Enhanced growth of an estrogen receptor-negative endometrial adenocarcinoma by estradiol in athymic mice.

The aim of this study was to investigate the effects of estradiol and tamoxifen (TAM) on the growth of human endometrial carcinomas in athymic mice. Tissues from primary tumors were implanted into estradiol-treated mice. In passage 2, animals were treated with (a) placebo, (b) estradiol, (c) estradiol plus TAM, and (d) TAM alone. The size of the tumors was measured weekly. Estrogen receptors (ER) were determined with the dextran-coated charcoal method and/or ER enzyme-linked immunoassay. Progesterone receptors were measured with the dextran-coated charcoal technique. Of 16 primary tumors, 2 grew in the athymic mice and were studied further. Tumor EL was positive for ER (145 fmol/mg protein) and progesterone receptors (993 fmol/mg protein). Tumor EL in passage 2 was not significantly stimulated by estradiol, but was stimulated by a combination of estradiol and TAM. Treatments (estradiol, estradiol plus TAM, or TAM) all increased tumor growth in passage 3. Tumor BR and a metastasis BR-MET were ER and progesterone receptor negative, applying dextran-coated charcoal, ER enzyme-linked immunoassay, and immunocytochemistry. The BR and BR-MET cells contain the complete ER gene but do not express any measurable amounts of ER mRNA as quantitated by Northern blot analysis, using a complete ER complementary DNA probe. In all animal passages the growth rate was significantly higher in estradiol-treated mice compared with the control. TAM alone had some growth stimulatory effect, but much smaller than observed in the estradiol group. TAM inhibited estradiol-stimulated growth. These results suggest that estradiol and possibly TAM are capable of stimulating tumor growth in the athymic mice independently from ER, potentially through a host-mediated mechanism.

Abdominopelvic irradiation for persistent advanced ovarian carcinoma.

The efficacy and toxicity of abdominopelvic irradiation following chemotherapy and positive second look laparotomy was assessed in 15 patients with advanced ovarian epithelial carcinoma. The patients received 30 Gy abdominal and 50.4 Gy pelvic irradiation. Three of ten patients with minimal disease are disease-free 30+, 72+, and 78+ months following therapy. A fourth patient survives disease-free 24+ months following third laparotomy. No patient with bulky disease is disease-free. Bowel obstruction was encountered in 5 of 15 patients; all episodes were associated with recurrent tumor. Abdominopelvic irradiation can potentially sterilize minimal volume ovarian carcinoma that persists following chemotherapy.

Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used.

PURPOSE: To update a previous retrospective study that compared inguinofemoral irradiation (N = 23) to lymphadenectomy (N = 25) for N0,N1 vulvar carcinoma with more patients and longer follow-up. These results, unlike the recent randomized Gynecologic Oncology Group (GOG study), suggest that radiation is a viable alternative to groin dissection, and the differences may be explained on the basis of irradiation technique. METHODS AND MATERIALS: Based on a growing body of data supporting control of subclinical nodal disease with irradiation in vulvar cancer, the decision was made to offer patients with squamous cell carcinoma of the vulva and clinically negative groins (N0,N1), either lymphadenectomy or inguinofemoral irradiation based on clinical factors. Because of the acute skin reaction and possible underdosing of deep femoral nodes with electrons as used in the GOG study, opposed photon fields to 50 Gy were used. From 1983 to 1991, 48 patients underwent a radical vulvectomy followed by either lymphadenectomy (Group I, n = 25) or inguinofemoral irradiation (Group II, n = 23). RESULTS: The actuarial nodal control was 100% in Group I and 91% in Group II (p = 0.14). In addition, there was no difference in cause specific survival at 3 years (96% and 90%, respectively, p = 0.47). The morbidity of lymphadenectomy (Group I) included: 16% lymphedema, 16% seromas, 44% infection, and 68% wound separation. In the irradiated patients (Group II), 16% developed lymphedema and only 9% had a significant skin reaction. CONCLUSION: Based on this analysis of local control and survival with longer follow-up and more patients, irradiation of the N0, N1 inguinofemoral nodes may be a viable alternative to lymphadenectomy for squamous cell carcinoma of the vulva if proper radiation technique and dose are used. In addition, the acute and delayed morbidity of lymphadenectomy exceeds that of irradiation.

