S. Greggi

Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis

No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46–1.21, P=0.16) and death (HR=0.85, 95%CI=0.49–1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=–3.4–14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=−7.0–9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.

Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Prognostic factors for response and survival

Between January 1986 and September 1988, 75 patients with locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stages IB–III) received three courses of neoadjuvant chemotherapy (NAC), including cisplatin, bleomycin, and methotrexate (PBM). Fifteen percent of patients achieved a complete response (CR) and 68% a partial response (PR). Pretreatment characteristics were analyzed for response to NAC. Significantly lower response rates were found in patients with tumor size more than 5 cm in diameter and bilateral parametrial involvement to the pelvic side wall. None of the biological parameters studied was related to chemoresponsiveness. Patients achieving CR or PR had a significantly improved 3‐year survival rate compared with those who did not respond. After NAC, radical surgery was possible in all responding patients. The median number of lymph nodes removed was 60. A lower than expected incidence of lymph node metastases was detected. None of the clinical and pathologic features considered was significantly correlated with the lymph node status. Twelve of the 62 operated patients had disease recurrence. Pathologic parametrial involvement and cervical infiltration equal to or deeper than 5 mm were found to be significant prognostic factors for recurrence. A 3‐year, disease‐free survival of 89%, 73%, and 43% for Stage IB–IIA, IIB, and III, respectively, was found. Among the operated patients these rates increased to 100%, 81%, and 66% for Stage IB–IIA, IIB, and III, respectively. A prospective randomized trial comparing NAC and surgery with radiotherapy alone is in progress.

Significance of epidermal growth factor receptor in advanced ovarian cancer.

PURPOSE The purpose of this study was to investigate the significance of epidermal growth factor receptor (EGF-R) expression in a group of advanced ovarian carcinomas. PATIENTS AND METHODS The study was conducted on 72 previously untreated patients with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV disease. The median follow-up was 24 months (range, 4 to 75 months). EGF-R was measured by a radioreceptorial assay. A cutoff of 1.5 fmol per milligram of protein was chosen to define EGF-R positivity. Medians and life tables obtained with the Kaplan and Meier method were analyzed by the log-rank test. The risk of progression was estimated by Coxs proportional hazards model. RESULTS EGF-R was detected in 54% of primary tumors. When EGF-R was analyzed in different tissue specimens of the same tumor, consistent findings were noted in 88% (seven of eight) of cases. A lower concordance rate (nine of 15; 60%) was found between primary tumors and omental metastases, with a tendency toward higher EGF-R levels in the latter. The EGF-R expression did not significantly correlate with age, stage, grading, and residual tumor after primary surgery. In the univariate analysis, stage IV disease, postoperative residual tumor diameter greater than 2 cm, presence of ascites, and EGF-R positivity were found to be significantly associated with a greater risk of disease progression. In the multivariate analysis, only the postoperative residual tumor and the EGF-R expression remained significantly associated with a high risk of progression. CONCLUSION Data reported here suggest that the presence of EGF-R in advanced ovarian tumor at the time of the primary surgery identifies a subset of patients with a particularly poor prognosis.

Technique and feasibility of radical para‐aortic and pelvic lymphadenectomy for gynecologic malignancies: a prospective study

