An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. PATIENTS AND METHODS: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. RESULTS: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). CONCLUSIONS: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. CLINICAL TRIALS: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Adjuvant Radiotherapy in Stage II Endometrial Cancer: Selective De-intensification of Adjuvant Treatment.

AIMS: Risk stratification, including nodal assessment, allows for selective de-intensification of adjuvant radiotherapy in stage II endometrial cancer. Patterns of treatment and clinical outcomes, including the use of reduced volume 'mini-pelvis' radiotherapy fields, were evaluated in a population-based study. MATERIALS AND METHODS: All patients diagnosed with pathological stage II endometrial cancer between 2000 and 2014, and received adjuvant radiotherapy in a regional healthcare jurisdiction were reviewed. Registry data were supplemented by a comprehensive review of patient demographics, disease characteristics and treatment details. The Charlson Comorbidity Score was calculated. Survival and recurrence data were analysed. RESULTS: In total, 264 patients met the inclusion criteria. Most patients had endometrioid histology (83%); 41% of patients had International Federation of Gynecologists and Obstetricians grade 1 disease. Half (49%) had surgical nodal evaluation; 11% received chemotherapy. Most patients (59%) were treated with full pelvic radiotherapy fields ± brachytherapy. Seventeen per cent of patients received mini-pelvis radiotherapy ± brachytherapy, whereas 24% received brachytherapy alone. Five-year recurrence-free survival was 87% for the entire cohort, with no significant difference by adjuvant radiotherapy approach. Only one patient receiving mini-pelvis radiotherapy ± brachytherapy recurred in the pelvis but outside of the mini-pelvis field. Recorded late toxicity rates were highest for full pelvis radiotherapy + brachytherapy. CONCLUSION: Risk stratification in a real-world setting allowed for selective de-intensification of adjuvant radiation with equivalent outcomes for stage II endometrial cancer. Mini-pelvis radiotherapy combined with brachytherapy is effective in highly selected patients, with the potential to decrease toxicity without compromising local control. Brachytherapy should be considered in low-risk stage II patients.

Palliative radiotherapy for women with breast cancer.

AIMS: Palliative radiotherapy (PRT) plays an important role in women with metastatic breast cancer. However, not all cancer patients with an indication for PRT receive it. The aim of this study was to measure the use of PRT for women who have died of breast cancer in the Canadian province of Alberta, and to identify factors that might affect this use. MATERIALS AND METHODS: All women who died of breast cancer in Alberta between 2000 and 2004 were identified from the Alberta Cancer Registry. PRT, defined as any radiotherapy given with palliative intent, was abstracted from the radiotherapy databases of the treatment facilities of the Alberta Cancer Board (ACB). The variables evaluated were: age at death, regional health authority (RHA), driving distance to nearest radiotherapy facility, receipt of initial treatment at an ACB facility, receipt of radiotherapy as part if initial treatment, residence in a city with an ACB facility, residence in a city with radiotherapy facilities or visiting radiation oncologists, median household income, and municipality population. Backwards stepwise logistic regression was used to determine the final set of predictor variables for the use of PRT. RESULTS: In total, 1906 women were identified as having died of breast cancer between 2000 and 2004, inclusive. Of these, 50.4% received at least one course of PRT. Factors associated with not receiving PRT in the final multiple logistic regression model for women who lived outside of the cities with radiotherapy facilities were: age>75 years, community size>10,000, median income<$47,000, and residence in RHA 4. For women living in cities with radiotherapy facilities, only age was significant. CONCLUSIONS: There are many factors that influence the receipt of PRT in Alberta that are unrelated to patient need. The education of physicians and patients, as well as the establishment of more radiotherapy facilities, will help to improve the use of PRT.

Patterns of disease progression and outcomes in a randomized trial testing ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: In the National Cancer Institute of Canada Clinical Trials Group/Eastern Cooperative Oncology Group HD.6 trial, progression-free survival was better in patients randomized to therapy that included radiation, compared to doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) alone. We now evaluate patterns of progression and subsequent outcomes of patients with progression. PATIENTS AND METHODS: After a median of 4.2 years, 33 patients have progressed. Two radiation oncologists determined whether sites of progression were confined within radiation fields. Freedom from second progression (FF2P) and freedom from second progression or death (FF2P/D) were compared. RESULTS: Reviewers agreed for the extended (kappa = 0.87) and involved field (kappa = 1.0) analyses. Progression after ABVD alone was more frequently confined within both the extended (20/23 vs. 3/10; P = 0.002) and involved fields (16/23 vs. 2/10; P = 0.02). There was no difference in FF2P between groups [5-year estimate 99% (radiation) versus 96% (ABVD alone)] [hazard ratio (HR) = 3.14, 95% confidence interval (CI) 0.63-15.6; P = 0.14]; the 5-year estimates of FF2P/D were 94% in each group (HR = 1.04, 95% CI 0.41-2.63; P = 0.93). CONCLUSION: Treatment that includes radiation reduces the risk of progressive Hodgkin lymphoma in sites that receive this therapy, but we are unable to detect differences in FF2P or FF2P/D.

