EORTC Study Research Articles

BICALUTAMIDE 150 MG IN ADDITION TO STANDARD CARE IN PATIENTS WITH LOCALIZED OR LOCALLY ADVANCED PROSTATE CANCER: RESULTS FROM THE SECOND ANALYSIS OF THE EARLY PROSTATE CANCER PROGRAM AT MEDIAN FOLLOWUP OF 5.4 YEARS

We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b-T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate.

Is there a role for local therapy alone in treatment of high grade prostate cancer?: Assessment of outcome with radical prostatectomy

Patients with high-grade clinically localized disease often have disease beyond the prostate and if so are likely to fail treatment with radical prostatectomy or radiation alone. Results of RTOG 92–02 indicate the subgroup of clinical T2c-T4 patients with Gleason 8–10 who received long-term androgen suppression therapy (AST) had improved survival and likewise survival benefit was demonstrated with long-term AST in a phase III EORTC study that included a minority of patients eligible based on high grade Gleason Score alone.

Is there a role for local therapy alone in treatment of high grade prostate cancer?: Assessment of outcome with radical prostatectomy

Patients with high-grade clinically localized disease often have disease beyond the prostate and if so are likely to fail treatment with radical prostatectomy or radiation alone. Results of RTOG 92–02 indicate the subgroup of clinical T2c-T4 patients with Gleason 8–10 who received long-term androgen suppression therapy (AST) had improved survival and likewise survival benefit was demonstrated with long-term AST in a phase III EORTC study that included a minority of patients eligible based on high grade Gleason Score alone.

846 Long term toxicity following definitive radiotherapy of prostate cancer: analysis of EORTC study 22863

No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer.We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, number NCT00683059.We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3–44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%).Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer.Abraxis Bioscience, Celgene.

Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial

Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial

Adding androgen suppression to radiotherapy may improve disease-free survival over radiotherapy alone in locally advanced prostate cancer: Abstracted from: Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–6.

Adding androgen suppression to radiotherapy may improve disease-free survival over radiotherapy alone in locally advanced prostate cancer: Abstracted from: Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–6.

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.

Transurethral Resection For Bladder Cancer Using 5-Aminolevulinic Acid Induced Fluorescence Endoscopy Versus White Light Endoscopy

Endoscopy done under fluorescence induced by 5-aminolevulinic acid has proved to be a procedure with high sensitivity for detecting transitional cell carcinoma of the bladder. In this multicenter, parallel group, phase III study we compared 5-aminolevulinic acid fluorescence endoscopy guided transurethral bladder resection with transurethral bladder resection done using only white light endoscopy. The proportion of tumor-free resected cases in the 2 groups was evaluated. After patient stratification according to participating centers and European Organization for the Research and Treatment of Cancer risk score 65 and 64 were randomized to the 5-aminolevulinic acid fluorescence and white light endoscopy groups, respectively. Residual tumor was evaluated in the 2 groups by repeat transurethral resection 10 to 14 days later. Analysis was performed according to the intent to treat principle with all patients randomized, followed by per protocol analysis. Intent to treat analysis revealed that in the white light endoscopy group 40.6% of cases were resected tumor-free at primary resection, whereas with 5-aminolevulinic acid fluorescence endoscopy guided transurethral resection 61.5% were resected tumor-free (p <0014). On protocol analysis 46.9% patients in the white light and 67.3% in the 5-aminolevulinic acid fluorescence endoscopy groups were resected tumor-free (p <0.031). No difference was noted in the 2 groups in regard to side effects or laboratory findings. The risk of residual tumor after transurethral resection of transitional cell carcinoma is significantly decreased by 5-aminolevulinic acid fluorescence endoscopy.

