Regimen-related toxicity and non-relapse mortality with high-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV) and CBV plus cisplatin (CBVP) followed by autologous stem cell transplantation in patients with Hodgkin's disease.

This analysis compares the regimen-related toxicity (RRT) and overall non-relapse mortality (NRM) in Hodgkin's disease patients conditioned with either CBV (cyclophosphamide, BCNU (carmustine), and VP16-213 (etoposide)) (26 patients) or CBVP (CBV + cisplatin) (68 patients) followed by autologous stem cell transplantation (ASCT). CBVP included a continuous infusion rather than intermittent doses of etoposide, a lower BCNU dose and the addition of cisplatin. RRT and NRM were determined for each regimen and compared; risk factors for each were examined by multivariate analysis. Grade IV (fatal) RRT occurred in five patients (pulmonary in two, cardiac in two, and central nervous system in one). Eighteen patients experienced grade II-III pulmonary RRT, consistent with BCNU damage in 15. Prior nitrosourea exposure was the main risk factor for pulmonary RRT. Grade II mucosal and hepatic RRT occurred less often after CBVP vs CBV (P = 0.031 and 0.0003, respectively). In addition, three other early and eight late non-relapse deaths were seen. Median follow-up of the entire group is 5.1 (range 2.8-10.2) years. The probability of overall NRM was 26% (95% confidence interval (CI) 13-50%) with CBV vs 23% (95% CI 12-41%) with CBVP (P = 0.40). The progression-free survival and relapse rates were similar. Although the rates of fatal RRT, pulmonary RRT and overall NRM were similar with CBV or CBVP, CBVP produced less mucosal and liver RRT with a comparable antitumor effect. As many autografted patients are cured, future efforts should include measures to decrease NRM.

Clinical use of asymmetric collimators.

PURPOSE: To illustrate some of the radiation treatment techniques with asymmetric collimators in one field dimension. METHODS AND MATERIALS: Treatment planning for various sites is done with an in-house developed treatment planning system. Dose distributions in the central plane are illustrated. RESULTS: The use of asymmetric collimation, in addition to being a replacement for cerrobend and lead blocks, can facilitate treatment setup with boost fields and with half-beam asymmetric fields as in matching two adjacent fields, in avoiding nearby critical organ or tissue, and in tangential breast treatment. The use of asymmetric collimators would alter the dose distribution across the radiation field and should be accounted for during treatment planning. In conjunction with arc rotation or multiple asymmetric fields, two-dimensional conformal radiotherapy is possible. CONCLUSION: The full potential of asymmetric collimation requires the use of a proper treatment planning algorithm. Some of the treatment techniques with asymmetric collimation in one field dimension are shown here.

High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy.

Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an induction failure (IF); this subset of patients has an extremely poor outcome with further conventional therapy. Since 1985, we have entered 30 IF patients into protocols using conditioning with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) followed by autologous stem cell transplantation (ASCT) with bone marrow (19 patients), peripheral blood stem cells (PBSCs; 8 patients), or both (3 patients). All except 2 patients had previously received chemotherapy regimens for HD that contained at least 7 drugs, and 9 had received prior radiotherapy (RT). After documentation of IF, the majority of patients received some cytoreductive therapy as specified by protocol (local RT in 9, two cycles of conventional chemotherapy in 2, both modalities in 2, or high-dose cyclophosphamide to enhance PBSC collection in 11) before CBV +/- P. Five treatment-related deaths occurred, all before day 150 posttransplant. Eleven patients have had progressive HD at a median of 6 months (range, 0.1 to 45 months) after ASCT. The actuarial progression-free survival (PFS) at a median follow-up of 3.6 years (range, 0.2 to 8.2 years) is 42% (95% confidence intervals, 21% to 61%). The statistical analysis identified only prior clinical bleomycin lung toxicity as an adverse risk factor for PFS, mainly because of the increased nonrelapse mortality seen in these patients. CBV +/- P and ASCT can produce durable remission in a substantial proportion of IF HD patients who otherwise have a poor survival, and we believed ASCT approaches represent the best therapy currently available for these patients. Additional measures are needed to reduce the primary problem of disease progression despite high-dose chemotherapy and stem cell transplantation.

Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy.