Is tumor cell radiation resistance correlated with metastatic ability?

Patients who experience local failure following radiation treatment of epithelial malignancies exhibit a substantially higher rate of distant metastasis than those patients who achieve permanent local control. This fact has raised concern that the local failure to control the primary/regional tumor may serve as a marker of a particularly malignant neoplasm, i.e., high metastatic activity and radiation resistance. If this were true, there would be no gains in survival by increasing the efficacy of treating the primary/regional disease because the new local controls would develop distant metastasis. To investigate this concept, the relationship between distant metastasis probability and tumor cell radiation resistance has been studied by examining laboratory and clinical data (in vitro and in vivo assays) from six collaborating centers. TCD50s (radiation dose which inactivates half of the irradiated tumors) and incidence of distant metastasis in mice with local control have been evaluated for 24 murine tumor systems. SF2s (surviving fraction after 2 Gy) were determined in vitro for cell lines from 8 human, 13 mouse, and 15 rat tumors/tumor sublines and the metastatic activity assessed after injection of the cells into syngeneic murine hosts and xenogenic hosts for the human tumors. SF2s of cells from carcinomas of the head/neck, cervix, and endometrium which were controlled locally by radiation +/- surgery from four centers were compared for those which did and those which did not metastasize. The total number of patients studied was 222. The cumulative distributions of SF2s of locally controlled tumors which did and did not metastasize were not different in each of the data sets. Similarly, there was no demonstrable relationship between TCD50s and metastatic frequency in local control mice. Furthermore, the SF2s of murine and human tumor cell lines did not track with metastatic activity. Radiation sensitivity of clinical and laboratory tumors did not correlate with metastatic activity in studies of data from six centers.

Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix.

PURPOSE: To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS: A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS: A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION: This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule?

PURPOSE: A literature review and analysis was performed to determine whether or not efficacious high dose rate (HDR) brachytherapy fractionation schedules exist for the treatment of cervical cancer. METHODS AND MATERIALS: English language publications from peer reviewed journals were assessed to calculate the total contribution of dose to Point A from both the external and intracavitary portions of radiation for each stage of cervical cancer. Using the linear quadratic formula, the biologically effective dose to the tumor, using an alpha/beta = 10, was calculated to Point A (Gy10) in order to determine a dose response relationship for local control and survival. Significant complications were assessed by calculating the dose to the late-responding tissues at Point A using an alpha/beta = 3 (Gy3) as a surrogate for normal tissue tolerance, since few publications list the actual bladder and rectal doses. RESULTS: For all stages combined, the median external beam fractionation schedule to Point A was 40 Gy in 20 fractions, while the median HDR fractionation schedule was 28 Gy in 4 fractions. For stages IB, IIB, and IIIB the median biologically effective dose to Point A (Gy10) was 96, 96 and 100 Gy10s, respectively. No correlation was identified between Point A BED (Gy10s) to either survival or pelvic control. A dose response relationship could also not be identified when correlating Point A Gy3s to complications. CONCLUSION: A dose response relationship could not be identified for either tumor control nor late tissue complications. These findings do not necessarily question the validity of the linear quadratic model, as much as they question the quality of the current HDR brachytherapy literature as it is currently presented and reported. Most of the HDR publications report inadequate details of the dose fractionation schedules. Only a minority of publications report significant complications using the actuarial method. In the future, all HDR publications for the treatment of cervical cancer should provide accurate fractionation details for each stage of disease, while reporting actuarial complication rates. The optimal fractionation schedule for treating cervical cancer using HDR brachytherapy is still unknown, and presently can be based only on single institutions with significant experience.

A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer.

PURPOSE: This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer. METHODS AND MATERIALS: Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ. RESULTS: Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease. CONCLUSION: Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.

