Tailoring adjuvant radiotherapy for stage IB-IIA node negative cervical carcinoma after radical hysterectomy and pelvic lymph node dissection using the GOG score

Objective

The use of adjuvant radiotherapy for early stage node negative patients varies for different institutions. The recognized factors such as deep stromal invasion, lymph vascular space invasion, and size of tumor are the most common factors cited for adjuvant radiotherapy. Studies done have shown that this increases local control but may increase chronic toxicity rates. We report on our use of the GOG score to tailor our treatment decisions.

Methods

A review of all patients staged IB–IIA who underwent Type 3 Radical Hysterectomy and pelvic lymph node dissection (RH) from 1997 to 2007. The GOG score proposed by Delgado et al. was applied, and patients were stratified into 3 groups; < 40: no adjuvant treatment, 40–120: Small Field RT (SmRT), and > 120: Standard Field RT (StRT)

Results

A total of 126 patients matched these criteria. Sixty one patients underwent either SmRT or StRT. There were only 2 known relapses and one death due to inter current illness. The median follow up was 57 months and the 5 year Disease Free Survival was 98.2%. There were no documented Grade 3 or 4 chronic toxicities. There were significantly less (p = 0.025) patients with lower limb lymphedema in the SmRT group compared to StRT.

Conclusion

Our study confirms the utility of the GOG score to tailor radiotherapy for this cohort of patients. This has been proven to be high in efficacy and low in morbidity.     

Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer

From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam radiotherapy. Presence of lymph node metastasis, large lesion (greater than 4 cm in diameter), histologic grade, race (noncaucasian), and age (greater than 40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy (P less than 0.001). However, patients receiving adjuvant radiation therapy had a higher incidence of lymphatic metastases, tumor involvement of the surgical margin, and large cervical lesions. Adjuvant pelvic radiation therapy did not improve the survival of patients with unilateral nodal metastases or those who had a large cervical lesion with free surgical margins and the absence of nodal involvement. Radiation therapy appears to reduce the incidence of pelvic recurrences. Unfortunately, 84% of patients who developed recurrent tumor after combination therapy had a component of distant failure. The incidence of severe gastrointestinal or genitourinary tract complications was not different in the two treatment groups. However, the incidence of lymphedema was increased in patients who received adjuvant radiation therapy. Although adjuvant radiation therapy appears to be tolerated without a significant increase in serious complications, the extent to which it may improve local control rates and survival in high-risk patients appears to be limited. In view of the high incidence of distant metastases in high-risk patients, consideration should be given to adjuvant systemic chemotherapy in addition to radiation therapy.     

A randomized trial of adjuvant chemotherapy after radical hysterectomy in stage Ib-IIa cervical cancer patients with pelvic lymph node metastases.

Seventy-one patients with Stage Ib-IIa cervical cancer treated by radical hysterectomy and found to have pelvic lymph node metastases were entered on a randomized trial comparing standard pelvic radiotherapy versus three cycles of combination chemotherapy with cisplatin, vinblastine, and bleomycin followed by pelvic radiotherapy. After a median follow-up of 2.5 years, 24 patients have relapsed. In 12 patients, the first evidence of relapse was in the pelvis, in 11 patients the first relapse was evident at a distant site, and in 1 patient the local recurrence and distant metastases were documented simultaneously. No difference in disease-free or overall survival has emerged between the two treatment groups. Relapse was more common in patients with non-squamous tumors (44%) and in those with metastases in several pelvic lymph nodes. We conclude that patients with pelvic lymph node metastases have a rather poor prognosis, but it remains to be determined how they should best be treated after radical surgery.     

