted in both patient groups. T (tumor) downstaging was seen in 41 of the total cases in the trial group during the surgery (47.67%). The blood loss was significantly decreased (P < 0.05), and 0.2 to 2 h (an average of 0.8 h) was saved during surgery in the trial group compared with the control group (P < 0.05) (Table 2). During the surgery, pelvic lymphadenectasis was found in 10 of the cases in the trial group (11.6 %), and 20 of the total cases in the control group (35.1%) (P < 0.05).
Postoperative pathological results
Postoperative paraffin-embedded sections of the specimens showed that after IVT, coagulation necrosis occurred in a multitude of cancer cells. Lymphocytes and macrophages increased in number in the tumorous lesion, somtimes covering the entire field of view seen through microscope. With an increase of the connective tissue, pathological grade was reversed in part of the non-necrotic cancer cells. Among the total cases, a reversal of the poorly differentiated squamous carcinoma (SqCa) before IVT to the moderate or well-differentiated SqCa after the treatment occurred in 18, and a vanishing of the cancer cells after IVT in 7, which were inverted into a moderate atypical hyperplasia. In the 86 cases of the trial group, lymphatic metastasis was found in 14, and parametrial infiltration in 21. In the control group, lymphatic metastasis occurred in 23 and parametrial infiltration in 15.
Efficacy of the IVT on Stage IB2 -IIB UCC
Comparison of the survival rates between the two groups
No statistically significant difference was found in the 2-year survival rate between the two groups (P > 0.05). The 5-year survival was significantly higher in the trial group than in the control group (P < 0.05), see Table 3.
Comparison of the recurrence rates within 2 and 5 years between the two groups
Recurrence after the treatment mainly occurred in the pelvic and vaginal residuals. The 2- and 5-year tumor relapse rates were both significantly lower in the trial group than the control group, and there was a significant difference between the two (P < 0.05). See Table 4.
Discussion
Surgery and radiotherapy are the main treatment methods for UCC. With development and practice of the IVT over the past few years, interventional therapy has come to play a more and more important role in treating the malignant gynecological tumor. Ultra-selective intra-arterial infusion plus chemo-embolization can allow the drugs to directly enter the blood-supply vessels of the tumor and the tumorous lesion, and can increase the concentration of the local chemotherapeutic agents. At the same time, the interventional embolotherapy may interrupt the blood supply for the tumor, which results in the ischemia, oxygen deficiency and necrosis of the tumor cells, and brings about a longer retention of the chemotherapeutics in the tumor, thus achieving an effective inhibition of the cancer cells.
Conduction of IVT before radical surgery for UCC may allow a reduction of the tumor size and a subsidence of the parametrial infiltration, with a downregulation of the clinical stages and an increased radical excision rate, paving the way for the radical surgery[2,3]. In our study, 86 patients with Stage IB2-IIB UCC underwent an ultraselective uterine arterial chemo-embolization (MFP regimen) before surgery, with a total effective rate of 93.02%. It was shown by vaginoscopy that after IVT, there was a complete regression or diminution in part of the cervical lesion in some patients, with a deepened and widened fornix and a softened parametrial tissue. The lymphatic metastasis rate and intra-operative blood loss was markedly lower in the patients, compared to those without a preoperative IVT. In some of the patients, clinical stage was reversed and the operation time was significantly shortened. The postoperative pathological examination indicated that coagulation necrosis was present in a multitude of cancer cells, with an increment in number of lymphocytes, macrophages and hyperplasy of the connective tissues. Reversion phenomenon occurred in part of the undamaged cancer cells, and no severe postoperative adverse reactions were seen. These results suggest that preoperative ultra-selective chemo-embolization of the Stage IB2-IIB UCC has a significant therapeutic efficacy, which allows a complete regression or diminution in some of the tumors, reversion of clinical stage and tumor grade, and shortening of the operation time in some cases, thus paving the way for radical surgery for the UCC in the patient. Therefore, the preoperative ultra-selective chemo-embolization for UCC is shown to be a safe and effective treatment method.
Prognosis of the UCC relates to factors such as physical status, TNM staging, histopathological type and size of the tumors, lymphatic metastasis, treatment methods and age, etc. Preoperative IVT can raise the radical excision rate, reduce the lymphatic metastasis and relapse of the tumor, and improve the quality of life and survival rate of the patients, and is a secure and effective therapy for UCC[4,5]. It was shown in our study that there was no significant increase in the 2-year survival rate of the patients with Stage IB2-IIB UCC who underwent the IVT (P > 0.05), however the 5-year survival rate attained to 83.7% in these patients, with an significant improvement in survivals (P < 0.05) and a decrease of the 2- and 5-year relapse rates, compared to the control group (P < 0.05). These results indicate that the combined IVT with surgery and radiotherapy in treating the UCC can reduce the recurrence, significantly prolong the disease-free survival time, and improve the prognosis of the patients. The reasons may be as follows: i) IVT can regress or can significantly reduce the tumor; ii) IVT may downstage the TNM staging of the patients, resulting in regression of the parametrial infiltration, and significantly diminishing the lymphatic metastasis, which in turn facilitates radical surgery in the patients; iii) IVT can reverse the cancer cells and increase the number of lymphocytes and macrophages in the cancer, and it has been shown that patients with increased numbers of lymphocytes in the cancerous tissue and an infiltration of eosinophilic leukocytes, have a satisfactory prognosis and a very high 5-year survival rate[6]. iv) Previous research indicated that while the UCC patients underwent the radio-chemotherapy, there was a significant correlation between hemoglobin (HG) level and prognosis, and those with a 100 g/L and more of HG had a favorable prognosis[7]. It was shown in our study that IVT could decrease the blood loss of the patients with UCC and could shorten the time of surgery, thus enabling the patients to keep a rather high HG level during the postoperative chemo-radiotherapy, providing the conditions for further timely adjunctive therapy, and increasing the patients’ tolerance towards the following treatment.
In conclusion, IVT can regress or diminish the cancerous lesions, reverse the TNM staging and grading of tumors and create the conditions for a radical surgery in some patients with Stage IB2-IIB UCC. Furthermore, IVT can decrease postoperative recurrence rates and improve their prognosis. Therefore, IVT is a therapeutic method that is significantly efficacious both in the shortterm and in the long-term and it is worthy of clinical application and recommendation.
Footnotes
↵* Contributed equally to this work
- Received June 3, 2008.
- Accepted September 17, 2008.
- Copyright © 2008 by Tianjin Medical University Cancer Institute & Hospital and Springer