The optimal timing in which to use intensive chemotherapy and autologous bone marrow transplantation (BMT) in Hodgkin's disease (HD) is uncertain. In 1985, we initiated a program in which this modality was used as the initial salvage therapy in patients relapsing after combination chemotherapy. Fifty-eight patients with HD in first relapse after primary chemotherapy received conditioning with high-dose cyclophosphamide, carmustine, etoposide (VP16-213) +/- cisplatin (CBV +/- P) followed by autologous BMT. All but six of these patients were given a median of two cycles of conventional chemotherapy +/- involved field radiation therapy before CBV +/- P and autologous BMT. These measures were not used as a means for patients selection; all patients receiving such therapy ultimately were transplanted. The probability of nonrelapse mortality, progression of HD, and progression-free survival post-BMT were calculated, and prognostic factors for progression-free survival were evaluated using the Cox proportional hazards method. Treatment-related deaths occurred in only three patients. Thirteen patients have relapsed at a median 0.7 years (range 0.1 to 3.5) post-BMT. At a median follow-up of 2.3 years (range 0.4 to 7.2), the actuarial progression-free survival is 64% (95% confidence interval, 46% to 78%). In the statistical analysis, three similarly weighted but independent prognostic factors were identified: "B" symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with no risk factors had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors. CBV +/- P and autologous BMT is highly effective salvage therapy for HD patients in a first relapse, particularly in the subset of patients with less than two adverse factors. Therapy must be improved in the future for patients with > or = 2 adverse factors.

Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy.

PURPOSE: At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. PATIENTS AND METHODS: One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. RESULTS: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. CONCLUSIONS: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.

Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease.

Fifty-six consecutive patients with advanced Hodgkin's disease considered incurable with further conventional chemotherapy were entered into a protocol that included high-dose cyclophosphamide (7.2 g/m2), carmustine (BCNU; 0.6 g/m2), and etoposide (VP16-213; 2.4 g/m2) (CBV) followed by autologous bone marrow transplantation (BMT). Prior combination chemotherapy had failed in all the patients, and all but five had been previously treated with both mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, and vinblastine with or without dacarbazine (ABV[D]). Thirty-four eligible patients received short-course conventional chemotherapy and/or involved-field radiotherapy before CBV. However, formal restaging was not performed after these conventional therapies; ie, the therapies were not used to select responding patients for transplantation, and all who received such therapy subsequently received CBV and autologous marrow grafts. Forty-four patients (80%; 95% confidence interval [CI], 69% to 91%) achieved a complete response after CBV and BMT. Performance status at protocol entry and the use of conventional cytoreduction therapy before CBV correlated with response. Median follow-up is now 3.5 years (range, 2.5 to 5.0 years). Kaplan-Meier estimates for overall and event-free survival 5 years after transplant are 53% (95% CI, 37% to 67%) and 47% (95% CI, 33% to 60%), respectively. In a univariate analysis, patients with a normal performance status and those without constitutional ("B") symptoms at protocol entry had an improved overall and event-free survival. In a multivariate analysis, only a normal performance status remained significant. Disease progression occurred in 17 patients at an actuarial rate of 39% (95% CI; 26% to 56%) and occurred at previous sites of active disease in all but one patient; our analysis did not identify prognostic factors for progression. Toxic deaths, caused by either neutropenic sepsis or interstitial pneumonitis (IP), occurred in 12 patients (21%; 95% CI, 10% to 32%). CBV with autologous marrow support can produce durable remissions in a substantial number of patients with Hodgkin's disease considered incurable with conventional measures. Regimen refinements may even further improve the therapeutic index of BMT in this malignancy.

Outcome of treatment of first relapse of Hodgkin's disease after primary chemotherapy: identification of risk factors from the British Columbia experience 1970 to 1988.

The outcome of treatment for a first relapse of Hodgkin's disease after primary chemotherapy was analyzed in 80 patients. They were divided into four groups: group 1 (n = 24) had initially been treated with three cycles of (mechlorethamine, vincristine, prednisone, and procarbazine [MOPP]) and wide-field irradiation therapy; group 2 (n = 25) had six cycles of MOPP; group 3 (n = 15) and group 4 (n = 16) both initially received MOPP/ABVD (MOPP plus doxorubicin, bleomycin, vinblastine, and dacarbazine) or MOPP/ABV hybrid, but group 3 received conventional salvage regimens whereas group 4 was treated with high-dose chemotherapy and autologous bone marrow transplantation as salvage therapy (n = 16). Freedom from second failure (FF2F) was used as the major endpoint. Actuarial FF2F for all patients was 38% after a median follow-up of 75 months for patients who were alive. Risk factor analysis was performed on the 71 patients who had been treated with curative intent. The presence or absence of any one of three risk factors had a strong negative impact on outcome: stage IV disease at primary diagnosis, B symptoms at relapse, or a time from primary treatment to relapse of less than 1 year. Actuarial FF2F at 5 years was 17% in the group of patients with one or more of these three factors present (n = 49). If none of these factors was present, FF2F was 82% (n = 22) (P less than .001). Even high-dose chemotherapy and autologous bone marrow transplantation were not able to overcome the negative impact of one or more risk factors (FF2F = 19%, n = 12). The outcome of salvage treatments depends most on the presence or absence of these three risk factors and less on the type of salvage treatment. Patients with none of these risk factors present have an excellent outcome if they are treated with non-cross-resistant chemotherapy, or radiotherapy, or both. Novel approaches are needed for patients with one or more of these factors present. Reports on salvage treatments for Hodgkin's disease in first relapse after primary chemotherapy should include data on the proportion of patients having stage IV disease at diagnosis, B symptoms at relapse, and a time from primary treatment to relapse of less than 1 year.