子宫颈癌根治术中的淋巴显影和前哨淋巴结识别

目的 探索子宫颈癌根治术中淋巴显影和前哨淋巴结识别的方法及其可行性,评价前哨淋巴结预测盆腔淋巴结有无肿瘤转移的准确性。方法 应用染料法对20例宫颈癌患者(临床分期为Ib期3例、Ⅱa期12例、Ⅱb期5例)在根治术中于宫颈肿瘤周围的正常组织中分4点(3、6、9、12点处)注入美蓝或专利蓝溶液4ml,识别和定位蓝染的淋巴结(即前哨淋巴结),然后再按常规行盆腔淋巴清扫术,所有淋巴结一起送病理检查。结果 20例宫颈癌患者中淋巴管有蓝色染料摄取者18例,共有蓝染淋巴结33枚,其中左侧15枚,右侧18枚,前哨淋巴结识别成功14例,识别率为78％(14／18)。共有6例有淋巴结转移,淋巴结转移率为33％(6／18)。成功识别前哨淋巴结的14例中,淋巴结转移5例,其中前哨淋巴结和盆腔淋巴结均转移者2例,仅有前哨淋巴结转移者3例,准确性为100％,假阴性率为0。结论 宫颈癌根治术中淋巴显影和前哨淋巴结识别技术是可行的,但识别率尚有待提高。     

Prognostic factors in FIGO stage IB cervical cancer without lymph node metastasis and the role of adjuvant radiotherapy after radical hysterectomy

OBJECTIVES: The aim of this study was to evaluate the clinical and pathologic prognostic variables for disease free survival, overall survival and the role of adjuvant radiotherapy in FIGO stage IB cervical carcinoma without lymph node metastasis. METHODS: A retrospective review was performed of 393 patients with lymph node negative stage IB cervical cancer treated by type 3 hysterectomy and pelvic lymphadenectomy at the Hacettepe University Hospitals between 1980 and 1997. RESULTS: The disease free survival and overall survival were 87.6 and 91.0%, respectively. In univariate analysis, tumor size, depth of invasion, vaginal involvement, lympho-vascular space involvement (LVSI) and adjuvant radiotherapy were found significant in disease free survival. Overall survival was affected by tumor size, LVSI, vaginal involvement and adjuvant radiotherapy. Tumor size, LVSI and vaginal involvement were found as independent prognostic factors for overall and disease free survival in multivariate analysis. Disease free survival, recurrence rate and site did not differ between patients underwent radical surgery and radical surgery plus radiotherapy. CONCLUSION: Tumor size, LVSI and vaginal involvement were independent prognostic factors in lymph node negative FIGO stage IB cervical cancer. Adjuvant radiotherapy in stage IB cervical cancer patients with negative nodes provides no survival advantage or better local tumoral control.     

Treatment of cervical cancer with adjuvant chemotherapy versus adjuvant radiotherapy after radical hysterectomy and systematic lymphadenectomy

Aim:  To compare the clinical efficacy focused on post-treatment morbidity between adjuvant chemotherapy (CT) and pelvic radiotherapy (RT) after radical hysterectomy for patients with cervical cancer.
Methods:  A total of 125 patients with cervical squamous cell carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy at Hokkaido University Hospital between 1991 and 2002 were enrolled in the study for retrospective analysis. Seventy patients with recurrent risk factors, including deep stromal invasion, lymph vascular space invasion, parametrial invasion, lymph node metastasis (LNM), and bulky tumor (≥4 cm), received adjuvant therapy; 42 were treated with RT, and 28 were treated with CT. Almost all patients with multiple LNM received RT. Analyses were also performed on a subgroup of 50 patients without multiple LNM (23 RT, 27 CT). Clinical efficacy of post-treatment morbidity and survival was evaluated.
Results:  Because there were more patients with multiple LNM in the RT group, we analyzed disease-free survival in 50 patients without multiple LNM. The 3-year disease-free survival rate was 82.6% with RT and 96.3% with CT ( P  = 0.16). Postoperative bowel obstruction was significantly more frequent in the RT group versus the CT ( P  = 0.007) and no-therapy ( P  = 0.0026) groups. Urinary disturbance was also more frequent in the RT group than in the CT ( P  = 0.0016) and no-therapy ( P  = 0.089) groups.
Conclusion:  CT has the equivalent therapeutic effect as RT with fewer postoperative complications for patients with intermediate risks. A prospective randomized trial is needed to compare CT combined with radical hysterectomy and pelvic lymphadenectomy to RT or chemoradiotherapy.     