Radiographic visualization of vaginal cylinders in gynecologic high dose rate brachytherapy.

PURPOSE: To develop a marker system allowing an accurate determination of vaginal applicator dimensions and geometry from a radiograph. METHODS AND MATERIALS: The markers consist of two sets of gold seeds embedded into each cylinder identifying the cylinder diameter, and a thin stainless steel disk interposed between adjacent cylinders identifying their interface. An evaluation of the dosimetric properties of the markers was undertaken. An applicator was assembled using four cylinders (4 cm diameter) surrounding a stainless steel uterine tandem with a stainless steel disk 0.05 mm thick and 3.6 cm in diameter interposed between each consecutive pair of cylinders. The assembly was placed on a film and an Ir-192 high dose rate source was programmed to a single dwell position within the applicator. The markers were removed and a second film was exposed with the same dwell position and time. This procedure was repeated with various dwell positions along the applicator. A scanning densitometer was used to measure the density profiles and isodensity distributions of each film. RESULTS: The optical density profiles and isodensity distributions with and without the markers in place were identical for all source dwell positions except when the source was centered in the plane of one of the stainless steel disks, where a maximum decrease of less than 2% in the dose rate was measured. The disks had no effect on the profiles measured along axes more than 2 cm from the projection of the applicator central axis on the film. CONCLUSION: The markers provide geometrical information about the position of the applicator relative to the anatomy necessary for optimized treatment planning. Slight dose perturbations resulting from the markers do occur, but only for dwell positions that center the source in the plane of a disk, and even then only at points very close to the disk. The markers can therefore be ignored from a dosimetric point of view.

High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: II. Procedural and physical considerations.

The loss in therapeutic ratio accompanying a conversion from low dose-rate (LDR) to high dose-rate (HDR) intracavitary brachytherapy (ICR) requires increased attention to the precision and accuracy of dose distribution calculations and treatment delivery. While the HDR-ICR treatment unit allows better custom-tailored dose distributions compared to LDR, it also requires more attention to detail to achieve the distribution desired. Because the relative biological effectiveness of different isodose levels in a dose distribution varies with the absolute dose (as described in Part 1 of this article), the relative dose distribution used with LDR must be modified for HDR to produce the same expected biological effect. Because of the difference in the radiobiology and physical positioning, simply duplicating applications as performed with LDR misses opportunities for dose distribution improvement as well as opens possibilities for significant complications. Due to differences in positioning the applicator (e.g., retraction of the cervix low in the pelvis instead of packing the applicator high), traditional definitions of points of interest (such as point A) apply poorly with HDR-ICR, compelling new systems of dose specification. With HDR-ICR, irreparable mistakes can happen very quickly, and quality assurance for the treatment plan and calculated dwell times prove much more important than with LDR. Key features of the dose distribution and constant relationships involving doses and dwell times help screen planned treatments for mistakes. This paper details the procedural and physical consideration of the Madison system for HDR-ICR brachytherapy for carcinoma of the cervix.

High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. Clinical and radiobiological considerations.

