Chih-Jen Tseng

Randomized Trial of Neoadjuvant Cisplatin, Vincristine, Bleomycin, and Radical Hysterectomy Versus Radiation Therapy for Bulky Stage IB and IIA Cervical Cancer

PURPOSE To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. PATIENTS AND METHODS Women with previously untreated bulky (primary tumor >/= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. RESULTS Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. CONCLUSION NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.

The prognostic significance of pre- and posttreatment SCC levels in patients with squamous cell carcinoma of the cervix treated by radiotherapy

PURPOSE To investigate the prognostic significance of the pre- and posttreatment serum squamous cell carcinoma antigen (SCC) levels in patients with Stage I-IVA squamous cell carcinoma of the cervix primarily treated by radiotherapy. MATERIALS AND METHODS 401 patients with squamous cell carcinoma of cervix primarily treated with radiotherapy (RT) were included in this study. All had preRT, and 249 patients had postRT serum SCC values. The association of pretreatment SCC level with the clinical parameters, including stage, hemoglobin (Hb) level, age, cell differentiation, and lymph node status, was assessed by univariate and multivariate analysis. The prognostic significance of pretreatment SCC level and these clinical parameters were evaluated. The impact of postRT residual induration and SCC levels on survival was analyzed. RESULTS 1. PreRT SCC level strongly correlated with stage. After controlling for stage, only SCC levels higher than 10 ng/ml were associated with enlarged lymph nodes shown in CT scan. No association of preRT SCC level with other clinical parameters was found. 2. SCC level higher than 10 ng/ml, but not between 2-10 ng/ml, had significant impact on survival in a multivariate analysis. Stage, Hb levels (<10 g/dl) and positive lymph node shown by CT scan were also independent prognostic factors for survival. No significant difference in failure pattern in terms of local and/or distant sites was found in patients with different SCC levels. 3. Patients with residual induration and/or persistently elevated SCC level at 2-3 months after RT had a significantly higher incidence of treatment failure. Persistently elevated SCC level is a stronger predictor for treatment failure than residual induration by pelvic examination, and is associated with a higher incidence of distant metastasis. One third of patients with initial SCC level higher than 10 ng/ml had persistently elevated SCC. CONCLUSION Pretreatment SCC levels higher than 10 ng/ml are an independent predictor for poor prognosis in patients included in this study, and can be used as one of the prognostic factors for selection of patients for intensive treatment. Persistently elevated SCC levels after RT is a strong predictor for treatment failure. A combination of clinical pelvic examination and SCC levels provides useful information for the need of further work-up and management.

Isolated paraaortic lymph node recurrence after definitive irradiation for cervical carcinoma.

PURPOSE To evaluate the clinical features of isolated paraaortic lymph node (PALN) recurrence after definitive radiotherapy, and analyze the prognostic factors and effect of salvage treatment. METHODS AND MATERIALS Of a total 876 patients who received pelvic radiotherapy after the diagnosis of primary cervical carcinoma, 26 were found to have isolated PALN recurrence as the first recurrent site, and these patients enrolled in this study. Only those with primary-site carcinoma controlled and who were free of other distant metastases were eligible. Nineteen of the 26 patients accepted salvage therapy. Fourteen patients accepted concurrent chemoradiation (CCRT), 1 accepted radiation to the paraaortic region, and 4 accepted chemotherapy alone. Clinical parameters evaluated included tumor markers (SCC and CEA) and image studies. RESULTS Seven of the 26 patients were alive and disease-free. All 7 survivors had salvage treatment with radiation to the paraaortic region and concurrent cisplatin-based chemotherapy. None of the patients receiving chemotherapy or radiation alone enjoyed long-term, disease-free survival. The 5-year survival rate for isolated PALN recurrence of the 14 patients who accepted salvage concurrent chemoradiation (CCRT) was 51.2%. The presence of a clinical symptom at the time of PALN recurrence was analyzed. Seven of the 12 asymptomatic patients and none of the 14 symptomatic patients survived without disease after salvage treatment. The SCC levels at recurrence showed a statistically significant relationship to disease-free survival. CONCLUSIONS An SCC level of < or = 4 ng/ml and a lack of symptoms at the time of recurrence were good prognostic factors in isolated PALN recurrence after primary radiation therapy. In addition to concurrent CCRT, periodical surveillance with tumor markers and imaging studies allowed early detection and salvage of those patients.