Early stage cervical cancer: aborted versus completed radical hysterectomy.

In a retrospective study, the treatment results of patients with stage IB and IIA cervical cancer were evaluated. In 26 patients radical hysterectomy was discontinued after intra-operative finding of positive lymph nodes. These patients received radiotherapy. In 57 patients lymph nodes were negative, and radical hysterectomy was completed. Of these, 13 patients received adjuvant radiotherapy because of positive surgical margins or parametrial involvement, and 44 patients received no adjuvant therapy. Five-year survival was 61% in patients with positive pelvic lymph nodes and 88% in patients with negative pelvic lymph nodes, comparable with the results mentioned in the literature. The complication rate did not differ from similar other reports. This management shows treatment results comparable with other reports with minimal morbidity.     

Radical hysterectomy with adjuvant radiotherapy versus definitive radiotherapy alone for FIGO stage IIB cervical cancer

Objectives

The aim of this study was to compare the treatment outcomes and adverse effects of radical hysterectomy followed by adjuvant radiotherapy with definitive radiotherapy alone in patients with FIGO stage IIB cervical cancer.

Methods

We retrospectively reviewed the medical records of FIGO stage IIB cervical cancer patients who were treated between April 1996 and December 2009. During the study period, 95 patients were treated with radical hysterectomy, all of which received adjuvant radiotherapy (surgery-based group). In addition, 94 patients received definitive radiotherapy alone (RT-based group). The recurrence rate, progression-free survival (PFS), overall survival (OS), and treatment-related complications were compared between the two groups.

Results

Radical hysterectomy followed by adjuvant radiotherapy resulted in comparable recurrence (44.2% versus 41.5%, p = 0.77), PFS (log-rank, p = 0.57), and OS rates (log-rank, p = 0.41) to definitive radiotherapy alone. The frequencies of acute grade 3–4 toxicities were similar between the two groups (24.2% versus 24.5%, p = 1.0), whereas the frequencies of grade 3–4 late toxicities were significantly higher in the surgery-based group than in the RT-based group (24.1% versus 10.6%, p = 0.048). Cox multivariate analyses demonstrated that treatment with surgery followed by adjuvant radiotherapy was associated with an increased risk of grade 3–4 late toxicities, although the statistical significance of the difference was marginal (odds ratio 2.41, 95%CI 0.97–5.99, p = 0.059).

Conclusions

Definitive radiotherapy was found to be a safer approach than radical hysterectomy followed by postoperative radiotherapy with less treatment-related complications and comparable survival outcomes in patients with FIGO stage IIB cervical cancer.     

Parametrial spread of cervical cancer in patients with negative pelvic lymph nodes.

OBJECTIVE: We studied the incidence and prognostic implications of parametrial involvement according to tumor volume in a series of cervical cancer patients with negative pelvic lymph nodes. METHODS: We reviewed a series of 351 node-negative patients with stage IB, IIA, or IIB cervical cancer treated with class III radical hysterectomy. The surgical specimens were processed as step-serial giant sections and tumor volume was calculated. Overall, 180 patients had tumors <5 mL, 120 had tumors of 5-20 mL, and 51 had tumors >20 mL. Parametrial involvement was classified as continuous, discontinuous, or involvement of blood vessels or lymph nodes and according to location as medial or lateral. A total of 302 patients had squamous cell tumors and 49 had adenocarcinomas. The mean duration of follow-up was 9.3 years. RESULTS: Overall, 44 of 351 patients (12.5%) had parametrial involvement. The rate of parametrial involvement in patients with tumors <5, 5-20, and >20 mL was 6.7, 12.5, and 33%, respectively. Isolated involvement of the medial parametrium increased with tumor size (3.8, 8.3, and 27.5%, respectively), whereas isolated involvement of the lateral parametrium was seen in 2.2, 1.6, and 0% of the cases. Involvement of both the medial and the lateral portions of the parametrium was seen in 0.5, 2.5, and 5.9% of the specimens, respectively. There were no differences in the rate of parametrial involvement between squamous cell carcinomas and adenocarcinomas. The 5-year disease-free survival rates in patients without or with parametrial involvement were 90.2% vs 90%, 91.7% vs 92.9%, and 84.7% vs 67%, respectively. CONCLUSION: The lateral portion of the parametrium can be involved in patients with cervical cancer and negative pelvic lymph nodes, but this is uncommon. In this series of patients treated with type III radical hysterectomy, parametrial involvement had no influence on disease-free survival.     