Of 284 patients evaluated for entry into the study between January 1986 and June 1990, systematic para-aortic and pelvic lymphadenectomy was performed in 208 cases (108 cervical cancer, 43 and 57 ovarian and endometrial cancer, respectively). The median number of nodes removed was 58, 49 and 54 for cervical, ovarian and endometrial cancer, respectively. The operating data are divided into 2 groups according to the consecutive number of the cases. The median operating time and the median estimated blood loss of lymphadenectomy was 230 minutes (range 120–270) and 390 ml (range 200–3300) in the first 95 cases. These operating data decreased to 150 minutes (range 100–240) and 250 ml (range 100–2800) in the second 113 cases. No surgery-related deaths occurred. Severe hemor-rages (blood loss exceeding 1000 ml) occurred in 6 patients. The obturator nerve was dissected in 1 patient and in 1 case the left ureter was cut. Formation of lymphoceles occurred in 20.4% of patients. Eighteen patients (8.8%) developed deep venous thrombosis. Nine of these patients experienced pulmonary microembolism. In 3 patients a retroperitoneal abscess was diagnosed. One patient developed a fistula of the most proximal part of the right ureter during the third postoperative week. The resection or coagulation of branches of the genito-femoral and obturator nerves determined mild paresthesis localized at the supero-anterior and internal side of thigh in 11 cases (5.4%). No statistically significant differences were found between the clinical (age, weight and previous chemotherapy) and pathological (type of cancer and lymph node status) parameters considered on one hand and postoperative complications on the other.

Squamous cell carcinoma antigen: prognostic significance and role in the monitoring of neoadjuvant chemotherapy response in cervical cancer.

PURPOSE The aim of the study was to investigate the role of squamous cell carcinoma antigen (SCC) in the management of patients with locally advanced cervical cancer treated by neoadjuvant chemotherapy and radical surgery. PATIENTS AND METHODS SCC assay was performed with a radioimmunoassay kit in a series of 102 patients with locally advanced cervical cancer. The values of 2.5, 5, and 7 ng/mL were used to define SCC antigen positivity. The chi 2 and Fishers exact test and the stepwise logistic regression were used to evaluate the distribution of marker values. Analysis of survival was performed using the Kaplan and Meier test and Cox multivariate regression analysis. RESULTS SCC levels were elevated in 65%, 45%, and 32% of patients with primary tumors for cutoff values of 2.5, 5, and 7 ng/mL, respectively. SCC pretreatment levels correlated with stage, tumor volume and lymph node status. In the multivariate analysis, SCC expression proved to be an independent predictor of response to neoadjuvant chemotherapy. SCC posttreatment levels were strongly related to chemotherapy response. Moreover, the overall correlation between the clinical course of the disease and the variation of SCC levels was 83%. In patients with squamous cell tumors, survival was significantly longer in SCC-negative cases compared with SCC-positive cases (P = .04). Moreover, in patients undergoing surgery after response to neoadjuvant chemotherapy, low SCC values were associated with better prognosis (P = .02). In the multivariate analysis, parametrial involvement and SCC status proved to retain an independent prognostic value. CONCLUSION Our data show that SCC assay may provide useful information to improve the prognostic characterization and disease monitoring of patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy.

Autologous blood stem cell harvesting and transplantation in patients with advanced ovarian cancer

We investigated the feasibility of a programme of autologous blood stem cell (ABSC) harvesting and transplantation in 13 patients with advanced ovarian cancer, previously untreated by chemotherapy or radiotherapy and entering a phase II study of high‐dose cisplatin, etoposide and carboplatin with haematopoietic stem cell rescue. Prior to high‐dose treatment all patients underwent two courses of cisplatin and cyclophosphamide. An 8‐fold increase of the peripheral colony forming unit granulocytic‐macrophage (CFU‐GM) was observed during recovery from myelosuppression after the first chemotherapy course. The second course determined a 2·5‐fold increase of peripheral CFU‐GM. In 70% of enrolled patients (nine patients) we were able to perform ABSC harvesting by leukaphereses; in the apheresed patients we harvested an average of 20·8 × 104/kg CFU‐GM (range 10·9–37·0). Haematopoietic trilineage engraftment, established as the number of days necessary to reach white blood cells (WBC) >1·0 × 109/1, polymorphonuclear leucocytes (PMN) >0·5 × 109/1 and platelets (PLT) >50·109/1. occurred very promptly and was sustained in the same series after high‐dose cisplatin, carboplatin and etoposide, followed by autologous blood stem cell transplantation (ABSCT). In our experience we found a significant correlation (r = 0·77; P<0·05) between CFU‐GM infused dose and the engraftment speed of PMN. We conclude that the combination of cisplatin and cyclophosphamide is effective in mobilizing haematopoietic progenitors in the peripheral blood of patients with advanced ovarian cancer, previously untreated by chemora‐diotherapy. Moreover, ABSCT is capable of rapidly restoring the haematopoietic function after high‐dose treatment and for this reason it represents a particularly advisable therapeutic option for the treatment of solid tumours because these patients are commonly older than 50 and can be excluded from bone marrow transplantation.

