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.

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.

Metastatic adenocarcinoma of the cervix in a delivery-induced traumatic lower vaginal tear.

BACKGROUND: Noncontiguous vaginal metastasis is rare in cervical cancer and is usually reported in the context of traumatic implantation. Traumatic vaginal implantation of cervical carcinoma has been documented in episiotomy, port site, or incision scars. CASE: We report the only case in the literature with vaginal metastasis associated with traumatic vaginal tear presenting with concomitant metastasis and the second case in the literature with a concomitant vaginal metastasis. Treatment consisted of organ-sparing chemoradiotherapy. Although the previous literature suggests that nonsurgical management of traumatic implantation metastases is associated with survivals of less than 1 year, there is no confirmed recurrent disease after 1 year of follow-up in our reported case. CONCLUSION: The feasibility and initial favorable outcome with chemoradiation is demonstrated in this rare presentation.

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.

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.

The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix.

BACKGROUND: It is unclear whether blood transfusion can overcome the negative impact of anemia before or during radiotherapy (RT) in patients with carcinoma of the cervix. The objective of this retrospective study was to examine the impact of anemia and blood transfusion on 605 patients with carcinoma of the cervix treated with radical RT at 7 centers across Canada in 1989, 1990, and 1992. METHODS: The data collected included hemoglobin (Hgb) levels from the time of diagnosis to the end of therapy; blood transfusions administered; and identifiable patient-, tumor-, and treatment-related factors. Survival, disease free survival, and pelvic control analyses were evaluated by univariate and multivariate analysis. RESULTS: The median follow-up was 41 months (range, 0-92 months). Presenting Hgb level, average weekly nadir Hgb (AWNH) during RT, and blood transfusion were correlated significantly with local control, disease free survival, and overall survival on univariate analysis. However, the AWNH remained significant on multivariate analysis, whereas Hgb at presentation and blood transfusion did not. The 5-year survival was 74% for patients with an AWNH >/= 120 g/L, 52% for patients with AWNH levels 110-119 g/L inclusive, and 45% for patients with AWNH levels < 110 g/L (P < 0.0001). At each Hgb level, patients who were transfused and maintained a specific Hgb level had a survival rate that was not significantly different from patients who were at that level spontaneously. There was a significant reduction in both pelvic and distant recurrence (P < 0.0001 and P < 0.0006, respectively) in patients whose AWNH level during RT was >/= 120 g/L compared with < 120 g/L. A reduction in the rate of distant recurrence was observed in patients with and without pelvic recurrence. CONCLUSIONS: AWNH is highly predictive of outcome for patients treated with RT for carcinoma of the cervix. Blood transfusion appears to overcome the negative prognostic effects of low presenting Hgb levels and AWNH levels.

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.

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.

Phase II study to evaluate the toxicity and efficacy of concurrent cisplatin and radiation therapy in the treatment of patients with locally advanced squamous cell carcinoma of the cervix.

Sixty patients presenting with poor prognosis squamous cell cancer of the cervix have been studied in a phase II clinical trial. Patients were treated with radiotherapy and concurrent cisplatin chemotherapy every 10 days. Treatment was well tolerated with all patients completing radiotherapy as prescribed. There was one case of grade 4 acute bowel toxicity. Significant late morbidity was acceptable for this group of patients being restricted to two cases (3.3%) of grade 4 toxicity to the bowel. Pelvic control rates of 78% have been observed. There have been no pelvic recurrences after 26 months, although recurrences beyond the pelvis have occurred up to 4 years later. Actuarial 4-year survival is encouraging at 60%.

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.

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.

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.

The value of pre-operative intracavitary radiotherapy in patients treated by radical hysterectomy and pelvic lymphadenectomy for invasive carcinoma of the cervix.

Two hundred and twenty-four patients with invasive carcinoma of the cervix treated by radical surgery have been studied retrospectively to determine the impact of pre-operative intracavitary radiotherapy. Pre-operative radiotherapy made no difference to survival, the incidence of local recurrence, distant metastasis or complications.

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.

The daily reproducibility of large, complex-shaped radiotherapy fields to the thorax and neck.

A series of patients treated with complex fields to the thorax and neck utilising individually tailored shielding blocks made from low-melting-point alloy (LMPA), were investigated using treatment verification film to identify field placement errors. A total of 19 patients yielded 171 machine verification films, which were analysed. It was found that on 21% of occasions the intended treatment volume was partially shielded, by more than 1 cm, by the lead blocks prescribed to protect the lungs. On half of these occasions (11% of the total), the areas erroneously shielded contained known disease. Suggestions are made for minimising such errors in the future.

An investigation into the daily reproducibility of patient positioning for 'mantle' treatments.

Three patients treated for Hodgkin's disease by mantle radiotherapy have been studied in detail to quantify day-to-day variation in treatment position. The value of routine treatment verification films is again emphasised, this time to avoid underdosage or overdosage at field junctions in any subsequent treatment.