An analysis of the impact of pathology review in gynecologic cancer.

PURPOSE: To analyze the impact of pathology review in gynecologic malignancies. METHODS AND MATERIALS: For all new gynecologic patients seen between December 2, 1993 and January 4, 1996, we conducted a retrospective chart review to determine if a pathology review by the institute's consultant pathologist changed the diagnosis, and if so whether the change altered patient management. A total of 514 patients were seen, of whom 120 had cervical cancer, 226 had endometrial cancer, 122 had a primary ovarian or peritoneal malignancy, 9 had a vaginal malignancy, 28 had vulvar cancer, and 9 had a miscellaneous gynecologic malignancy. RESULTS: On pathology review the diagnosis changed for 200 of 599 specimens (33%). This altered management for 63 of 514 patients (12%). For patients with cervical cancer, the grade of tumor was the main change in pathologic diagnosis, with occasional change in the presence of lymph vascular invasion. These did not translate into patient management alterations. Eight patients (1.5%) had management alterations. The changes in depth of invasion and vascular invasion altered management for 3 patients. Changes in pap smears resulted in two management alterations, and changes in histologic diagnoses altered management for 3 cases. For endometrial primaries the changes in pathologic diagnosis included grade, depth of invasion, and the presence of cervical involvement. This did alter management in 40 cases (8%). For the ovarian malignancies, the main changes were grade, extent of disease, or histologic classification, some of which (10 patients, 2%) resulted in altered management. One patient with a vaginal lesion had the diagnosis changed, which did alter management. Of the patients diagnosed with vulvar cancer, the pathologic diagnosis changed for 11 patients. This included changes in grade and depth of invasion. This altered management of 2 patients. The remaining miscellaneous gynecologic malignancies had only two diagnosis changes that altered management. CONCLUSIONS: Pathologic review of gynecologic malignancies is justified as it can alter patient management. In addition, the process facilitates cooperation of the multidisciplinary team and provides a valuable educational forum to enhance patient care.

Quality control in radiotherapy: the reduction of field placement errors.

A 'blind' study using treatment verification films has been performed on two series of patients to assess the accuracy of placement of complex infradiaphragmatic fields planned to include para-aortic nodes. Sequential verification films (VF) for each field on all patients studied were compared to determine variations in field position relative to the anatomy, especially lymph nodes, and the simulator plan. Nodes included in the plan but partially or completely missed by one or more treatments were identified, as were the error types involved. In series I, 21% of 157 VF showed a nodal miss, and after changes in practice designed to minimize the error types responsible for those, the figure was reduced in series II to 5.5% of 194 VF. In series II a 50% reduction in magnitude of the average systematic lateral shift and rotation of posterior fields is attributed mainly to the discontinuation of the practice of treating posterior fields through the couch. Apart from a prescribed width of less than 9 cm, three quantitative key factors were derived: greater than 6 mm lateral shift, greater than 7 mm field narrowing, 2 degree or more rotation of fields. The correction of these errors if identified on verification films, should eliminate the subsequent occurrence of node misses. The value of routine clinical treatment verification films at the start of treatment to identify and correct systematic errors is emphasized, as is the importance of precise and standardized technical practice.

Optimized low dose rate pellet configurations for intravaginal brachytherapy.

PURPOSE: The objective was to identify configurations of low dose rate pellet sources that optimize short treatment length brachytherapy dose distributions for a set of four intravaginal applicators. METHODS AND MATERIALS: The method of simulated annealing was used. Dose rates at calculation points on the surface of 2.0, 2.5, 3.0, and 3.5 cm diameter applicators along a fixed 3.0 cm treatment length were optimized for Cs-137 sources of strengths 0.74 and 0.63 GBq in trains having maximum lengths of 3.0, 3.5 and 4.0 cm. Variations in the optimization algorithm involving two different objective functions and different combinations of selectable parameters were investigated in an effort to standardize the approach. RESULTS: An objective function based on the maximum dose rate difference at the calculation points in conjunction with a single parameter set proved suitable for all applicators. Optimized solutions involving both a single configuration of sources and a combination of two such configurations were successfully identified. The latter consistently afforded superior dose rate uniformity, particularly for the smaller diameter applicators. A maximum source train length of 3.5 cm was found to provide a good compromise between attaining dose rate uniformity along the 3.0 cm treatment length and minimizing irradiation of adjacent normal tissues. For each applicator, an optimized 3.5 cm pellet train yielded better surface dose rate uniformity than a corresponding optimum-length linear source. CONCLUSION: Pellet configurations that optimize dose distributions for intravaginal brachytherapy applicators can be reliably identified with modest computational effort using the method of simulated annealing. The method is therefore suitable for use in routine clinical treatment planning for this site.

