G. Baiocchi

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.

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.

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.

Endometrioid stromal sarcomas arising from ovarian and extraovarian endometriosis: Report of two cases and review of the literature

Endometrioid stromal sarcomas arising from endometriosis are rare tumors. Two cases from our institution are presented and the literature is reviewed. The patients tend to be nulliparous. Presentations usually are related to the symptoms of a pelvic mass. However, extraovarian origin was frequently accompanied by hemorrhage. The tumors are usually of low histologic grade. Among 18 patients with ovarian origin, only 2 were reported dead of disease. However, 5 of 13 patients with extraovarian origin died mostly as a result of recurrent disease. Deaths generally occurred within 3 years of diagnosis. The efficacy of chemotherapy, radiotherapy, or hormonal therapy in the adjuvant or recurrent setting cannot be determined from the available reports.

Epidermal growth factor receptor expression in gynecological malignancies

Epidermal growth factor receptor (IEGF-R) levels were analyzed in 72 gynecological tumor specimens. Measurable EGR-R levels were found in a significant percentage of ovarian and uterine tumors. Moreover, all vulvar epidermoid carcinomas and uterine sarcomas analyzed were EGF-R positive. In all tumor types examined, scattered EGF-R levels were observed. Higher EGF-R levels were found in metastatic than in primary ovarian tumors. Moreover, EGF-R were found to be more expressed in less differentiated than in well-moderately differentiated endometrial tumors. Our results suggest a role of EGF or EGF-like substances in regulating the growth of gynecological malignancies, and indicate EGF-R expression as a possible prognostic factor.

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.

Immunological reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation for advanced ovarian cancer

We evaluated the immunological reconstitution of patients who underwent high-dose chemotherapy and autologous blood stem cell transplantation (ABSCT) for advanced ovarian cancer. Sixty days after transplantation a complete reconstitution of lymphocytes and of the CD3, CD4, CD8, CD19, and CD16/56 subsets was observed in this series. A significant increase in the count of interleukin-2 receptor expressing lymphocyte (CD25) was found on day +60 after transplantation compared to that obtained at diagnosis and before transplantation. A significantly higher lymphokine-activated killer (LAK) precursor activity was seen on day +60 compared to the values obtained at diagnosis and before transplantation while natural killer activity did not show any significant variation. We conclude that ABSCT gives prompt and complete immunohaematopoietic reconstitution after high-dose treatment. Moreover, our data support the feasibility of interleukin-2/LAK therapy as consolidative therapy after ABSCT.

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.

Steroid hormone receptors in carcinoma of the cervix: Lack of response to an antiestrogen

Levels of estrogen (ER) and progesterone (PR) receptors were measured in 81 patients with primary cervical cancer. In 10 patients, receptor levels were evaluated before and after a short course of tamoxifen treatment. Fifty-six percent of cervical tumors contained ER, and 58%, PR. Receptor level and expression were not related to any clinical and histological characteristic. Moreover, both survival time and response to neoadjuvant chemotherapy did not correlate with the presence of ER and PR. Tamoxifen treatment did not influence ER and PR levels. Our results suggest that steroid hormone receptors are of little value in the management of cervical cancer, and that in this neoplasia, ER is probably not functional.

A primary amelanotic melanoma of the vagina diagnosed by immunocytochemistry

A case of primary malignant melanoma of the vagina is discussed. The lesion consisted of a nodule in the middle third of the vagina that was histologically suspected of being an unpigmented malignant melanoma. The melanocytic origin of the lesion was confirmed by the pattern of reactivity to a battery of human melanoma associated antigens and to class 1 and 2 histocompatibility antigens. No secondary lesions or alternative primary sites were found. The patient underwent radical hysterectomy with bilateral salpingo‐oophorectomy, total vaginectomy and vulvectomy, radical inguinal, pelvic and para‐aortic lymphadenectomy. The pathology report showed the presence of multiple neoplastic foci in the vagina. Although the removed lymph nodes were histologically free of metastases, microscopic foci of neoplastic cells were detected by immunohistochemistry in three lymph nodes. There is no evidence of recurrence at the twelfth postoperative month. Our results show that immunohistochemical techniques may usefully complement diagnostic histopathology in the diagnosis of female genital tract melanoma.