Early invasive cervical cancer with pelvic lymph node involvement: to complete or not to complete radical hysterectomy?

The completion of radical hysterectomy in the face of pelvic lymph node involvement presents a dilemma for the surgeon. Some believe it is appropriate to abort the hysterectomy to avoid the excessive morbidity of combined treatment; others believe that completion of the hysterectomy enhances survival. This study was undertaken to define the impact of completing radical hysterectomy followed by adjuvant radiation therapy upon patient survival or pelvic control. Fifteen patients with stage IB and IIA invasive cervical cancer whose radical hysterectomies were aborted solely for reasons of pelvic lymph node involvement were compared to a control group of 15 patients matched for tumor size and number of lymph nodes involved whose radical hysterectomies were completed. Both groups were treated with radiation therapy postoperatively. Survival was not different between groups (P = 0.81). Unexpectedly, local control was slightly improved in the group treated by radiation only (P = 0.127). If radiation therapy is anticipated, completion of radical hysterectomy followed by radiation therapy appears to offer no advantage over radiation therapy with the uterus in place in patients with early-stage invasive cervical cancer and pelvic lymph node involvement.     

Radiation injury to intestine following hysterectomy and adjuvant radiotherapy for cervical cancer

OBJECTIVE: To evaluate the risk factors for nonrectal radiation-induced intestinal injury (NRRIII) following adjuvant radiotherapy (RT) for cervical cancer using a retrospective review of medical records. METHODS: From September 1992 to December 1998, 164 patients with uterine cervical cancer that had completed their allocated adjuvant radiotherapy at the Chinese Medical University Hospital were enrolled for NRRIII analysis. The patients were classified into two groups according to the extent of surgery. Group A consisted of 110 patients (International Federation of Gynecology and Obstetrics [FIGO] stage: IB, n = 87; IIA, n = 21; IIB, n = 2) undergoing radical hysterectomy and bilateral pelvic lymph node dissection, while Group B was composed of 54 analogs receiving adjuvant radiotherapy following incident extrafascial hysterectomy. Treatment consisted of external beam radiotherapy (EBRT) and high-dose-rate intravaginal brachytherapy (HDRIVB). Initially, the whole pelvis was treated with 10 MV X-rays. After irradiation (44 Gy in 22 fractions over 4-5 weeks), the field was limited to the true pelvis and a further 10-20 Gy delivered in 5-10 fractions. For 21 patients in group A without pelvic lymph node metastasis or lymphovascular invasion, the radiation field was confined to the lower pelvis, with a prescribed dose of 50-58 Gy delivered over 5-6 weeks. HDRIVB was performed using an Ir-192 remote after-loading technique at 1-week intervals. A total of 159 patients (97%) received two insertions, while 5 had only one. The standard prescribed HDRIVB dose was 7.5 Gy to the vaginal surface. Logistic regression analysis was performed for assessment of the factors associated with NRRIII. RESULTS: After 38-119 months of follow-up (median, 60), 22 patients (13.4%) developed Radiation Therapy Oncology Group (RTOG) grade 2 or greater NRRIII at a median latency of 18 months (range, 5-48). Four patients were diagnosed as grade 3 complications requiring surgery and three had expired. The independent factors for NRRIII were radical hysterectomy (P = 0.04, relative risk 2.45), lower-pelvic dose >54 Gy (P = 0.0001, relative risk 10.27), and age over 60 years (P = 0.001, relative risk 5.45). The incidence of NRRIII for patients receiving whole and lower-pelvic irradiation was 14.5% and 10.6%, respectively (P = 0.45). Although there was no statistical significance comparing the two external beam irradiation strategies in terms of NRRIII, all four patients with grade 3 NRRIII underwent whole pelvic irradiation. CONCLUSION: This study identifies three predictive factors for the development of NRRIII following adjuvant radiotherapy for cervical cancer. Limiting the EBRT dose to less than 54 Gy, meticulous patient selection in the elderly, careful planning of the irradiated field, and the constraint of vaginal brachytherapy are four approaches to optimization of postoperative adjuvant radiotherapy.     

