Multimodality therapy: radiation and continuous concomitant cis-platinum and PKC inhibition in a cervical carcinoma model.

The addition of chemotherapy to radiation therapy has the potential to sterilize micrometastases and tumor foci adjacent and peripheral to the treatment field, so as to enhance local control of malignancy and improve primary and salvage therapy. Studies were done to investigate the effects of combining cisplatin (CP), the most active single agent in squamous-cell cancer of the cervix, with irradiation and the addition of a protein kinase C (PKC) inhibitor. This initial report of these studies describes our experience in exposing human cervical carcinoma (HeLa-S3) cells grown in culture as multicellular tumor spheroids to continuous CP combined with radiation in an attempt to mimic both clinically achievable serum concentrations of CP and a weekly fractionated-dose environment. Radiation-dose-dependent delays of spheroid growth were not significantly increased in the presence of the PKC inhibitor 7-OH-staurosporine (UCN-01) at 1.0 nM and 10.0 nM concentrations. When dose comparisons at 8 Gy alone (2 Gy x 4 fractions) were made for combined therapy with either CP alone (1.0 microgram/ml) or UCN-01 alone, absolute delays in spheroid growth at the highest concentrations used were comparable (range: 37-41 days). Although these data alone would not support minimal chemotherapeutic interaction, it appears that the overall effects observed for combination therapy were predominately radiation-dose dependent. The combination of UCN-01 plus CP (0.5 and 1.0 mu/ml, respectively) was effective in increasing the cytostatic and cytotoxic effects of irradiation at 4 Gy (2 Gy x 2 fractions). Observations made as early as day 4 and day 7 posttreatment were indicative of > or = 40% and 60%, respectively, of morphological damage. Spheroid growth was essentially static at these doses over the evaluation time of 60 days. Intracellular junctions were disorganized, and spheroid swelling was evident and contributed to the modest dimensional changes observed after treatment. No surviving fractions could be generated from spheroids that were mechanically disrupted, trypsinized, and plated at day 7 after the initiation of treatment. At 2 months, 88% (14/16) and 94% (15/16) of the multimodality treatment groups (4 Gy + UCN-01 + CP [0.5 and 1.0 mu/ml], respectively) had sterilized spheroids, indicating that the CP concentration dependence may not be a sole determinant of efficacy. Our therapeutic strategy for combining irradiation with CP was based on the contemporary use of CP as the most successful agent in producing high survival rates in gynecological malignancy. The combination of UCN-01 with CP and irradiation may, however, represent a more effective strategy for enhancing future cisplatin-based chemotherapy regimens.

Outcome of recurrent cervical carcinoma following definitive irradiation.

This report is a retrospective analysis of 376 patients with recurrent cervical carcinoma, following definitive radiation therapy to 1054 patients with stage IB-IVA carcinoma of the uterine cervix treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, from January 1959 through December 1982. The sites of failure after treatment by stage at initial diagnosis were classified as pelvic only (P), pelvic plus distant metastasis (P + DM), or distant metastasis only (DM). The sites of first failure were for stage IB, P = 0.8%, P + DM = 7.4%, DM = 7.9%; for stage IIA, P = 1.7%, P + DM = 14.7%, DM = 17.2%; for stage IIB, P = 10.4%, P + DM = 11.0%, DM = 14.9%; for stage III, P = 15.4%, P + DM = 23.9%, DM = 18.9%; and for stage IV, P = 16.7%, P + DM = 61.1%, DM = 16.7%. The actuarial probability of pelvic failure at 5 years from initial therapy was 8% for stage IB, 16% for stage IIA, 21% for stage IIB, 42% for stage III, and 100% for stage IV. The incidence of distant metastasis at 5 years was 14, 32, 28, 47, and 100% for stages IB, IIA, IIB, III, and IV, respectively. The therapy after failure was surgery, irradiation, irradiation plus surgery, or chemotherapy. There appeared to be no major difference in survival after recurrence by type of treatment or initial stage. The overall survival at 5 years for all untreated patients was 1%. The median survival was evaluated as a function of time to failure after initial treatment. Patients who developed disease more than 36 months after initial treatment had a median survival of 22.5 months. The median survival was 12.1, 7.6, 9.4, and 9.1 months for those failing less than 6, 6-12, 13-24, and 25-36 months after initial treatment. Severe treatment complications occurred in 3.6% (5/140).

Daunorubicin conjugated to a monoclonal anti-CA125 antibody selectively kills human ovarian cancer cells.

