Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation.

BACKGROUND: Disseminated neuroblastoma after infancy has a dismal prognosis; long-term survival with conventional therapy occurs in approximately 10% of cases. PATIENTS AND METHODS: Between 1985 and 1992, we followed a strategy aimed to achieve remission with an induction combination of intensive chemotherapy, primary resection, and tumor-bed radiotherapy (TBRT). Patients who achieved remission proceeded to myeloablative chemoradiotherapy and unpurged autologous bone marrow transplant (ABMT). Twenty-eight patients older than 1 year presented with stage IV disease during the study period; six died of progressive disease and three died of complications of therapy. Nineteen patients achieved remission, two of whom did not receive ABMT. Seventeen patients proceeded to ABMT. Conditioning was with teniposide 130 mg/m2, doxorubicin 30 mg/m2, melphalan 120 mg/m2, cisplatin 80 mg/m2, and total-body irradiation 12 Gy in six fractions (modified VAMP-TBI). RESULTS: Principal nonhematologic toxicities were mucositis and diarrhea. There were no ABMT-related deaths. Two patients relapsed at 8 and 26 months post-ABMT, respectively. Fifteen patients remain in complete remission (CR) at 24 to 102 months (median, 71) from ABMT and 30 to 114 months (median, 78) from diagnosis. Survival rates of all 28 patients are 61% and 50% at 2 and 5 years, respectively, and the disease-free survival (DFS) of the ABMT group is 94% and 87% at 2 and 5 years, respectively. CONCLUSION: Modified VAMP-TBI appears to be an effective conditioning regimen, with 15 of 17 patients remaining disease-free, with no toxic deaths. This result compares favorably with that of other groups. Larger numbers of patients need to be treated to confirm the efficacy of this therapy.

Synchronous cisplatin infusion during radiotherapy for the treatment of metastatic melanoma.

In two pilot studies, 55 patients with symptomatic metastases from malignant melanoma were treated with irradiation and concurrent cisplatin. In the first group, cisplatin was given as a continuous intravenous infusion of 20 mg/m2 per day on days 1-5 and 22-26, with irradiation on days 2, 5, 9, 16, 23 and 26. The second group received 20 mg cisplatin over 24 h commencing 1 h before each fraction of irradiation on days 1, 4, 8, 11, 15 and 18. The first series of 28 patients had 30 lesions treated. Nine (30%) of these lesions responded completely and 10 (33%) achieved partial response for an overall response rate of 63% (95% confidence interval 44-80%). Survival was not evaluated in this group. The second group was comprised of 27 patients, with one irradiated lesion each. 1 patient achieved a complete response and 13 (48%) a partial response for an overall response rate of 52% (32-71%). Median survival was 21 weeks (16-31 weeks). Treatment was well tolerated with nausea and vomiting being the most common toxicity. Synchronous cisplatin infusion with radiotherapy achieves high response rates in metastatic melanoma. Whether it is superior to radiotherapy alone will require evaluation in a randomised trial.

Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder.

PURPOSE: To assess prognostic factors for bladder relapse and distant failure following definitive radiotherapy for invasive transitional cell carcinoma (TCC) of the bladder. METHODS AND MATERIALS: Retrospective review of patients treated in the period 1977 to 1990 by definitive radiotherapy. The factors studied included age, sex, T stage, histological grade, tumor multiplicity, ureteric obstruction, total radiation dose, and use of neoadjuvant chemotherapy. The endpoints studied were bladder relapse and distant failure. RESULTS: There were 342 patients with a mean follow-up time of 7.9 years. Bladder relapse was observed in 159 patients. The overall actuarial bladder relapse rate at 5 years was 55% (SE = 3%). Prognostic factors for a higher bladder relapse rate were: tumor multiplicity (p < 0.001), presence of ureteric obstruction (p = 0.001), and higher T stage (p = 0.044). Distant failure occurred in 39 patients. The overall actuarial distant failure rate at 5 years was 28% (SE = 3%). Prognostic factors for a higher distant failure rate were: ureteric obstruction (p = 0.003) and higher T stage (p = 0.030). CONCLUSION: In our study, patients with invasive bladder TCC fell into distinct prognostic groups determined by the three independent factors, ureteric obstruction, tumor multiplicity, and T stage. These factors provided estimated risks of bladder relapse by 5 years which ranged from 34% to 91%. Knowledge of these prognostic factors can help in the selection of patients more suited for bladder preservation by definitive radiotherapy.