CA 15-3 as a tumor marker in gynecological malignancies

Serum levels of CA 15-3 were measured in 778 samples from 270 patients with benign and malignant gynecological conditions. Malignant tumors were present in 180 patients including 58 cases with cancer of the ovary, 47 of the endometrium, 61 of the cervix, and 14 of the vulva. The 90 cases with benign conditions included 24 patients with ovarian tumors, 28 with fibromyomatosis, 18 with endometriosis, and 20 with endometrial hyperplasia. Of 180 cancer patients, CA 15-3 serum levels were elevated (greater than 30 U/ml) in 74 cases (41%) and the frequency of abnormal marker values increased with clinical stage. Of 90 patients with benign conditions, high CA 15-3 levels were found in 5 cases (6%) with benign ovarian tumors. Elevated levels of the marker were most commonly seen in ovarian cancer patients (71%). In endometrial, cervical, and vulvar cancer abnormal CA 15-3 values occurred in 32, 26, and 14%, respectively. In endometrial cancer the percentage of positive marker levels increased with more infiltrating and/or less differentiated tumors. A positive correlation was found between residual tumor after surgery and CA 15-3 levels. Serial measurements in sera of patients who underwent chemotherapy showed a good correlation with response to treatment. CA 15-3 values were correlated with clinical course of disease in 87% of cases.

The pelvic retroperitoneal approach in the treatment of advanced ovarian carcinoma

Objective To evaluate the feasibility, complications, and clinical role of pelvic cytoreduction using the retroperitoneal approach in the treatment of advanced ovarian cancer. Methods We studied 66 women with previously untreated advanced ovarian cancer who underwent pelvic retroperitoneal surgery. The possibility of achieving extrapelvic cytoreduction (residual disease less than 2 cm), involvement of the Douglas cul-de-sac or vesicouterine fold, or the presence of a frozen pelvis were indications for the retroperitoneal approach. Operative time, blood loss and transfusions, perioperative complications, and postoperative stay were analyzed prospectively. The performance status of each patient was assessed preoperatively and postoperatively. Results The pelvic retroperitoneal approach was used in 66 of 147 (45%) consecutive patients who underwent primary surgery with intent of cytoreduction. This approach was necessary in 60 of 94 (64%) patients with residual tumor less than 0.5 cm and contributed to achieving such a minimal residual disease in 36 of 38 (95%) stage IIB-IIIB and 58 of 109 (53%) IIIC-IV patients. Severe morbidity, but with no longterm sequelae, occurred in six (9%) patients. Before surgery, only ten (15%) of these patients had performance status grade 0–1,21 (32%) had grade 2, and 35 (53%) grade 3–4. After surgery, These figures were 52 (79%), 14 (21%), and 0, respectively. The 5-year survival rate was 37%, with a median survival and follow-up time of 27 months (range 4–98) and 43 months, respectively. Conclusion If the proper technique is used, complete pelvic cytoreduction is always feasible and morbidity is acceptable. In our series, it was necessary to approach the pelvis retroperitoneally in 64% of optimally cytoreduced patients, which suggests that this technique has an importent clinical role in the treatment of patients with advanced ovarian cencer.

