High Dose Rate Brachytherapy in High-Risk Localised Disease - Why Do Anything Else?

The management of high-risk prostate cancer is challenging, as patients have a high risk of both local and distant relapse. Although adjuvant systemic treatment remains an important component of management, for those receiving radiotherapy, optimal local treatment should include a brachytherapy boost. This may be given by low dose rate (LDR) or high dose rate (HDR) techniques, but HDR has several advantages over LDR by virtue of more consistent dose optimisation, ability to treat outside the prostate and lower toxicity. A significant body of evidence now supports the use of HDR brachytherapy in addition to supplementary pelvic external beam radiotherapy for men with high-risk disease. Consistent evidence has emerged from randomised clinical trials, meta-analyses, and from institutional and multicentre cohort studies. It has been shown to improve local disease control and possibly reduce metastases and improve cancer-specific survival compared with external beam radiotherapy alone. It should be considered as standard treatment.

The emerging role of high-dose-rate brachytherapy for prostate cancer.

By placing radioactive sources directly into the cancer, brachytherapy allows delivery of a highly conformal radiation dose to the prostate. Permanent seed brachytherapy is most commonly used for low-risk cancer, whereas high-dose-rate (HDR) brachytherapy is combined with external-beam radiotherapy to treat higher risk disease. The high rate of dose delivery and the large fraction size may be a radiobiological advantage for tumours with high sensitivity to radiation fraction size. The ability to optimise dose delivery allows for exquisite shaping of dose around the prostate and sparing of normal tissues. HDR brachytherapy is most commonly delivered in two or more fractions of 810 Gy combined with 40-50 Gy external beam. Published studies are almost entirely limited to single-institution case series. Most of the patients treated have relatively unfavourable localised disease, with a reported disease-free survival of 68-93%, and a local control rate of over 90%. Treatment is well tolerated, with urethral stricture the most common late effect (risk around 8%). Early results using HDR monotherapy in low-risk disease seem promising. Patients most likely to benefit from a combined HDR/external-beam approach have bulky local disease (stage T2b-T3) or intermediate to high-grade cancers. Prospective multicentre studies of HDR brachytherapy have begun in this patient group in Canada and the USA, which hopefully will allow future comparisons with high-dose conformal external-beam techniques.

PSA doubling time of prostate carcinoma managed with watchful observation alone.

PURPOSE: To study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma. METHODS AND MATERIALS: A prospective single-arm cohort study has been in progress to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, or PSA progression as treatment indication in untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2bN0 M0, Gleason Score < or = 7, and PSA < or = 15 ng/mL). Patients are conservatively managed with watchful observation alone, as long as they do not meet the arbitrarily defined disease progression criteria. Patients are followed regularly and undergo blood tests including PSA at each visit. PSA doubling time (Td) is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model. RESULTS: As of March 2000, 134 patients have been on the study for a minimum of 12 months (median, 24; range, 12-52) and have a median frequency of PSA measurement of 7 times (range, 3-15). Median age is 70 years. Median PSA at enrollment is 6.3 (range, 0.5-14.6). The distribution of Td is as follows: <2 years, 19 patients; 2-5 years, 46; 5-10 years, 25; 10-20 years, 11; 20-50 years, 6; > 50 years, 27. The median Td is 5.1 years. In 44 patients (33%), Td is greater than 10 years. There was no correlation between Td and patient age, clinical T stage, Gleason score, or initial PSA level. CONCLUSION: Td of untreated prostate cancer varies widely. In our cohort, 33% have Td > 10 years. Td may be a useful tool to guide treatment intervention for patients managed conservatively with watchful observation alone.

Should pathological T3 and/or margin positive prostate cancer receive adjuvant therapy? A radiation oncologist's view.

Patients with pathological stage T3 and/or margin positive prostate cancer after radical prostatectomy have a high risk of tumor recurrence, usually heralded by rising PSA. Adjuvant therapy such as radiotherapy and/or hormone therapy needs to be explored to provide a better outcome. To date the exact role and result of adjuvant therapy remains unclear. However there has been increasing suggestion that adjuvant radiotherapy improves local control and disease free survival. Also adjuvant hormone therapy may play a role in this group of patients with a high metastatic potential. This review article addresses the clinical significance of PT3 and/or margin positive prostate cancer and explores the rationale behind considering adjuvant therapy including postoperative radiotherapy and/or hormone therapy.

