Michael B. Hanson

Therapeutic implications of patterns of recurrence in cancer of the uterine cervix

Five hundred twenty‐six patients with invasive cervical cancer, treated at the University of Kentucky from 1964 to 1976, were followed 2–12 years after therapy. One hundred and sixty patients (31%) developed tumor recurrence. Recurrent cancer was noted within 1 year after therapy in 58% of patients and within 2 years of treatment in 76% of patients. Only 6% of patients with recurrent cervical cancer survived 3 or more years. Stage of disease, cell type, lesion size, and the presence of lymph vascular space invasion by tumor cells were all shown to be prognostically significant. The addition of extrafascial hysterectomy to radiation therapy significantly decreased the incidence of recurrence in stage IB cervical tumors 5 cm or more in diameter. Analysis of this data suggests that radical hysterectomy and pelvic lymphadenectomy is as effective as irradiation only in the treatment of large cell squamous carcinomas 2 cm or less in diameter.

The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer.

Surgical specimens from 111 patients with Stage I endometrial cancer were reviewed for the presence of lymph‐vascular space invasion by tumor cells. Lymph‐vascular space invasion was noted in 16 cases, and occurred most frequently in poorly differentiated tumors with deep myometrial penetration. Tumor recurrence developed in 44% of patients whose tumors demonstrated lymph‐vascular space invasion as opposed to only 2% of patients without this finding (p < 0.001). Of seven patients with lymph‐vascular space invasion who experienced tumor recurrence, five developed extra‐pelvic metastases. Discriminant function analysis of these data revealed a statistically significant correlation between lymph‐vascular space invasion and tumor recurrence, independent of histologic differentiation of myometrial penetration. These findings suggest that lymph‐vascular space invasion by tumor cells is an important prognostic variable in Stage I endometrial cancer which should be considered in treatment planning.

Microinvasive carcinoma of the cervix.

One hundred seventy-seven patients with squamous cell carcinoma that invaded the cervical stroma to a depth of 5.0 mm or less were the subjects of this investigation. Fifty-one patients were treated primarily by vaginal hysterectomy, 42 by total abdominal hysterectomy, and 84 by radical hysterectomy with pelvic lymphadenectomy. In 52 patients with lesions that invaded the cervical stroma to a depth of 3.0 mm or less, 984 lymph nodes were examined and none contained metastatic tumor. Conversely, lymph node metastases were present in three of 32 patients with lesions that had stromal invasion of 3.1 to 5.0 mm. After therapy, all patients were followed up from 2 to 14 years, and none was lost to follow-up. Among 145 patients with lesions that invaded the stroma to a depth of 3.0 mm or less, only two developed recurrences, both of which were intraepithelial. Among the 32 cases of carcinoma that invaded the stroma 3.1 to 5.0 mm, there were three invasive recurrences, and two deaths.

Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel‐shaped cervical cancer

Seventy‐five patients with bulky barrel‐shaped Stage IB cervical cancers, treated at the University of Kentucky from 1965 to 1981, were the subjects of this investigation. Thirty‐two of these patients were treated with radiation therapy alone and 43 were treated with radiation followed by extrafascial hysterectomy. There were no significant differences in age, gravidity, or tumor cell type between the two treatment groups. Patients were seen at regular intervals from 2 to 11 years after treatment and none were lost to follow‐up. Recurrent cancer was noted in 47% of patients treated by radiation alone as compared to 16% of those treated with combined therapy (P < 0.01). The incidence of pelvic recurrence was reduced from 19% to 2% and extrapelvic recurrence from 16% to 7% in patients treated by combination therapy. No rectal or urinary tract fistulae were noted after extrafascial hysterectomy. The findings of this study suggest that the use of extrafascial hysterectomy following radiation therapy in patients with bulky Stage IB cervical cancer causes a significant reduction in tumor recurrence without producing an increase in treatment‐related complications.

Radiation‐induced tumor regression as a prognostic factor in patients with invasive cervical cancer

Radiation‐induced tumor regression was evaluated as a prognostic factor in 200 patients with invasive cervical cancer treated at the University of Kentucky Medical Center during the years 1973–1977. Radiation responses were classified as complete (Type A), intermediate (Type B), or incomplete (Type C) based upon pelvic examination findings one month following completion of therapy. Patients with Type A response to radiation had a recurrence rate of 5%, as compared with 27% in patients with a Type B response and 85% in patients with a Type C response. The direct relationship between radiation response and the incidence of tumor recurrence was observed in all stages of disease. Seventy‐five percent of patients with Stages IB and IIB disease and a Type C response to radiation developed recurrent cancer, and tumor recurrences were confined to the central pelvis in the majority of cases. Patients with keratinizing squamous cell cancers had the lowest incidence of complete response to radiation. These findings suggest that careful observation of cervical cancer throughout radiation therapy can provide prognostically significant information concerning radiation‐induced tumor regression. The therapeutic implications of this data is discussed.

Prognostic parameters in invasive vulvar cancer.

