PostOperative Radiation

With early stage cancers, surgery alone (radical hysterectomy with pelvic and paraaortic node dissection) is often the best treatment and all that is necessary to cure the patient. Generally no additional treatment is necessary if the pathology report shows: all nodes negative, tumors less than 4cm, no lymphvascular invasion, clear margins and the depth of stromal invasion no deeper than 1/3 (Leibel and Phillips 1998.)

     The GOG (Gynecologic Oncology Group) has completed a number of studies on cervix cancer and identified factors that carry a higher risk of relapse after surgery. They also completed a study (GOG #92 noted below) which showed that these high risk patients benefit from postoperative radiation with a 47% reduction in the risk of recurrence.

 The NCCN recommends postOp radiation (as per GOG 92) if there is a large tumor, lympvascular invasion or deep stromal invasion, and (as per INT 0107) recommends chemo-radiation if + nodes or + margins or parametrial invasion (see section on chemoradiation , read this review, see the update of GOG 92 here, and read the NCCN guidelines.) Another article on close margins here. Some of these studies are included below.

Gynecol Oncol 1999 May;73(2):177-83

A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. GOG #92

Sedlis A, Downstate Medical Center,Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.

Gynecol Oncol 1999 May;73(2):196-201

Chemotherapy versus radiotherapy versus observation for high-risk cervical carcinoma after radical hysterectomy: A randomized, prospective, multicenter trial.

Lahousen University of Graz, Seventy-six patients with stage IB-IIB cervical cancer treated with radical hysterectomy with pelvic lymph node metastases and/or vascular invasion randomly received adjuvant chemotherapy (400 mg/m2 carboplatin, and 30 mg bleomycin), standardized external pelvic radiation therapy, or no further treatment. RESULTS: After a median follow-up of 4.1 years (range, 2-7) there were no statistically significant differences (P = 0.9530) in disease-free survival among the three treatment arms. CONCLUSION: The data suggest that adjuvant chemotherapy or radiation do not improve survival or recurrence rates in high-risk cervical cancer patients after radical hysterectomy.

Gynecol Oncol 1996 Apr;61(1):3-10

Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): a randomized phase III trial.

Curtin Memorial Sloan-Kettering . Patients with Stage IB-IIA cervical cancer undergoing RH-PLND were eligible. Risk factors include deep cervical invasion, tumor > or = 4 cm, parametrial involvement, nonsquamous histology, and/or pelvic lymph node metastasis. Chemotherapy consisted of cisplatin and bleomycin, alone or in combination with whole pelvic RT. Nine of 44 (20%) patients receiving chemo alone recurred compared to 10/45 (22%) patients receiving chemo and RT (P=ns).CT + RT did not prove a superior adjuvant therapy for patients at high risk of recurrence after RH-PLND for early cervical cancer in this limited trial.

Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):833-8

Postoperative radiation for cervical cancer with pathologic risk factors.

Hart K,  Wayne State University, We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. CONCLUSION: Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.

Cancer 1999 Apr 1;85(7):1537-46

Preoperative prognostic variables and the impact of postoperative adjuvant therapy on the outcomes of Stage IB or II cervical carcinoma patients with or without pelvic lymph node metastases: an analysis of 891 cases.

Lai CH,Taoyuan, Taiwan.Eight hundred ninety-one patients with Stage IB or II cervical carcinoma who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment at a single institution were analyzed. Among patients with pelvic lymph node metastases who were free of parametrial extension, those who received postoperative chemotherapy or chemoradiotherapy had significantly better RFS and OS  than those who received no adjuvant therapy. Among patients without pelvic lymph node metastases but at high risk of recurrence, those who received adjuvant radiotherapy had significantly better RFS  and marginally improved OS compared with those who received no adjuvant therapy.

Gynecol Oncol 1998 Jul;70(1):61-4

Indication and efficacy of radiation therapy following radical surgery in patients with stage IB to IIB cervical cancer.

Okada Yonago, Japan.The criteria for postoperative radiotherapy included positive lymph node involvement, compromised surgical margin, parametrial extension, or deep stromal invasion of cervix with less than 3 mm of distance from serosa. Postoperative radiotherapy consisted of 10-20 Gy whole pelvis and an additional parametrial dose with a midline block to deliver a total of 44-50 Gy to the pelvic side wall. The estimated 5-year survival rate for patients undergoing surgery alone was 97.6% and that for patients receiving postoperative radiotherapy was 82.7% (P = 0.038). Multivariate analysis showed that lymph node metastasis and parametrial extension were major prognostic factor, but the survival rate did not relate to depth of stromal invasion. CONCLUSION: Postoperative radiotherapy may improve the survival of patients with cervical cancer exhibiting lymph node metastasis or parametrial extension.