The present study was designed to test the in vitro efficacy for human ovarian cancer cells of daunorubicin (DNR) conjugated to a monoclonal antibody (OC125). The OC125 antibody specifically binds to the antigenic protein CA125 from human ovarian carcinoma. New analogs of DNR containing various linker groups were conjugated to mouse monoclonal anti-CA125 antibody (DNR-OC125); nonspecific murine IgG1 (DNR-IgG1); or bovine serum albumin (DNR-BSA). The DNR-protein conjugates were all stable for several days in neutral solutions at room temperature. The DNR-OC125 conjugates selectively killed dividing cell populations but not nondividing cell populations of two human ovarian cancer cell lines (SK-OV-3 or OVCAR-3) that express the CA125 antigen. Equivalent concentrations of DNR-IgG1 or DNR-BSA conjugates were neither toxic to the dividing nor the nondividing populations of SK-OV-3 or OVCAR-3 cells. Only those DNR-protein conjugates linked to OC125 were cytotoxic to dividing cell populations of both cell lines. This indicates that cytotoxicity is dependent on OC125 antibody-CA125 antigen binding which concentrates DNR on the ovarian cancer cells. We advance the hypothesis that following antibody-antigen binding, DNR is released from the conjugate and it intercalates in DNA by a mechanism similar to that of the unmodified DNR. The new DNR-OC125 conjugate may be useful for delivering DNR to ovarian tumors that express the CA125 antigen because the drug-antibody conjugates (1) retain the cytotoxic characteristics of the unmodified drug: (2) specifically kill the human ovarian cancer cells that express the CA125 antigen; and (3) are completely stable for days in neutral solutions at room temperature.

Therapy of ovarian carcinoma: the relationship of dose level and treatment intensity to survival.

Following primary maximal cytoreduction, 71 previously untreated patients with advanced epithelial ovarian carcinoma received at least six courses of combination chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide. The cumulative dose (CD) through three (CD3) and six (CD6) courses was calculated for each drug and for all drugs combined. The dose intensity (DI) through three (DI3) and six (DI6) courses was calculated for each drug by dividing CD3 and CD6 by the interval (in weeks) between surgery and the third and sixth course. The interval from surgery to the third or sixth course had no effect on survival. Similarly, there was no significant difference in survival between patients with high and low CD3 or CD6 for any drug or for all drugs combined. Patients with high DI6 for cisplatin, doxorubicin, and all drugs combined survived significantly longer than those with low DI6. The survival difference for patients with high and low DI6 for cyclophosphamide approached, but did not attain, statistical significance at the 0.05 level. The intensity with which combination chemotherapy is administered may have an impact upon survival in patients with ovarian carcinoma.

Radiation therapy and conservation surgery for primary and recurrent carcinoma of the vulva: report of 40 patients and a review of the literature.

Forty patients with histologically confirmed primary or recurrent vulvar carcinoma were treated with radiation therapy for loco-regional disease. Nineteen of the patients with primary tumors received postoperative radiotherapy (5000 cGy in 6 weeks). Fifteen of the 19 exhibited local tumor control. Five patients with Stage III or IV disease were managed with radiotherapy alone. Four had a complete response with two currently NED. Two patients who received preoperative radiotherapy with local excision are also currently free of disease. The 4-year NED survival for the study population is 100%, 28%, 50%, 0% and 10% for Stage I, II, III, IV and recurrent tumors respectively. The poor results obtained in Stage II tumors is likely due to selection criteria since four of seven patients developed distant metastases. Two of the 14 patients treated for recurrent disease remain NED after local excision of their tumors prior to irradiation. Even though the number of patients is small no dose response for subclinical disease could be found between 4500 and 7000 cGy. Treatment morbidity was acceptable with two patients developing severe long-term complications requiring surgical intervention.

Serum copper in ovarian carcinoma.

The serum copper and CA 125 levels of 31 patients with epithelial ovarian carcinoma were determined. Serum copper was elevated in seven patients and CA 125 was elevated in 22 patients. A rise in serum CA 125 always was associated with disease progression. In comparison, serum copper fluctuation did not correlate with the natural history of the malignancy. We concluded that serum copper determination has no use in epithelial ovarian carcinoma management.

Six independent neoplasms in one woman. A case report.

A woman had six independent neoplasms. In reviewing the world literature, no case report was found of a patient with carcinomas of the skin, cecum, kidney, ovaries (bilateral, independent and synchronous) and endometrium.

Prognostic significance of squamous differentiation in stage I endometrial adenocarcinoma.

The prognostic implication of benign and malignant squamous differentiation was examined in 267 consecutive patients with stage I endometrial carcinoma. Patients with adenosquamous carcinoma had a significantly poorer ten-year survival rate (54.7%) than patients with adenocarcinoma (70.5%) or adenoacanthoma (87.4%). This was related to a tendency for adenosquamous carcinoma to be associated with poorly differentiated glandular elements and to deeply invade the myometrium. The mean depth of myometrial penetration was 57% for adenosquamous carcinoma compared with 24% for adenocarcinoma and 19% for adenoacanthoma. To examine the prognostic significance of malignant squamous differentiation independently of the grade of the associated glandular component, the subgroup of patients with well-differentiated adenocarcinoma was compared. Patients with well-differentiated adenosquamous carcinoma persisted in having a worse prognosis (58.3% ten-year survival rate), compared with adenocarcinoma (84.3% ten-year survival rate), which was explained by the propensity of adenosquamous carcinoma to deeply invade the myometrium.

A case of endometrioid carcinoma of the ovary associated with pregnancy.

This is the second report of endometrioid carcinoma of the ovary associated with an intrauterine pregnancy. The previous report presented six cases, making this the seventh. Characteristics of the tumor are reviewed, as are the guidelines for the management of ovarian carcinoma complicating pregnancy.