The decision to use five high dose rate intracavitary (HDR-ICR) insertions at weekly intervals for invasive carcinoma of the cervix treated at the University of Wisconsin Comprehensive Cancer Center (UWCCC) was made clinically. It was based on practical considerations and on previous clinical experience worldwide which showed that between 2 and 16 insertions have been used with apparently acceptable results. Although radiobiological considerations favor a large number of small doses, such a large number of HDR-ICR insertions is not clinically practical. Our strategy was to keep the biological effects of external beam and intracavitary insertions in the same ratio as used on a large series of patients treated here with low dose rate (LDR) therapy. This means keeping the same external beam treatment scheme and finding high dose rate (HDR) doses that are biologically equivalent to the previous LDR therapy, as far as possible. External beam and HDR intracavitary dose schedules for the Madison System of treating cervical carcinoma are described in detail. Because there is more repairable damage in late-reacting normal tissues, there is a bigger loss of sparing in these tissues than in tumors when changing from LDR to HDR, so total doses should be reduced more for equal late complications than for equal tumor control. The clinical decision was made to aim at equal tumor control. The possible increase in late complications has to be avoided by reducing the doses to critical normal tissues using extremely careful anatomic positioning of the HDR sources. Critical normal tissues must be kept further away from the radiation sources so that their doses are about 20% lower than with LDR geometry. This requires an extra separation of some millimeters depending on the anatomy and geometry of the individual insertion. The strategy is that the unfavourable radiobiological effects of a few large fractions must be counteracted by better physical dose distributions with HDR-ICR than with the previous LDR insertions. These good distributions are obtainable with the short exposures at HDR.

A comparison of the efficacy and complication rates of low dose-rate versus high dose-rate brachytherapy in the treatment of uterine cervical carcinoma.

PURPOSE: To compare the outcome and complication rates for treatment of uterine cervical carcinoma with low dose-rate (LDR) vs. high dose-rate (HDR) brachytherapy at the University of Wisconsin Comprehensive Cancer Center (UWCCC). METHODS AND MATERIALS: One-hundred ninety-eight evaluable patients with cervical carcinoma, Stages IB to IIIB, treated with curative intent with a combination of megavoltage teletherapy and LDR brachytherapy from 1977 to 1988 were the subject of an initial review. In 1989, a HDR treatment program was initiated where all patients with cervical carcinoma were subsequently treated with a combination of HDR brachytherapy and teletherapy. Using the linear-quadratic model (LQ), the dose and schedule of HDR brachytherapy and teletherapy were designed to give similar tumor control and late effects as LDR therapy. Technically, the HDR schedule required meticulous attention to treatment geometry to limit severe late effects. Forty patients treated with the HDR program with 2-4 year follow-up were reviewed and compared to the previous LDR patient group. The LDR and HDR treatment groups were comparable with regards to age, weight, stage distribution, bulk of disease, and histology. RESULTS: No significant difference in survival was found between the LDR and HDR groups with 3-year actuarial overall survival being 66% and 77%, respectively. Three-year actuarial pelvic control rates were similar at 80% and 77% for the LDR and HDR groups, respectively. No significant difference in late treatment complications requiring hospitalization or surgery was found between the two treatment groups with a complication rate of 10% (20/198) for the LDR patients and 2.5% (1/40) for the HDR patients. CONCLUSION: As predicted by our LQ calculations, treatment results for LDR and HDR brachytherapy were similar with respect to survival, pelvic control and late complications in the treatment of cervical carcinoma. The HDR brachytherapy program at the UWCCC appears to be a safe and effective alternative to LDR therapy in the treatment of cervical carcinoma.

Postoperative vaginal cuff irradiation using high dose rate remote afterloading: a phase II clinical protocol.