Prevention of radiation-induced stenosis of the nasolacrimal duct.

Epiphora is a recognized complication of radiotherapy of medial canthal tumours. We reviewed the records of 36 patients who underwent prophylactic nasolacrimal duct intubation with silicone tubing before superficial x-ray beam therapy and 42 patients who did not undergo intubation before radiotherapy. The mean length of follow-up was 3.4 years in the intubated group and 7.2 years in the nonintubated group. A total of 31% of the patients in the nonintubated group reported chronic epiphora during the follow-up period, compared with 6% in the intubated group (p less than 0.003).

Clinical results in carcinoma of the cervix: radium compared to caesium using remote afterloading.

In 1979 the Cancer Control Agency of British Columbia changed from radium to remote controlled afterloaded caesium in the treatment of carcinoma of the cervix. In the 3 years prior to the change, 139 patients received radium as part of their treatment and in the 3 years after the change, 158 patients received caesium. Overall referral patterns, patient and cancer demographics, and treatment policies were stable throughout the 6-year period. Radiotherapy technique, dose, dose distribution and dose rate were comparable for both radium and caesium treated patients. The results of treatment in the two time periods showed no difference in survival, local tumour control or complications. The use of afterloading has not compromised treatment results and has allowed better nursing care for patients and protection from radiation for all staff.

Fatal outcome of pelvic radiotherapy for carcinoma of the cervix in a patient with systemic lupus erythematosis.

Although there is an impression that patients with connective tissue disorders tolerate radiotherapy less well than other patients, this is not well documented in the literature. We present the case of a patient with a 7-year history of systemic lupus erythematosis who developed fatal pelvic necrosis as an unexpectedly severe complication after radiotherapy for carcinoma of the cervix.

Testicular lymphoma: improved outcome with early brief chemotherapy.

We investigated the impact of early brief chemotherapy on the natural history of primary testicular lymphoma. We compared the outcome for patients seen before 1980--a group primarily managed with orchiectomy and regional radiation--with those seen from 1980 to 1986--a prospectively and consecutively gathered group who were offered brief chemotherapy in addition to standard orchiectomy and irradiation. The historical and study groups were similar in clinical characteristics. However, the chemotherapy group had a better relapse-free survival, 93% v 50% (P less than .02), and overall survival, 93% v 50% (P less than .02). With a median follow-up of 44 months in the chemotherapy group, it is clear that the use of early, brief chemotherapy strongly alters the natural history of testicular lymphoma by preventing relapses, the large majority of which occur early after regional therapy. We conclude that a program incorporating orchiectomy, early brief chemotherapy, and involved-field radiation therapy confers the following benefits on patients with primary testicular lymphoma: (1) laparotomy is not needed for staging; (2) relapses, including those in the opposite testicle and CNS, are largely prevented; and (3) toxicity can be kept to a modest level acceptable in elderly patients.

Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma.

STUDY OBJECTIVE: To determine the efficacy and toxicity of brief chemotherapy and involved field radiation therapy for treatment of limited-stage, histologically aggressive malignant lymphoma. DESIGN: Single-arm prospective trial. SETTING: Comprehensive cancer treatment center serving the entire population of British Columbia. PATIENTS: Consecutive enrollment of 78 patients ranging in age from 21 to 82 years (median, 64) with limited-stage (no B symptoms, Ann Arbor stage I or II, tumors less than 10 cm in diameter), diffuse large cell, mixed or immunoblastic histologic characteristics of malignant lymphoma seen at our institution between May 1980 and December 1984. All eligible patients were evaluated for response and relapse-free and overall survival. INTERVENTIONS: Chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for three cycles followed by involved field radiation therapy to the original site of disease in a dose equivalent to 3000 cGy in ten fractions. MAIN RESULTS: The complete response rate was 99% (77 of 78 patients). With a median follow-up off treatment of 30 months the actuarial relapse-free survival is 84% and the overall survival is 85%. No deaths due to toxicity occurred. CONCLUSIONS: Brief chemotherapy and involved field radiation therapy is highly successful treatment for patients with limited-stage, histologically aggressive malignant lymphoma. Toxicity of this approach is acceptable, even in the elderly. Staging laparotomy is not needed to select these patients. Future trials should incorporate more effective chemotherapy programs.