Effect of cisplatin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines.

PURPOSE: To evaluate the effect of clinically relevant levels of cisplatin on the radiosensitivity of human cervical tumor cells, and to estimate what changes in local control rates might be expected to accrue from the concomitant use of cisplatin during fractionated radiotherapy. METHODS AND MATERIALS: The effects of concomitant cisplatin (1 microgram/ml, a typical intratumor concentration) on the clinically relevant radiosensitivity, i.e., surviving fraction after 2 G (SF2) values, was determined in 19 cloned human cervical tumor cell lines. These early passage cell lines had SF2 values ranging from 0.26 to 0.87. RESULTS: The concomitant administration of cisplatin reduced the clinically relevant radiosensitivity in the majority (11 out of 19) of the human tumor cell lines investigated. In only 4 out of 19 was any radiosensitization observed, and in 4 out of 19 cell lines there was no significant change in radiosensitivity. However, the sum of the independent cell killing by radiation and cisplatin, was approximately twofold higher than after radiation alone. There was no apparent dependence of the cisplatin-induced changes in SF2 values upon the level of cell killing by cisplatin. However, there is a suggestion that concomitant cisplatin administration may have a differential effect in inherently radiosensitive and resistant human tumor cell lines. CONCLUSIONS: Our data suggest that concomitant cisplatin/radiotherapy regimens may result in a higher level of local tumor control, but primarily through additive toxicity and not through radiosensitization. Future improvements in local tumor control may, thus, be derived by increasing the total dose of cisplatin.

Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer.

BACKGROUND AND PURPOSE: This paper investigates the outcome using different dose/fractionation schedules in high dose rate (HDR) post-operative vaginal vault radiotherapy in patients with low to intermediate risk endometrial cancer. MATERIALS AND METHODS: The world literature was reviewed and thirteen series were analyzed representing 1800 cases. RESULTS: A total of 12 vaginal vault recurrences were identified representing an overall vaginal control rate of 99.3%. A wide range of dose fractionation schedules and techniques have been reported. In order to analyze a dose response relationship for tumor control and complications, the biologically effective doses to the tumor and late responding tissues were calculated using the linear quadratic model. A threshold was identified for complications, but not vaginal control. While dose fractionation schedules that delivered a biologically effective dose to the late responding tissues in excess of 100 Gy(3) (LQED=60 Gy) predicted for late complications, dose fractionation schedules that delivered a modest dose to the vaginal surface (50 Gy(10) or LQED=30 Gy) appeared tumoricidal with vaginal control rates of at least 98%. CONCLUSIONS: By using convenient, modest dose fractionation schedules, HDR vaginal vault - brachytherapy yields very high local control and extremely low morbidity rates.

Intratumoral heterogeneity as a confounding factor in clonogenic assays for tumour radioresponsiveness.

The level of intra-tumoral heterogeneity of cellular radiosensitivity within primary cultures of three carcinomas of the cervix has been established. All three cultures contained clones that varied by as much as 3-fold in their clinically relevant radiosensitivity (SF2). The level of intra-tumoral heterogeneity observed in these cervical tumour cultures was sufficient to be a major confounding factor to the use of pre-treatment assessments of radiosensitivity to predict for clinical radioresponsiveness. Mathematical modeling of the relative elimination of the tumour clones during fractionated radiotherapy indicates that, in two of the three biopsy samples, the use of pre-treatment derived SF2 values from the heterogeneous tumour sample would significantly overestimate radioresponsiveness. We conclude that assays of cellular radiosensitivity that identify the radiosensitivity of the most radioresistant clones and measure their relative abundance could potentially increase the effectiveness of SF2 values as a predictive marker of radioresponsiveness.

Inherent radiosensitivity testing of tumor biopsies obtained from patients with carcinoma of the cervix or endometrium.