Correlation of angiogenesis and recurrence-free survival of early stage cervical cancer patients undergoing radical hysterectomy with pelvic lymph node dissection

AIM: To assess the correlation between the intensity of tumor angiogenesis, expressed as microvessel density, and recurrence-free survival in patients with early stage cervical cancer. METHODS: In a historical cohort study of patients with early stage cervical cancer undergoing radical hysterectomy with pelvic lymph node dissection at Songklanagarind Hospital during January 1998-December 2004, histological slides were immunostained for factor VIII-related antigen. Microvessel density was scanned at low magnification to identify the area with the highest number of vessels. Stained microvessels were counted at high magnification (x200) in an examination area of 0.25 mm2. Microvessel density and other potential prognostic factors were considered as covariates in multivariate Cox-proportional hazards regression models to evaluate their association with recurrence-free survival. RESULTS: One hundred and sixty-four patients were included in the study, and 16 patients developed recurrent disease during follow-up. The overall 5-year recurrence-free survival was 86.9% (95% confidence interval [CI] 78.9-92.0). In the multivariate analysis, microvessel density (hazard ratio [HR], for > or =9 vs <6 vessels per high power field: 5.8, 95% CI 1.5-22.7; P = 0.013), tumor size (HR for maximum diameter > or =2 vs <2: 3.6, 95% CI 1.2-10.7; P = 0.017) and parity (HR for > or =3 vs <3: 3.6, 95% CI 1.2-10.7; P = 0.018) were identified as significant independent prognostic factors for recurrence-free survival. CONCLUSION: Microvessel density is an independent prognostic parameter for recurrence-free survival in patients with early stage cervical cancer. Microvessel density at or above the cut-off point of nine vessels per high power field had significantly poorer recurrence-free survival.     

Prognostic factors and failure pattern in lymph node-negative stage IB and II cervical carcinoma treated with radical hysterectomy and postoperative irradiation

The aim was to determine the prognostic factors and recurrence pattern in stages IB and II cervical carcinoma patients with negative pelvic lymph nodes. 224 patients with stages IB and II cervical carcinoma underwent radical hysterectomy (RH) from 1982 through 1995. Of 161 patients with negative lymph nodes, 65 patients received postoperative irradiation (RT) and 96 patients were given no further therapy according to surgical pathological findings. The overall 5-year disease-free survival was 94.1%. Two of 96 RH patients (2%) and 10 of 65 RH + RT patients (15%) had recurrence in pelvic and distant sites almost equally. Multivariate analysis revealed deep cervical invasion as the only independent prognostic factor. The 5-year disease-free survival was 98.8% for patients with shallow invasion and 85.8% for patients with deep invasion (p < 0.0001). It is worthwhile to develop new strategies for the lymph node-negative patients with deep stromal invasion.     

Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer with cervical involvement