High-dose Chemotherapy with Autologous Peripheral Stem Cell Support in Advanced Ovarian Cancer

Twenty patients with advanced (stage III-IV), previously untreated ovarian carcinoma were treated by: (a) induction chemotherapy (40 mg/m2 cisplatin, days 1-4; 1.5 g/m2 cyclophosphamide, day 4; every 4 weeks for two cycles) followed by (b) intensification chemotherapy (100 mg/m2 cisplatin, day 1; 650 mg/m2 etoposide, day 2; 1.8 g/m2 carboplatin, day 3). Eligibility criteria further included: age less than 55 years, moderately good to poor tumour grade, macroscopic (> 0.5 cm) residual tumour. Autologous peripheral stem cells were recruited after the induction cycles and, to ensure haematological support, autologous bone marrow harvesting was routinely performed in the first 14 cases. Haematological support consisted of autologous peripheral stem cells and autologous bone marrow transplant in 16 and four patients, respectively. All patients are evaluable for toxicity and 19 for pathological response, one being dead of systemic mycosis 35 days after the autologous bone marrow transplant. Severe extra-haematological toxicities were the following: gastrointestinal (100%), neurological (10%), hepatic (10%). Pathological response was detected in 84% of cases (CR 37%, microscopic PR 26%, macroscopic PR 21%). Median follow-up times of 48 and 41 months have been reached respectively from enrolment and second-look. Four-year 62% overall and 57% progression-free survivals have been reached. Ten patients are still alive with NED (six of seven with CR, three of five with microscopic PR, and one of four with macroscopic PR). Autologous peripheral stem cell transplant significantly reduced the duration of aplasia compared with autologous bone marrow transplant, and toxicity was proved to be manageable in those patients undergoing autologous peripheral stem cell transplant. The prolonged disease-free survival in patients showing CR and microscopic PR suggests that further investigation on this new approach is worthwhile.

Efficacy and toxicity of very high‐dose cisplatin in advanced ovarian carcinoma: 4‐year survival analysis and neurological follow‐up

Given the steep dose-response relationship with cisplatin, a pilot study on very high-dose cisplatin (HD-CDDP) was conducted in previously untreated patients with advanced ovarian carcinoma and postoperative residual tumor (RT). Thirty-seven patients (FIGO stages III–IV; RT> 0.5 cm) received three courses of HD-CDDP (a course of 40 mg m−2 day−1 for days 1–5, every 28 days). Twenty patients (54%) achieved clinical complete response (CR), 12 (32%) partial response (PR), and the remaining five (14%) showed stable or progressive disease (NC-P). All 20 clinically complete responders underwent second-look laparotomy and CR was confirmed in all but five cases (pathologic CR: 40%) and in 71% of patients with> 0.5-2 cm RT vs. 15% of those with> 2 cm RT (P < 0.001). The 4-year overall survival was 35% (median: 27 months, range: 7–58+), and 53% vs. 20% for patients with> 0.5–2 cm and> 2 cm RT, respectively (P = 0.01). The overall progression-free survival was 29.5% (median: 16 months, range 2–58+) and for patients with more or less than 2 cm RT it was 20 and 41.2% (P < 0.05). Pathologically complete responders received no further treatment and showed a 3-year disease-free survival of 53%. The major toxic effect was a delayed-onset peripheral neuropathy observed in all patients, five of them (13.5%) with gait disturbances requiring continuous assistance. Nevertheless, none of them became wheelchair dependent and about 90% of the alive patients recovered at the 18-month neurologic follow-up, suggesting that cisplatin damage can be reversible. Ototoxicity was detected in all patients although only 19% of patients were symptomatic. HD-CDDP showed high activity in patients with> 0.5–2 cm RT, suggesting that the adverse significance of minimal RT may be partially overcome through an intensive chemical cytoreduction. Substantial neurotoxicity and the need for intensive care represent the major drawbacks. Further studies should delineate the exact role of HD-CDDP in optimally debulked patients, and a considerable effort should be made in rapidly achieving reliable data on the value of neuroprotectors in the prevention of the dose-limiting neurotoxicity.