The inherent radiosensitivity of tumor biopsies obtained from a series of patients with carcinoma of the uterine cervix or endometrium has been characterized. Early passage cell lines were irradiated and assayed for cell survival using a clonogenic assay system. Survival curves were generated using the alpha/beta model and the surviving fraction at 2 Gy (SF2) was estimated. A wide range of SF2 values was observed among histologically similar tumors. The mean (+/- SD) SF2 value was 0.29 +/- 0.12 (range = 0.11-0.59) for the cervical biopsies and 0.30 +/- 0.13 (range = 0.11-0.67) for the endometrial biopsies. No correlation between inherent radiosensitivity and tumor DNA index or histopathology was observed. Patient accrual continues with the expectation that these results may help to determine whether SF2 values are of clinical value in predicting the response of individual patients to treatment with radiotherapy.

Invasive squamous cell carcinoma of the vagina during pregnancy.

BACKGROUND: Squamous cell carcinoma of the vagina in pregnancy is rare. CASE: A 28-year-old primigravida with antepartum bleeding at 20 weeks' gestation was diagnosed with squamous cell carcinoma after biopsy of a vaginal mass. The histology revealed an invasive grade 3 squamous cell carcinoma of large-cell, nonkeratinizing type. The patient declined pregnancy termination and immediate radiation treatment. She continued to have episodes of vaginal bleeding and was admitted at 30 weeks' gestation. A decision was made in consultation with the neonatal unit to deliver her at 32 weeks' gestation. After corticosteroid treatment, she was delivered by cesarean delivery. Positive pelvic lymph nodes were noted at surgery. Postoperatively, she received external beam radiation and brachytherapy and concurrent cisplatin chemotherapy. She is disease free 3 years from her original diagnosis. CONCLUSION: This case emphasizes the importance of a thorough pelvic examination to assess the vaginal walls and cervix at the first prenatal visit and with any antepartum bleeding episode.

Disposition of ifosfamide in patients receiving ifosfamide infusion therapy for the treatment of cervical carcinoma.

The disposition of ifosfamide was investigated in nine patients receiving a total of 23 72-h infusions. There was no linear relationship between steady-state plasma concentrations and either vomiting or CNS toxicity. The steady-state plasma concentrations were reproducible within patients, but there was a wide variation between patients. The progress of the disease did not affect the disposition of ifosfamide.

DNA double-strand break rejoining in human follicular lymphoma and glioblastoma tumor cells.

Follicle center cell lymphoma is among the most radioresponsive of human cancers. To assess whether this radioresponsiveness might be a result of a compromised ability of the tumor cells to accomplish the biologically-effective repair of DNA double-strand breaks (DSBs), we have measured i) the extent of the mechanical rejoining of radiation-induced DSBs in biopsy-derived follicle center cell lymphoma cells and ii) the fidelity with which nuclear protein extracts from these cells rejoin restriction enzyme-induced DSBs. Cell suspensions derived from two lymphoma biopsies, designated FCL1 and FCL2, as well as two established human glioblastoma cell lines, M059J and M059K, were exposed to 30 Gy of gamma-rays and evaluated for their ability to rejoin DSBs using a Southern transfer-pulsed-field gel electrophoresis assay. The fidelity of rejoining of restriction enzyme-induced DSBs was assessed using a cell-free plasmid reactivation assay. Both lymphoma suspensions rejoined DSBs relatively slowly and exhibited a similar phenotype to the known DSB-rejoining deficient M059J line. The level of DSB mis-rejoining in the cell-free plasmid reactivation assay was also similar in M059J and FCL2 cells and was considerably ( approximately 6-fold) higher than in M059K cells. Because of insufficient numbers of cells, we were unable to perform this assay with the FCL1 lymphoma. These limited data suggest that follicle center cell lymphoma cells may be intrinsically deficient in performing the biologically-effective rejoining of DSBs. Such a deficiency might contribute to the radioresponsiveness of this disease and may be exploitable in the development of improved treatment strategies, such as radioimmunotherapy.

A phase I/II study combining radical radiotherapy with concurrent cisplatin in the treatment of advanced squamous cell carcinoma of the cervix.

Sixteen patients with advanced cervix cancer have been treated in a phase I/II study of concurrent radiotherapy and cisplatin chemotherapy. The external beam radiotherapy was given as a 'split course' because of initial concerns about acute toxicity. The treatment was well tolerated with all patients completing the prescribed radiotherapy and all patients received the intended four doses of cisplatin. One of 5 patients with stage IVB disease is alive and disease free 35 months after treatment. Six of the 11 patients with disease confined to the pelvis are alive and disease free between 28 and 53 months after treatment. One patient has required surgery for a recto-sigmoid stricture.