OBJECTIVE: The goal of this work was to assess retrospectively the role of wide/radical hysterectomy (RH) and pelvic lymph node dissection (LND) in endometrial cancer with cervical involvement. METHODS; From 1984 to 1993, 82 patients with endometrial cancer and cervical involvement were surgically managed at our institution. Of 57 patients with stage II (59%) or III (41%) disease receiving no preoperative therapy, 22 (39%) had simple hysterectomy (SH) and 35 (61%) had RH. Forty-four patients (77%) had pelvic LND, and 38 (67%) had adjuvant radiotherapy (RT). Median follow-up was 70 months. RESULTS: The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 73 and 63%, respectively. Five-year DRS and RFS were 68 and 50%, respectively, in the SH group compared with 76% (P = 0.1) and 71% (P = 0.04) in the RH group. Distant recurrences occurred in 45% of patients with SH and in 23% with RH (P = 0.08). Local recurrence rates did not differ significantly. Considering only stage II tumors, we did not observe any recurrence among patients with negative nodes who had RH, irrespective of the administration of adjuvant RT. By contrast, adjuvant RT improved local control (even if not significantly) in stage II patients who had SH. Five-year DRS of stage III patients was 47%, but it was improved by adjuvant RT in the subgroup of patients who had RH. Independent variables associated with prognosis were stage III disease, deep myometrial invasion, RH, and adjuvant RT. CONCLUSION: RH and adjuvant RT appear to improve prognosis in endometrial cancer with cervical involvement. In particular, radical surgery alone is therapeutic in stage II patients with negative nodes, irrespective of the administration of RT. By contrast, RT can possibly improve local control in stage II patients who previously had SH. Overall, stage III patients have a poor prognosis that can be improved by a combination of radical surgery and adjuvant RT; however, associated therapy directed to extrapelvic sites is probably needed in patients with extrauterine disease.     

Surgical pathologic factors in patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection: association with administration of adjuvant radiotherapy and effect on survival

PURPOSE OF INVESTIGATION: To identify surgical pathologic factors that best correlate with administration of adjuvant radiotherapy and best predict survival in early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection (RHND). METHODS: Data from the files of 126 patients with cervical carcinoma treated by RHND at the Soroka Medical Center from 1962 through 2005 were analyzed. RESULTS: Fifty-four percent of the patients received postoperative adjuvant radiotherapy. In a univariate analysis, each of the following factors: positive pelvic lymph nodes, lower uterine segment involvement, lymph vascular space involvement, penetration > or = 50% of the cervical wall, grade 2+3, parametrial and/or paracervical involvement, vaginal margin involvement, non-squamous histologic type, tumor size > or = 3 cm and Stage IB2 + IIA was significantly associated with administration of radiotherapy. In a multivariate analysis, positiviy of pelvic lymph nodes was persistently the most significant factor associated with administration of radiotherapy. The 5-year survival rate was 82.6% overall. In a univariate analysis, a significant worsening in survival was demonstrated with positivity of pelvic lymph nodes and positivity of lymph vascular space involvement. In a "better fit" model of multivariate analysis, pelvic lymph node status was the strongest and the only significant predictor of survival. CONCLUSIONS: In patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection, pelvic lymph node status is the strongest factor affecting administration of adjuvant radiotherapy and the most significant predictor of survival.     

Number and distribution of pelvic lymph nodes and effect of surgical pathologic factors on pelvic lymph node status in patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection

PURPOSE OF INVESTIGATION: To report the number and distribution of pelvic lymph nodes and to identify surgical pathologic factors that best predict positive pelvic lymph nodes in patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection (RHND). METHODS: Data from the files of 126 patients with cervical carcinoma treated by RHND at the Soroka Medical Center from 1962 through 2005 were analyzed. RESULTS: The status of pelvic lymph nodes was known in 114 patients. The exact number of lymph nodes removed from the pelvis of each patient was known in 111 patients. The mean number of lymph nodes removed from the pelvis per patient was 26.6 (median 23; range 1-62). Positive pelvic lymph nodes were found in 35 (30.7%) of the patients with a mean of 3.4 (median 2; range, 1-15) positive pelvic lymph nodes per patient. In a univariate analysis, positive lymph vascular space invasion and positive parametrial and/or paracervical involvement were significant predictors of positive pelvic lymph nodes, whereas penetration > or = 50% of the thickness of the cervical wall and grade 2+3 were of borderline significance. In a multivariate analysis, positive lymph vascular space invasion was the strongest and the only significant predictor of positive pelvic lymph nodes, whereas positive parametrial and/or paracervical involvement was of borderline significance. CONCLUSIONS: In patients with early-stage cervical carcinoma treated with RHND, positive lymph vascular space invasion emerged to be the strongest and most significant predictor of positive pelvic lymph nodes.