Radiation treatment of carcinoma of the vulva, 1950-1980.

A retrospective study of all patients with carcinoma of the vulva treated by radiation therapy at the A. Maxwell Evans Clinic of the Cancer Control Agency of British Columbia, between 1950 and 1980, is reported. Sixty-eight patients, representing 30% of all referred patients with vulvar cancer, were analyzed for survival, recurrence patterns, complications, and clinical features. This group is companion to a series of patients treated with operation reported in 1979. The data confirm a major role for radiation therapy both in palliation and in combined radiotherapy-operation. For 13 cases, radiotherapy with curative intent was used in combination with operation resulting in a 5-year actuarial survival of 92%, with acceptable posttreatment morbidity. The advantages of preoperative radiotherapy, particularly for posterior vulvar lesions, are suggested by the data, and the need for a reappraisal of the role of radiotherapy in vulvar carcinoma is stressed.

Radiation oncology--the misunderstood specialty.

A shortage of radiation oncologists has been a problem in both Canada and the United States of America. The fundamental step to rectify this situation is the recruitment of interested medical students. A mail-in survey was sent to 214 third- and fourth-year medical students at the University of British Columbia to evaluate attitudes to and the level of understanding of radiation oncology. The response rate was 59%. Seventy-five percent of the students were planning postgraduate training in clinically orientated specialties with good lifestyle and availability of job opportunities. However, only 18% of the respondents considered radiation oncology as a possible specialty. This survey suggests that this lack of interest is the result of misconceptions about training in the practice of radiotherapy. To better inform the medical students, teaching clinics providing them with direct contact with radiation oncologists and their patients, are invaluable. In order to generate the correct image of the specialty and the types of patients encountered, teaching in an ambulatory care setting is not to be neglected. Distribution of information pamphlets describing the radiation oncology program and the nature of radiation oncology practice is also suggested as an efficient means of informing medical students.

Primary invasive carcinoma of the vagina.

Data are presented from 97 patients treated for invasive primary epithelial carcinoma of the vagina between 1950 and 1980. The disease is primarily one of the elderly as 63% were found to be older than 60 years of age. Eleven of the 97 patients either refused or were unable to complete treatment because of poor medical condition or advanced stage of disease. Combined external and intracavitary radiation was the most common form of treatment. The overall two-year survival rate was 47%, or 59% when corrected for deaths due to other causes. Patients with stages I and II disease had corrected survival rates of 75% and 68%, respectively. Our results indicate that stage of disease is the most significant prognostic factor. Optimal results will be obtained with early diagnosis and individualized treatment.

Squamous carcinoma of the vulva: results of treatment, 1938 to 1976.

Clinical data on 264 patients with squamous cell carcinoma of the vulva seen between 1938 and 1976 are reported. Two hundred and four patients were "eligible" for 5 year assessment for a 55% survival rate. Patients treated with radical vulvectomy and bilateral lymphadenectomy had a corrected 5 year survival rate of 86% if the lymph nodes failed to show metastatic disease. Twenty-eight percent of the patients treated with lymphadenectomy had lymph node metastasis at the time of surgery. The presence of lymphatic metastasis appeared to be the most significant prognostic factor. The results obtained have led to a degree of individualization in current treatment policies, together with a re-evaluation of the possible role of radiotherapy.

Granulosa cell tumors. A clinical review of 61 cases.

Sixty-one patients with granulosa cell tumors of the ovary were treated in the A.M. Evans Clinic of the British Columbia Cancer Control Agency between 1944 and 1974. Their treatment and follow-up are reviewed, and while the 5-year survival rate was 78%, the 15-year rate fell to 50%. The material suggests that the trend to total hysterectomy and bilateral salpingo-oophorectomy has improved the prognosis, but other explanations are, of course, possible as this is a historical comparison.

Adenocarcinoma of the fallopian tube. Experience with 41 patients.

Forty-one cases of primary fallopian tube carcinoma treated at our institution over the years 1946 to 1976 are described. The overall 5-year survival rate was 34.4%, although patients with early tumors had a 72.7% survival rate. The single most important factor affecting survival appeared to be the extent of disease at the time of diagnosis. Past and present treatment modalities are discussed, and proposals for management of this disease are outlined.