Cancer 1997 Oct 1;80(7):1234-40

Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes.

Samlal RA, University of Amsterdam, In multivariate analysis, the following factors were identified as independent risk factors for recurrence: adenocarcinoma (P = 0.003), depth of invasion as a fraction of tumor penetration of the cervical stroma (P = 0.01), and an extensive stromal inflammatory cell infiltrate (P = 0.04). An evaluation of the recurrence patterns for these patients showed a predominance of pelvic recurrences.Because the majority of recurrences in the lymph node negative group were pelvic recurrences, the value of adjuvant radiotherapy as a treatment for selected lymph node negative patients should be evaluated in a prospective study.

Gynecol Oncol 1997 Jul;66(1):31-5

Stage IB and IIA cervical cancer with negative lymph nodes: the role of adjuvant radiotherapy after radical hysterectomy.

Schorge JO, Harvard Factors predictive of recurrence for the entire group of patients included lymph-vascular space invasion (LVSI) (P = 0.003) and grade 3 histology (P = 0.04). After controlling for confounding variables, patients with LVSI who received RH + RT were less likely to develop disease recurrence than patients receiving RH alone (P = 0.04). LVSI is an important prognostic variable in lymph node-negative stage IB and IIA cervical cancer.

Gynecol Oncol 1999 Dec;75(3):328-33

The prognostic factors for patients with early cervical cancer treated by radical hysterectomy and postoperative radiotherapy.

Tsai CS, Taipei, Taiwan.222 patients with stage IB-IIA cervical cancer, treated by radical surgery and a full course of post-OP RT, were included in this study. The indications for post-OP RT were based on pathological findings, including lymph node metastasis, positive surgical margins, parametrial extension, lymphovascular permeation, and invasion of more than two-thirds of the cervical wall thickness. The radiation dose of external beam was 44-45 Gy to the whole pelvis and 50-54 Gy to the true pelvis. One hundred seventy-two patients also received intravaginal brachytherapy as a local boost. The minimal follow-up period was 2 years. Results. The actuarial 5-year overall and disease-specific survival rates for all patients were 76 and 82%, respectively. The tumor control rate within the pelvis reached 94%, and distant metastasis was the major cause of treatment failure. Univariate analysis of clinical and pathological parameters revealed that clinical stage, bulky tumor size, positive lymph nodes, parametrial extension, and histologic type were significant prognostic factors. After multivariate analysis, only positive lymph nodes (P = 0.01), bulky tumor size (P = 0.02), and parametrial extension (P = 0.05) independently influenced the disease-specific survival (DSS). For patients with lymph node metastasis, the number and location of the nodal involvement significantly affected the prognosis. The 5-year DSS for patients with no, one, and more than one lymph node metastasis were 87, 84, and 61% (P = 0.0001), respectively. Patients with upper pelvic lymph node metastasis had a higher incidence of distant metastasis (50% vs 16% in lower pelvic node group, P = 0.03). In the subgroup of single lower pelvic nodal metastasis, the prognosis was similar to that of patients without lymph node involvement (5-year DSS 85% vs 87%, P = 0.71). Conclusion. Our results indicate that post-OP RT can achieve very good local control in stage IB-IIA cervical cancer patients whose pathological findings show risk features for relapse after radical surgery. The prognostic factors for treatment failure identified in this study can be used as selection criteria for clinical trials to test the effects of other adjuvant treatments, such as chemotherapy. Patients with a single lower pelvic lymph node metastasis have a relatively good prognosis and may not need adjuvant treatment beyond radiation therapy.

Gynecol Oncol 1999 Nov;75(2):233-7

A limited role for adjuvant radiotherapy after the Wertheim/Okabayashi radical hysterectomy for cervical cancer confined to the cervix.

van der Velden J, The Netherlands.\ Our retrospective results fail to support a survival benefit of extending indications for adjuvant radiotherapy other than postive nodes, parametrial extension, and positive margins.

J Clin Oncol 1999 May;17(5):1339-48

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

Whitney All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU.The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Int J Radiat Oncol Biol Phys 1998 Dec 1;42(5):1015-23

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.

Varia A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.