PURPOSE: In September 1989, a postoperative Phase II high dose rate (HDR) brachytherapy protocol was started for International Federation of Gynecology and Obstetrics (FIGO) Stage I endometrial adenocarcinoma. This review reports the overall survival, local control, and complication rates for the initial 63 patients treated in this Phase II study. METHODS AND MATERIALS: High dose rate brachytherapy was delivered using an Iridium-192 HDR remote afterloader. Sixty-three patients were entered into the Phase II protocol, each receiving two vaginal cuff treatments 1 week apart (range 4-12 days) with vaginal ovoids (diameter 2.0-3.0 cm). No patient received adjuvant external beam radiation. A dose of 32.4 Gy in two fractions was prescribed to the ovoid surface in 63 patients. The first three patients treated at our institution received 15, 16.2, and 29 Gy, respectively, to determine acute effects. RESULTS: At a median follow-up of 1.6 years (range 0.75-4.3 years) no patient has developed a vaginal cuff recurrence. One regional recurrence (1.6%) occurred at 1.2 years at the pelvic side wall. This patient is alive and without evidence of disease 7 months after completion of salvage irradiation, which resulted in the only vaginal stenosis (1.6%). Fourteen patients (22%) experienced vaginal apex fibrosis by physical exam, which was clinically symptomatic in four patients. Two patients reported stress incontinence; however, these symptoms were noted prior to their HDR therapy. One patient died 2.4 years after HDR therapy due to cardiovascular disease without evidence of cancer at autopsy. CONCLUSION: Preliminary results of our phase II HDR vaginal cuff protocol for postoperative FIGO Stage IA, Grade 3 or Stage IB, Grade 1-2 patients demonstrate that 32.4 Gy in two fractions is well tolerated by the vaginal cuff mucosa. Local control appears comparable to our prior experience and others with low dose rate (LDR) brachytherapy. Additional patient accrual and further follow-up will better determine the late morbidity, local control, and overall survival of these patients.

Impact of "optimized" treatment planning for tandem and ring, and tandem and ovoids, using high dose rate brachytherapy for cervical cancer.

PURPOSE: Different treatment techniques are used in high dose rate (HDR) remote afterloading intracavitary brachytherapy for uterine cervical cancer. We have investigated the differences between "optimized" and "nonoptimized" therapy using both a tandem and ring (T/R) applicator, and a tandem and ovoids (T/O), applicator. METHODS AND MATERIALS: HDR afterloading brachytherapy using the Madison System for Stage IB cervical cancer was simulated for 10 different patients using both a T/R applicator and a T/O applicator. A treatment course consists of external beam irradiation and five insertions of HDR afterloading brachytherapy. Full dosimetry calculations were performed at the initial insertion for both applicators and used as a reference for the following four insertions of the appropriate applicator. Forty dosimetry calculations were performed to determine the dose delivered to Point M (similar to Point A), Point E (obturator lymph nodes), vaginal surface, bladder, and rectum. "Optimized" doses were specified to Point M and to the vaginal surface. "Nonoptimized" doses were specified to Point M only. Using the linear-quadratic equation, calculations have been performed to convert the delivered dose using HDR to the biologically equivalent doses at the conventional low dose rate (LDR) at 0.60 Gy/h. RESULTS: Major differences between "optimized" and "nonoptimized" LDR equivalent doses were found at the vaginal surface, bladder, and rectum. Overdoses at the vaginal surface, bladder, and rectum were calculated to be 208%, nil, and 42%, respectively, for the T/R applicator with "nonoptimization." However, for the T/O applicator, the overdoses were smaller, being nil, 32%, and 27%, respectively, with "nonoptimization." CONCLUSION: Doses given in high dose rate intracavitary brachytherapy border on tissue tolerance. "Optimization" of either applicator decreases the risk of a dose that may have potential for complications. Optimization of a tandem and ovoids best ensures that the doses are not diminished at the treatment sites, and that the potential for overdose is reduced.

Minimization of small bowel volume within treatment fields utilizing customized "belly boards".

Thirty consecutive patients with pelvic malignancies were evaluated prospectively for the impact of a novel bowel minimization device ("belly board") on the volume of small bowel included within a four field pelvic radiation plan. A customized polyurethane and styrofoam bowel immobilization mold was created for each patient in the prone position. Using contrast enhanced CT scanning on a dedicated radiation treatment planning scanner, we imaged the location of the small intestine in the supine position and the prone position aided by the "belly board". Custom in-house interactive image analysis software was developed to allow volumetric determination of small bowel within the treatment portals. The mean small bowel volume was reduced by 66% (299 cm3 to 102 cm3), comparing the standard supine position to the prone position assisted by the "belly board". In 13 patients without prior pelvic surgery, the small bowel volume reduction was a more dramatic 74% (334 cm3 to 88 cm3). All patients were found to benefit from this prone "belly board" setup regardless of body habitus, weight, and age. Compliance with the set-up including use of bladder distension was excellent. All patients completed their pelvic radiotherapy without requiring a treatment break. Weight loss at completion averaged less than 5%. Seventy-six percent of patients experienced little or no diarrhea. This technique is comfortable, inexpensive, highly reproducible, and permits maximal bowel displacement from standard pelvic radiotherapy fields.