Prognostic parameters were studied in 66 patients with invasive squamous cell vulvar cancer treated with radical vulvectomy and bilateral inguinal and femoral lymph node dissection. Patients with metastases in regional lymph nodes had a 46% survival for 3 or more years compared to 76.3% in patients without evidence of nodal spread. The presence of lymph nodal metastases correlated directly with stage, lesion size, depth of invasion, and the presence of lymph-vascular space involvement with tumor. However, even the best prognostic groups had a 30% incidence of positive nodes. No patient with less than 5 mm of stromal invasion without vascular involvement had positive nodes. These preliminary data suggest that careful observation of vascular space invasion by tumor cells together with measurement of the depth of stromal invasion may help define a group of patients with vulvar cancer that can be treated conservatively. Further studies are needed to confirm these findings in larger numbers of patients.

Therapy of endodermal sinus tumor of the ovary.

Endodermal sinus tumor of the ovary can be differentiated histologically and immunohistochemically from ovarian embryonal cell carcinoma. A case report of a patient with endodermal sinus tumor is presented in which a long-term remission was achieved by unilateral adnexectomy and combination chemotherapy. Review of the current literature indicates that tumor removal followed by combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide is the most effective method of therapy for this highly malignant ovarian neoplasm. The addition of hysterectomy with contralateral ovariectomy or radiation therapy does not appear to significantly improve the survival of patients with this tumor. Serial plasma determinations of alpha fetoprotein provide biochemical monitoring of response to therapy and may be useful in predicting occult tumor recurrence.

Adjuvant vincristine, dactinomycin, and cyclophosphamide therapy in stage i uterine sarcomas. A pilot study

Seven patients with Stage I uterine sarcomas (10 mitoses/10 high‐power fields) were treated with surgery plus adjuvant vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy in a pilot study conducted at the University of Kentucky Medical Center from 1978 to 1983. Surgery consisted of total abdominal hysterectomy, bilateral salpingo‐oophorectomy, and para‐aortic lymph node sampling. Chemotherapy was begun within 1 week of surgery, and all patients received at least six monthly courses of VAC. This chemotherapeutic regimen was well‐tolerated, and toxicity was minimal. Two patients had recurrent sarcoma, and one of them has died of disease. The remaining five patients are alive and well with no evidence of disease 48 to 73 months after therapy. The recurrence rate of patients with Stage I uterine sarcomas treated with adjuvant VAC chemotherapy was significantly (P < 0.02) less than that for similar patients treated at this institution (1964–1977) by surgery alone or surgery plus pelvic radiation. These results suggest that primary adjuvant chemotherapy is beneficial in patients with Stage I uterine sarcomas. Cancer 57:1451–1454, 1986.

Immature teratoma of the ovary

Four cases of immature teratoma of the ovary are presented and the recent literature is reviewed. The majority of these tumors were confined to one ovary at the time of diagnosis, and more than 75% occurred in women under 25 years of age. The two most important prognostic parameters were stage of disease and histologic grade. Optimal survival occurred when surgical tumor debulking was followed by combination chemotherapy. The addition of hysterectomy with contralateral adnexectomy did not improve the survival of patients with disease confined to one ovary. Similarly, postoperative radiation therapy was not shown to be beneficial in patients with this disease. Analysis of presently available data suggests that patients with teratocarcinoma of the ovary should be treated with tumor excision followed by at least 12 courses of chemotherapy with vincristine, actinomycin D, and cyclophosphamide. alpha-Fetoprotein may be useful as a biochemical marker of disease status in selected patients.

Biochemical markers in the plasma and tumors of patients with gynecologic malignancies

Tumor markers in gynecologic malignancies can be classified generally as oncofetal proteins, carcinoplacental proteins, and more specific tumor‐associated antigens. Carcinoembryonic antigen (CEA) is most effective as a tumor marker in mucinous adenocarcinomas of the endocervix and ovary and in keratinizing squamous cell carcinomas of the cervix. In contrast, the use of alphafetoprotein (AFP) in gynecologic cancer is limited to patients with germ cell tumors of the ovary and specifically endodermal sinus tumors. The beta subunit of human chorionic gonadotropin (β‐hCG) remains an exemplary tumor marker for trophoblastic malignancies and may be useful in selected patients with epithelial carcinomas of the ovary. Plasma levels of these antigens are generally related to total tumor burden (tumor antigen concentration x extent of disease). Although the lack of specificity of these markers has limited their use in the diagnosis of gynecologic malignancies, they have been effective as a means of monitoring disease status in patients whose tumors contain high antigen concentrations. More specific tumor‐associated antigens have been described in ovarian cervical cancers, but their clinical efficacy remains to be demonstrated in large numbers of patients. Immunohistochemical staining of tissue specimens identifies patients whose tumors contain high antigen concentrations and who therefore should benefit most from serial plasma determinations following therapy. Potential future uses of biochemical markers include radioimmunodetection procedures using radiolabelled antibodies to tumor‐associated antigens and antigen‐directed chemotherapy.