Radiation hepatitis following moving strip radiotherapy.

A 71 year-old woman developed acute veno-occlusive disease of the liver after receiving moving strip radiotherapy to the whole abdomen according to the Toronto technique for carcinoma of the ovary. The dose of 22.5 Gy in 10 fractions to the liver is compared with other regimens which have produced this complication, and factors which may have sensitized the liver to irradiation are considered.

Testicular doses in definitive radiation therapy for localized prostate cancer.

PURPOSE: To measure the dose received by the unshielded testes during a conventional course of 18 MV photon radiotherapy for localized prostate cancer and to identify the factors influencing it. METHODS AND MATERIALS: For each of four patients, a wax block containing thermoluminescent chips was attached to the posterior aspect of the scrotum in close proximity to the testes on each day of treatment during a full course of radical radiotherapy, and dose measurements were obtained. The distances between the thermoluminescent chips and the beam edge were verified by measurement from port films. The accuracy of the in vivo measurements and the factors influencing the testis dose were studied using a phantom arrangement. Six factors were considered: (a) the relative contributions from primary and scattered radiation, (b) the amount of buildup required for the thermoluminescent chips that monitored testis dose, (c) the position of the testes within the scrotum, (d) field size, (e) distance from the field lower border, and (f) the effect of port films. RESULTS: Median daily doses to the testes in four patients ranged from 5 to 7 cGy. Daily doses for the four patients ranged from 4 to 14 cGy. The total dose to the testes over the full course of therapy ranged from 1.8 to 2.4 Gy. The daily dose depended primarily on the distance from the field lower border. This was increased by approximately 2.5 cGy when a 6 MV port film was taken. The relative contributions from primary and scattered radiation were found to be similar. Dose measurements at the posterior aspect of the scrotum overestimated the testis dose by approximately 15%. CONCLUSION: The most important factors influencing the dose received by the testis are the distance from the testes to the field lower border and the occasion of a port film. A knowledge of the number of port films and the average distance from the field lower border to the testes allows a reasonable prediction of testes dose without daily measurement.

Bowel complications after radiotherapy for carcinoma of the prostate: the volume effect.

Late radiation-induced bowel complications were studied in 218 patients treated for localized carcinoma of the prostate by radical radiotherapy at the Prince of Wales Hospital between 1980 and 1986. Mild to moderate toxicity was seen in 38 cases, and severe toxicity requiring surgery occurred in 3 patients. The total actuarial complication rate (by 5 years) for all grades was 24% and for severe complications was 1.8%. Significant patient-related risk factors were older age at the time of radiotherapy (p = 0.035) and a previous history of abdominal operations (p = 0.028). Among treatment-related risk factors only inclusion of the whole pelvis in the irradiated volume had a significant association with this complication (p = 0.015). The risk of bowel complications was not related to the total radiation dose or to the use of interstitial implants as employed in this series.

The effect of oral sucralfate on the acute proctitis associated with prostate radiotherapy: a double-blind, randomized trial.