The adverse effect of treatment prolongation in cervical carcinoma.

PURPOSE: Proliferation of surviving tumor clonogens during a course of protracted radiation therapy may be a cause of local failure in cervical carcinoma. The effect of total treatment time was analyzed retrospectively in relation to pelvic control and overall survival for squamous cell carcinomas of the uterine cervix. METHODS AND MATERIALS: Two hundred and nine patients (Stage IB-IIIB) treated with a combination of external beam and low dose rate intracavitary irradiation were evaluable for study. Multivariate analysis and Kaplan-Meier statistical methods were used to determine the effect of treatment time on pelvic control and survival at 5 years. RESULTS: The median treatment duration was 55 days. For all stages combined, the 5-year survival and pelvic control rates were significantly different with treatment times < 55 days vs. > or = 55 days: 65 and 54% (p = 0.03), 87 and 72% (p = 0.006), respectively. By stage, a shorter treatment duration (i.e., < 55 days vs. > or = 55 days) was significant for 5-year overall survival and pelvic control for Stages IB/IIA and III, but not for Stage IIB: Stage IB/IIA (81 and 67%, 96 and 84%), Stage III disease (52 and 42%, 76 and 55%) and Stage IIB (43 and 50%, 74 and 80%, respectively). Survival decreased 0.6%/day and pelvic control decreased 0.7%/day for each additional day of treatment beyond 55 days for all stages of disease. Additionally, significant late complications were not influenced by treatment time. CONCLUSION: These results suggest that prolongation of treatment time is associated with decreased local control and survival in patients with cervical carcinoma. This is consistent with emerging data from other institutions. Therapeutic implications include avoidance of unnecessary treatment breaks, the design of fractionation schemes that decrease treatment duration, and possibly the use of tumor cytostatic drugs during conventional radiation.

Primary invasive squamous carcinoma of the vagina.

Forty-three cases of primary vaginal squamous cell cancer were treated at the University of Wisconsin Hospital between 1956 and 1971. These cases comprised 1.2% of patients admitted to the University Hospital with female genital tract cancer. Evidence is presented to support a modification of the currently accepted FIGO staging system for vaginal carcinoma (Stage II disease). Radiation therapy using both external beam and brachyradium equivalents or interstitial implantation of suitable isotopes was an effective method for the treatment of patients having early and locally advanced invasive vaginal cancer. The 5-year absolute survival rate for the entire series was 37.2%. Absolute survival rate by modified FIGO clinical staging was 66% for Stages I and IIA, 31% for Stage IIB, 25% for Stage III, and 0% for Stage IV.

The structure and origin of giant nuclei in human cancer cells.

The structure and origin of giant nuclei in human cancer cells were studied in two cases of squamous cell carcinoma of the cervix. Feulgen-squash preparations of untreated biopsies showed the following types of nuclei: fairly evenly stained nuclei, nuclei with distinct chromocenters from which individual chromosomes sometimes seemed to radiate, and nuclei with banded structures which we tentatively interpret as some type of "polytene" chromosomes possibly showing prophase chromomeres. In neither tumor did either the small or large nuclei display any X chromatin bodies. The main processes giving rise to the different types of nuclei are endoreduplication, true endomitosis, and a kind of polytenization. The multichromosome chromocenters that fell apart possibly represent polytene chromosomes separating into individual chromosomes.

Mitotic modifications and aberrations in human cervical cancer.