Conservative conization for microinvasive carcinoma of the cervix.

OBJECTIVE Our purpose was to examine conservative conization as treatment for microinvasive carcinoma of the cervix with depth of invasion < 3 mm. STUDY DESIGN Twelve patients with microinvasive carcinoma of the cervix underwent cervical conization under colposcopic guidance followed by careful observation. RESULTS The 12 patients were alive without evidence of disease after a mean follow-up of 6.7 years. Four pregnancies with term deliveries were identified. CONCLUSION Microinvasive carcinoma with a depth of invasion < 3 mm without confluent invasion or lymph vascular involvement can be treated successfully with conservative conization and provided a good pregnancy outcome.

Postoperative low-pelvic irradiation for stage I–IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis

PURPOSE To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I-IIA cervical cancer patients. METHODS AND MATERIALS A total of 228 Stage I-IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30-50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. RESULTS The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (>or=4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, <or=50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I-V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p = 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP-PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. CONCLUSION Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I-IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients.

Neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin and radical surgery in early-stage bulky cervical carcinoma

SummaryNeoadjuvant chemotherapy consisting of 2–3 courses of cisplatin, vincristine, and bleomycin was used in the primary treatment of 36 consecutive patients with locally advanced early-stage cervical carcinoma [International Federation of Gynecology and Obstetrics (GIGO) stages I b or IIa; tumor size, ≥4 cm]. The effectiveness of the preoperative chemotherapy was evaluated in the surgical specimens. Among the 33 evaluable patients, the overall clinical response rate was 84.8%, which included a complete response in 8 patients (24.2%) and a partial response in 20 subjects (60.6%). No residual tumor was found in the surgical speciments obtained from 2 complete responders. This therapy induced varying degrees of tumor shrinkage and rendered radical surgery feasible in all evaluable cases despite the initial bulky size of the lesions. No significant difference was observed in the response rate according to age and disease stage. Lymph-node metastases were found after chemotherapy in 18.2% (6/33) of the patients. Grade II and III hematological toxicities occurred in 23.3% of the 90 chemotherapy cycles completed. Nausea and vomiting occurred to a mild to moderate degree in 75 (83.3%) cycles. These preliminary results suggest that the administration of induction chemotherapy involving two to three courses of cisplatin, vincristine, and bleomycin prior to surgery is effective in reducing the tumor volume and in providing better circumstances for surgical removal of the early yet bulky cervical tumors and results in tolerable toxicity. This protocol is now undergoing prospective randomized trials to test its impact on long-term survival.

Adjuvant concurrent chemoradiotherapy with intensity-modulated pelvic radiotherapy after surgery for high-risk, early stage cervical cancer patients.

Purpose:This study was undertaken to assess local control and toxicity with adjuvant intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy (CCRT) for early stage cervical cancer. Patients and Methods:Between June 2004 and February 2007, 54 patients with early stage cervical cancer (stage IB–IIA) with high-risk factors for treatment failure after surgery were treated with adjuvant pelvic IMRT and CCRT. Adjuvant chemotherapy consisted of cisplatin (50 mg/m2) weekly for 4 to 6 courses. All the patients received 50.4 Gy of external beam radiotherapy with IMRT in 28 fractions and 6 Gy of high-dose rate vaginal cuff brachytherapy in 3 insertions. Results:Adjuvant CCRT with IMRT provided good local tumor control in posthysterectomy cervical cancer patients with high-risk pathologic features. The 3-year locoregional control and disease-free survival were 93% and 78%, respectively. Histology and lymph node metastasis were indicators for disease-free survival. Low acute and chronic treatment-related toxicities were noted with IMRT. All the patients completed the radiotherapy treatment without any major toxicity. In terms of chronic toxicity, only 1 patient had grade 3 genitourinary toxicity and none had grade 3 gastrointestinal toxicity. Conclusion:Our results indicate that adjuvant CCRT with IMRT technique for adjuvant treatment of early stage cervical cancer is associated with excellent local control and low toxicity.

A prospective study of nerve-sparing radical hysterectomy for uterine cervical carcinoma in Taiwan.