PURPOSE: Acute rectal complications occur in the majority of patients receiving external-beam radiotherapy for carcinoma of the prostate. Sucralfate has been proposed to reduce radiation-induced mucosal injury by forming a protective barrier on ulcer bases, binding local growth factors, and stimulating angiogenesis. However, there is conflicting clinical evidence as to whether sucralfate, taken prophylactically during radiotherapy, can ameliorate the symptoms of acute radiation proctitis. METHODS AND MATERIALS: A double-blind randomized trial was conducted at four Radiation Oncology Departments in Sydney, Australia, between February 1995 and June 1997. A total of 338 patients with clinically localized prostate cancer receiving small volume radiotherapy, of whom 335 were evaluable, were randomized to receive either 3 g of oral sucralfate suspension or placebo twice a day during radiotherapy. Patients kept a daily record of their bowel symptoms and were graded according to the RTOG/EORTC acute toxicity criteria. RESULTS: One hundred sixty-four patients received sucralfate and 171 received placebo. Both groups were well balanced with regard to patient, tumor, treatment factors, and baseline symptoms, except that the placebo group had a significantly more liquid baseline stool consistency score (p = 0.004). Patients kept a daily diary of symptoms during radiotherapy. After adjusting for baseline values, there was no significant difference between the two groups with regard to stool frequency (p = 0.41), consistency (p = 0.20), flatus (p = 0.25), mucus (p = 0.54), and pain (p = 0.73). However, there was more bleeding in the sucralfate group, with 64% of patients noticing rectal bleeding, compared with 47% in the placebo group (p = 0.001). There was no significant difference between the two groups with respect to RTOG/EORTC acute toxicity (p = 0.88; sucralfate 13%, 44%, 43% and placebo 15%, 44%, 40% for grade 0, 1, and 2, respectively). CONCLUSION: This study suggests that oral sucralfate taken prophylactically during radiotherapy does not ameliorate the symptoms of acute radiation proctitis and may increase acute bleeding. The cause of the increased bleeding in the sucralfate group is unclear. As the pathogenesis of acute and late reactions are different, late follow-up, which includes sigmoidoscopic evaluation, is currently being performed on this cohort of patients.

Ewing's sarcoma: long-term follow-up in 49 patients treated from 1967 to 1989.

PURPOSE: Review of long-term results of therapy for Ewing's sarcoma in terms of survival, local tumor control, distant failure and complications rates. METHODS AND MATERIALS: Retrospective review of the records of patients with Ewing's sarcoma of bone and soft tissues treated at The Prince of Wales Children's and Prince of Wales Hospitals, Sydney, between 1967 and 1989 and followed-up to July 1991. RESULTS: There were 49 patients with median age 16 years (range 3-33 years) and average potential follow-up time 12.3 years (range 2-24 years). Forty patients presented with localized disease (three with regional lymph node involvement) and nine with distant metastases. Local therapy for the primary was by amputation in three patients, by resection and postoperative radiotherapy in five, and by definitive radiotherapy in 41 (median dose 50 Gy). Forty-four patients received adjuvant multi-agent chemotherapy. The overall actuarial survival rate was 33% (SE = 7%) at 5 years and 30% (SE = 7%) at 10, 15, and 20 years. The factors predictive of shorter survival were distant metastases at diagnosis (p = 0.036) and older age (p = 0.025). The actuarial local control rate for all 49 patients was 75% (SE = 8%) at 5, 10, 15, and 20 years. The only factor predictive of local failure was an inadequate target volume irradiated (p = 0.003). In 40 patients who presented with localized disease only, the actuarial rate of freedom from distant failure at 5 years was 44% (SE = 8%) and at 10, 15, and 20 years was 40% (SE = 8%). Seven patients experienced severe or fatal complications (defined as requiring investigation and treatment in hospital), namely stress fracture in two, fatal osteogenic sarcoma in one, fatal cardiotoxicity in one and severe hemorrhagic cystitis in three. The rate for severe or fatal complications at 5 years was 19% (SE = 8%), at 10 years was 29% (SE = 12%) and at 15 and 20 years was 53% (SE = 21%). CONCLUSION: Survival to 5 years appears to confer probable cure and one third of our patients have achieved this. Long-term follow-up also reveals that an increasing number of patients experience treatment-related complications, the majority of which, however, can be corrected.

Clinical thermoluminescence dosimetry: how do expectations and results compare?