Mitotic modifications and aberrations characteristic of human malignant tumors have been analyzed and illustrated in cervical cancer. Most of them can be explained by assuming that the coordination of the centrosomal and chromosomal mechanisms, typical of normal mitosis, is disturbed. When the spindle mechanism is ahead of the chromosomes, the prophase is relatively shortened. This expresses itself in an increase of the ratio of metaphases to prophases (M/P), which in normal tissues is around 1. With M/P values of 4-6, the first tripolar metaphases are formed, and with higher ratios, divisions having more and more poles appear. The spindle and the chromosomes are out of step in the opposite direction in endocycles, in which the spindle is slowed down or absent. The most common of the endocycles is endoreduplication, followed by endomitosis, which is found in more than half of the cervical cancers. Mitotic abnormalities include lagging chromosomes in metaphase and anaphase and bridges in anaphase, which, when numerous, may lead to restitution. More sporadically occurring are C-mitosis and other abnormalities, including cell and nuclear fusions. There is a wide range of variation in the occurrence and frequency of chromocenters within a tumor, and an even greater variation between tumors. About one-fifth of cervical cancers lack X chromatin bodies. The abnormal chromosome constitutions in cancer are the result of various mitotic modifications and aberrations, as well as chromosome rearrangements. New chromosome combinations are constantly created and selection promotes the fastest dividing ones, which, in turn, become new stem lines of the tumor.

X chromatin, endomitoses, and mitotic abnormalities in human cervical cancer.

The incidence of X chromatin bodies and mitotic modifications and aberrations has been analyzed using Feulgen-squash preparations in 47 cervical cancers from Helsinki and 35 from Madison. Sixteen of the 82 tumors did not display any X chromatin bodies, and some others showed a lower than normal frequency, especially in the large nuclei. Different hypotheses to explain the absence of Barr bodies in female tumors have been reviewed. A new observation is that 44/82 tumors contained endomitoses. The metaphase/prophase ratio (M/P) was higher than 1.5 in all but three cases, reaching values as high as 23.0 (Madison) and 34.2 (Helsinki), and in one exceptional case, 51.8. The different types of cells, mitotic, endomitotic, and those with large to giant nuclei, form their own strands or layers. Cervical cancer is diagnosed earlier in Finland than in Madison due to a Pap mass screening program, and consequently, the survival of the patients after 5 years was 27/47 in Helsinki and 6/35 in Madison. No correlation could be established between the M/P (or other mitotic phenomena) or the stage and grade of the tumor, the age of the patient, or survival time.

A retrospective review of nodal treatment for vulvar cancer.

From 1983 to 1990, 42 clinical N0, N1 patients with invasive squamous cell carcinoma of the vulva underwent surgery for the primary cancer, followed by nonrandomized assignment to either surgery or radiation therapy for nodal management. This is a retrospective analysis reviewing treatment outcome and complications of inguinofemoral dissection versus photon irradiation. Group I (N = 24) underwent either bilateral or unilateral inguinofemoral dissection; Group II (N = 18) underwent bilateral groin irradiation. The 3-year disease-free survival was 84.5% and 79.7% for Group I and II (p = 0.74). The nodal failure rate at 3 years was not significantly different. The postoperative complications in the surgically treated nodes were: 17% seromas, 46% wound infection, and 71% wound separation. Of those patients developing either an infection or wound separation, 41% required daily wound care for more than 2 weeks by a visiting nurse after discharge. Only 1 of 18 (6%) irradiated patients developed a clinically significant skin reaction. The median time for complete skin/wound healing was 8 weeks (range 4-24 weeks) in Group I and 2 weeks (range 2-6 weeks) in Group II. Late postoperative complications in the surgically treated patients included meralgia paresthetica (8%) and lymphedema (12%); 1 (6%) Group II patient developed lymphedema. Based on this limited retrospective review, we conclude that inguinofemoral radiation achieves reasonable local control and may represent an alternative to surgery in selected patients. The acute and delayed morbidity of lymphadenectomy exceeds that of irradiation.