OBJECTIVE Surgical therapy for cervical carcinoma carries a significant risk of functional impairment to the bladder. This study evaluates the feasibility and complications of nerve-sparing radical hysterectomy (NRH) in Taiwan. METHODS Between March 2010 and March 2011, consecutive patients diagnosed with early stage cervical cancer (FIGO stage Ia2 to Ib1) and tumor size < 3 cm were recruited prospectively to undergo NRH or conventional radical hysterectomy (RH). Patients with histories of urinary stress incontinence or bladder dysfunction disease were excluded. A modified Tokyo nerve-sparing radical hysterectomy was performed. RESULTS A total of 30 patients were enrolled. Among these, 18 patients underwent NRH with successful bilaterally nerve-sparing procedures in 15 cases (83%), unilaterally nerve-sparing procedures in 2 cases (11%), and a failure in 1 case (6%). The indwelling catheter was removed on postoperative day 6. The mean±SD duration from operation to spontaneous voiding was 6.8 ± 1.5 days for women who underwent NRH; the corresponding duration for women who underwent RH or failed NRH was 20.6 ± 3 days. None of the patients who underwent NRH required intermittent catheterization. All 12 patients who underwent RH needed self-catheterization after discharge. There was a significant reduction in the incidence of postoperative self-catheterization (p<0.01) and bladder dysfunction (p<0.006). Average satisfaction score analyzed by the Likert-scale questionnaire was 4.5 for the NRH group and 1.9 for RH group (p<0.0001). CONCLUSIONS We concluded that the new technique of NRH can reduce postoperative bladder dysfunctions.

Phase II trial of neoadjuvant chemotherapy in early-stage small cell cervical cancer.

Clinical complete response (CR) to chemotherapy is not uncommon in small cell carcinoma. To understand its pathologic response, we conducted a phase II trial with neoadjuvant chemotherapy followed by hysterectomy in patients with small cell cervical cancer and reviewed all reported cases receiving neoadjuvant chemotherapy followed by hysterectomy through a MEDLINE search. From December 1993 to December 1997, the enrolled patients were treated with two to three courses of vincristine, adriamycin and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE) before hysterectomy. Another three courses of chemotherapy were added after surgery. A total of seven patients was enrolled. Clinical CR was observed in six patients, but microscopic residual tumor was present in all. Lymphatic permeation, scattered residual tumor clusters and residual superficial invasive adenocarcinoma over the cervix presented in five cases, and another had a metastatic pelvic node with no residual cervical tumor. Three of these seven patients have been alive with no evidence of disease for 16.2, 45.2 and 56.6 months, respectively. The other four died from disease 10.3-23.6 months after diagnosis. These findings indicate the discrepancy between clinical and pathologic responses in small cell cervical cancer after chemotherapy and emphasize the necessity of local treatment.

Identification of human papillomavirus types 16 and 18 deoxyribonucleic acid sequences in bulky cervical cancer after chemotherapy

OBJECTIVE The objectives of this study were to evaluate the effect of chemotherapy on the continual presence of human papillomavirus deoxyribonucleic acid sequences in bulky cervical cancer tissues and the relationship between the presence of human papillomavirus and the response of these patients to chemotherapy. STUDY DESIGN Multiple tissue sections obtained from 33 patients with bulky cervical cancer both before and after chemotherapy were analyzed for the presence of human papillomavirus types 16 and 18 by deoxyribonucleic acid amplification. RESULTS The cytotoxic effects of chemotherapy did not significantly alter the continual presence of human papillomavirus deoxyribonucleic acid sequences in these tissues (p = 0.8048). The presence of human papillomavirus type 16 deoxyribonucleic acid in tumors treated with neoadjuvant chemotherapy was significantly associated with favorable tumor response compared with type 18-positive patients and type 16/18-negative patients (94.7% vs 42.9%, p = 0.0059 and 94.7% vs 44.4%, p = 0.0004, respectively). Additionally, patients with type 18 deoxyribonucleic acid had a significantly higher risk of recurrence than did type 16-positive patients (p = 0.0123). CONCLUSIONS These results seem to suggest that the presence of human papillomavirus deoxyribonucleic acid sequences may serve as a marker to predict the response of bulky cervical cancer to chemotherapy and may be useful in reassessing neoadjuvant treatment for those patients who are free of human papillomavirus or those with type 18 deoxyribonucleic acid.