Is there a place for whole abdominal radiotherapy in the management of ovarian cancer?

Most patients with ovarian cancer require further therapy with chemotherapy or radiotherapy because of the high recurrence risk following surgery alone. Radiotherapy directed to the whole abdomen and pelvis is capable of producing survival rates of 70% in carefully selected patients. Such patients have no more than microscopic residual disease in the abdomen, and small volume residual disease in the pelvis. They are selected based on a prognostic matrix which considers grade, stage and the presence of pelvic residual disease. With optimal radiotherapy technique, long term serious toxicity occurs in less than 5% of patients. Patients with macroscopic residual disease are treated with chemotherapy. Patients who obtain a complete response have been treated with consolidative whole abdominal radiotherapy, although the benefit of such an approach is unclear.

Brachytherapy: current status and future strategies -- can high dose rate replace low dose rate and external beam radiotherapy?

Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10-15 Gy is commonly combined with EBRT to a dose of 40-50 Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is now being investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer.

Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer.

To test the hypothesis that the rate of rise in prostate-specific antigen (PSA) is slower during the spring-summer than during the rest of the year, we used PSA data from a prospective single-arm cohort study of men who had been followed to characterize a watchful observation protocol with selective delayed intervention for clinically localized, low-to-intermediate grade prostate adenocarcinoma. The rate of PSA increase was calculated as the visit-to-visit slope of log (PSA) against time, from 1 calendar-quarter visit to the next. The nonparametric Friedman test confirmed differences in rate of PSA rise among the calendar quarters (P = 0.041). Post hoc analysis showed the rate of PSA increase during Q2 was significantly slower than in each one of the other calendar quarters (Q1 versus Q2, P = 0.025; Q3 versus Q2, P = 0.002; Q4 versus Q2, P = 0.013), with no differences among quarters Q1, Q3, and Q4. These results are consistent with the vitamin D hypothesis that the higher 25-hydroxyvitamin D levels associated with spring and summer have a desirable effect on prostate biology. The therapeutic implication is that vitamin D supplementation in the range of 2000 IU/d, a dose comparable to the effect of summer, can benefit men monitored for rising PSA.

Does adjuvant chemotherapy change the prognosis of cervical cancer?

Although combination chemotherapy, which includes cisplatin, has a high response rate in cervical cancer, its usefulness as an adjunct to pelvic surgery or radiotherapy remains undefined. In most studies chemotherapy, either before, during, or after local treatment, has not been shown to improve outcome. Local treatment alone remains standard treatment, pending further randomized trials.

Pharmacokinetics of mercaptopurine: plasma drug and red cell metabolite concentrations after an oral dose.

Measurement of red cell 6-mercaptopurine (MP) derived 6-thioguanine nucleotide (TGN) and methylmercaptopurine metabolites (MeMPs) can be used to monitor therapy in children who are administered MP for childhood lymphoblastic leukemia. Red cell TGNs are not influenced by the time of blood sampling in relation to the last MP dose. The purpose of this study was to find out whether the same is true for the MeMPs. Plasma MP and red cell MP metabolite pharmacokinetics were studied in seven children immediately before and for 4 hours after a protocol standardized dose of MP. Duplicate blood samples were taken, one was processed immediately whereas one was left at an ambient temperature for 24 hours. The variation in TGN and MeMP metabolites over the 0- to 4-hour period (10 time points per child) was within the error of the assays used. The coefficients of variation for the TGNs ranged from 2.7% to 7% and for the MeMPs, 4% to 10.7%. There was no difference in the TGN and MeMP concentrations measured when the blood samples were left for 24 hours. If a child takes a MP tablet immediately before a clinic appointment, it has no major influence on MeMP measurements.

Synthesis and diversity analysis of lead discovery piperazine-2-carboxamide libraries.

A Lead Discovery Library of piperazine-2-carboxamide derivatives was produced for general screening. This paper discloses two novel solid phase synthetic routes used to produce 15,000 single compounds via the Irori directed sorting technique. Computational methods such as reagent clustering and library profiling were used to maximize reagent diversity and optimize pharmacokinetic parameters. The results of a four center pharmacophore analysis revealed the added diversity gained by using two independent synthetic routes.