Thermoluminescence dosimetry (TLD) for radiotherapy treatment verification is performed in the Prince of Wales Hospital in Sydney for a wide range of applications: (A) to determine the dose in difficult treatment geometries, (B) to record the dose to critical organs, and (C) to monitor special treatments such as total body irradiation (TBI). TLD measurements were performed with the aim to investigate cases where dose prediction is difficult and not as part of a routine verification procedure. We reviewed 1058 reports of TLD performed during the treatment of 502 patients between 1986 and 1991 to evaluate how the TLD results compare with the dose determined by the treatment plan. Reasons for possible discrepancies should be identified. In 19% of all investigated cases a discrepancy of more than 10% was found between expected and measured doses. The discrepancies could be divided into three groups: (1) errors made in the TLD determination or evaluation, such as placement errors of the TLD chips (21% of all discrepancies); (2) mistakes made during the patient set-up, such as insufficient shielding or inadequate patient immobilisation (30%); (3) inadequate treatment planning and dose calculation procedure, such as wrong inverse square law corrections or errors due to limitations of the two-dimensional treatment planning system used (41% of all). In 8% of all discrepancies the reason remained unclear. A number of changes to treatment plans and modalities (e.g. changed scrotal shield, modified bolus) were introduced due to TLD results. The increasing number of TLD requests per year attests to the value of TLD as a treatment verification method in clinical practice.

Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia.

We report successful pregnancies in two young women (aged 24 and 20 years) following allogeneic bone marrow transplantation (BMT) for acute non-lymphoblastic leukaemia. Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI, 12 Gy) in 2 Gy fractions once daily for 6 days or twice daily for 3 days. Graft-versus-host disease prophylaxis was with methotrexate alone. Both women were amenorrhoeic after BMT and gonadal testing indicated hypergonadotrophic hypogonadism. Both women had normal pregnancies (2 years and 5 years after BMT) resulting in normal healthy infants. Previously successful pregnancy has been reported after TBI in three women in whom the TBI dose was less than 8 Gy. Our cases illustrate that normal outcome of pregnancy is possible at even higher doses of TBI.

Bone marrow transplantation in children using closely matched related and unrelated donors.

Seventeen bone marrow transplants were undertaken on 15 patients with leukemia or aplastic anemia using marrow from closely matched (phenotypic or five out of six HLA-A, B and DR antigen matched related and unrelated) donors. Donors were siblings (four), parents (seven), aunt (one), great aunt (one) or matched unrelated (two). When compared with transplants using matched sibling donors, survival was not different (51.4 +/- 13.4% vs. 48.1 +/- 9.6%; p = 0.87) but transplant-related complications and morbidity were higher as follows: graft-versus-host disease (GVHD) (87% vs. 15%; p less than 0.001), interstitial pneumonitis (59% vs. 14%; p less than 0.003), days in hospital (51 vs. 26; p less than 0.001), and chronic transplant related morbidity 50% vs. 11%; p + 0.033). The age of donors who were closely matched was significantly greater than that of their recipients (29.7 +/- 13.9 years vs. 8.1 +/- 3.1 years; p less than 0.001) and was associated with poorer transplant outcome. Median transplant-related complication-free survival for patients receiving transplants from age non-disparate donors was 53 months (range 18-86 months) compared with 12 months (range 2-42 months) for age disparate donors (p = 0.028). Transplants from closely matched donors were undertaken in the ratio of one to every three matched donors, indicating the importance of this source of marrow in a transplant program.

Postoperative chemotherapy without radiation in young children with malignant non-astrocytic brain tumours. A report from the Australia and New Zealand Childhood Cancer Study Group (ANZCCSG).

Young children with malignant brain tumours have particularly poor survival and manifest severe sequelae of radiation therapy. A multi-institutional pilot study of post-operative primary chemotherapy for children under 3 years with primitive neuroectodermal tumours (PNET) or ependymoma was initiated in 1987. The chemotherapy protocol comprised carboplatin, vincristine and the "eight drugs in 1 day" regimen. Radiation was recommended only if tumour progression or recurrence was documented. A total of 14 patients between 5 and 36 months of age were enrolled. Seven had supratentorial tumours (PNET, pinealoblastoma, intracranial retinoblastoma) with multiple predictors of adverse outcome. Four of these responded to initial chemotherapy but subsequently progressed and all had died by 16 months from diagnosis. The seven patients with infratentorial tumours (three medulloblastomas, four ependymomas) had more favourable predictors of outcome: no meningeal dissemination and gross macroscopic resection in six of the seven cases. One patient progressed rapidly and died within 5 months. The other six are alive at 37-57 months from diagnosis. Four are in continuous complete remission at 57, 51, 41 and 37 months, respectively from the time of their tumour resection. One is described as having stable disease with a persistent radiographic lesion at 41 months from diagnosis. One has relapsed on two occasions and is the only surviving patient to have been irradiated. Intelligence scores for the six long-term survivors have thus for remained within the normal range. It is suggested that some infants with standard-risk ependymoma and, possibly, medulloblastoma may be cured without radiation therapy.

The prognostic significance of tumor-associated markers p53, HER-2/neu, c-myc, v-H-ras, PCNA and EGFr of local and distant recurrence in localized human prostatic adenocarcinoma.

The intracellular expression of the gene products of tumor-associated markers p53, proliferative cell nuclear antigen (PCNA), HER-2/neu, c-myc, H-ras, and epidermal growth factor receptor (EGFr) in 86 cases of localized prostatic adenocarcinoma was investigated immunohistochemically in formalin-fixed paraffin-embedded tissue sections after pretreatment with a novel antigen retrieval buffer. A scoring system was devised to assess strength, pattern, and combined strength/pattern of immunostainings in the nucleus and cytoplasm for each immunomarker. The results were evaluated to determine whether overexpression of the gene products in the nucleus and cytoplasm was predictive of local and/or distant tumor recurrence and whether their expression was associated with known clinical prognostic factors. There was no significant relation between p53, PCNA, HER-2/neu, c-myc, and H-ras protein expression with risk of recurrence. EGFr expression showed a trend of increasing risk of tumor recurrence with higher composite score. Analysis of the association with other known prognostic factors in prostatic adenocarcinoma showed that PCNA was significantly correlated with tumor stage while H-ras and HER-2/neu were marginally correlated with prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) pretreatment serum levels, respectively. Together our findings suggest that overexpression of these intracellular oncoproteins in the tumor cells may not play an important role in determining whether prostatic tumors are likely to recur in localized prostatic adenocarcinoma.

Relationship between radiation response and p53 status in human bladder cancer cells.

Mutations in the p53 tumour suppressor gene are found at high frequency in bladder cancer. There is strong evidence that p53 plays an important role in controlling the cell cycle after DNA damage by ionizing radiation. However, the effect of loss of p53 function on radiosensitivity is not yet clear. Radiotherapy combined with chemotherapy is the most common treatment for patients with invasive bladder cancer. Recently three bladder cancer cell lines have been established and this paper investigates the p53 status and clonogenic survival of these cell lines following irradiation. It was found that one line expresses wt p53 (UCRU-BL-13) and two lines contain a codon 72 polymorphism (UCRU-BL-17 and UCRU-BL-28). UCRU-BL-17 cells also contain a point mutation affecting codon 280. The level of p53 expression in the cell lines is clearly different, with UCRU-BL-17 expressing a higher level of p53 compared with UCRU-BL-13; UCRU-BL-28 expressed intermediate levels. The clonogenic survival of these cell lines has been determined. It was found that the line expressing a p53 mutation was more sensitive than those with wild type p53, providing support for a model in which loss of p53 function is associated with increased radiosensitivity, possibly due to reduced p53-dependent DNA repair.

Prostate cancer and PSA screening.

BACKGROUND: Each year over 12,000 men are diagnosed with prostate cancer in Australia and there is an increasing need to keep up with a reasonable knowledge of the disease for day to day patient management. OBJECTIVE: To summarise the main issues in prostate cancer screening including the methods of diagnosis, treatment and follow up of patients with prostate cancer in all stages of the disease. DISCUSSION: This review is intended as a practical guide to enable general practitioners to play an effective role alongside the other specialists involved in the multidisciplinary management of patients with this common and controversial disease.