Interval debulking surgery in advanced epithelial ovarian cancer

Cytoreductive surgery and chemotherapy are the mainstay for the treatment of advanced epithelial ovarian cancer. In order to minimize the tumour burden before chemotherapy, cytoreductive surgery is usually performed first. The importance of the amount of residual disease as the main prognostic factor for patients suffering from advanced disease has been almost universally accepted even in the absence of prospective randomized trials addressing the benefit of cytoreductive surgery. In the last decade, the value of debulking surgery after induction chemotherapy – interval debulking surgery, IDS – has been widely debated, especially after the completion of a prospective randomized study from the EORTC addressing the introduction of a surgical procedure with debulking intent preceded and followed by cytoreductive chemotherapy. The rationale of such a strategy in the context of the primary treatment of advanced ovarian cancer lies in a higher cytoreductibility to the ‘optimal’ status forwarded, and possibly facilitated, by chemotherapy. The results demonstrated a prolongation of both progression-free survival and median survival in favour of patients randomized to IDS (5 and 6 months, respectively). Multivariate analysis revealed IDS to be an independent prognostic factor which reduced the risk of death by 33% at 3 years and by 48% in subsequent re-evaluation after more than 6 years of observation. Despite the above, results have been questioned by many, leading the GOG to perform a similar study which has been concluded very recently. Nevertheless, the main concern regarding the application of IDS in all instances relates to the morbidity of two major surgical procedures integrated within a short period during which cytotoxic chemotherapy is also administered. Neoadjuvant chemotherapy has been recently proposed to avoid a non-useful surgical procedure in patients considered ‘optimally unresectable’ after diagnosis of advanced ovarian cancer. Whether or not this newer approach will translate into a longer survival with a better quality of life is going to be addressed by a novel EORTC study. Finally, the concept of a ‘chemical’ cytoreduction preceding and facilitating a subsequent ‘surgical’ effort has been recently introduced also in the treatment of recurrent disease. The EORTC has recently initiated a prospective randomized study (LOROCSON – Late Onset Recurrent Ovarian Cancer: Surgery or Not) to validate the importance of such an approach to be balanced with medical treatment alone not only in terms of survival but also as far as quality of life is concerned.

Bicalutamide as Immediate Therapy Either Alone or as Adjuvant to Standard Care of Patients with Localized or Locally Advanced Prostate Cancer: First Analysis of the Early Prostate Cancer Program

We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies.

To assess the variability between institutions in the recurrence rate at the first follow-up cystoscopy (RR-FFC) after transurethral resection (TUR) in patients with stage Ta T1 bladder cancer. A total of 2410 patients from seven EORTC phase III trials conducted between 1979 and 1989 were included. Patients with single and with multiple tumors were analyzed separately according to whether or not they received adjuvant intravesical treatment. The RR-FFC varied greatly between institutions. For patients with a single tumor, it ranged from 3.4% to 20.6% for patients not receiving any intravesical adjuvant treatment and from 0% to 15.4% in those receiving it. In patients with multiple tumors who had adjuvant treatment, it varied between 7.4% and 45.8%. There was a slight decrease over time in the recurrence rate for patients with single tumors, particularly in those receiving adjuvant intravesical treatment. For both patients with single and with multiple tumors, the percentage of patients with a recurrence in the bladder at the first follow-up cystoscopy after TUR varies substantially between institutions and cannot be explained by the factors that were assessed. It is suggested that the quality of the TUR performed by the individual surgeons may be responsible.

Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity?

Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy. The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions. The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity. More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome. ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.

A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer

Purpose: To evaluate the irradiation techniques used for the irradiation of the internal mammary and medial supraclavicular lymph node chain (IM-MS) in the EORTC 22922 study, which evaluates its impact on survival in stage I–III breast cancer patients with axillary node invasion and/or central or medial location of the primary tumour. Materials and methods: The analysis was performed based on the dummy run data of the Quality Assurance Programme of the study. A standard irradiation technique was proposed within the study protocol, and the use of other treatment set-up techniques was allowed. Results: By March 2000, 39 centres from 12 different countries had participated in the study; 32 of these had already fulfilled the dummy run procedure. No centres had to be excluded from the study. Seventy-eight percent of the centres are using the standard irradiation technique, 64% of these with minor variations. Twenty-two percent of the centres developed an alternative irradiation technique. The remarks to the centres using the standard set-up were most often related to the junction problem and the possible under- or overdosage in the target volumes. The remarks to the centres with alternative techniques most often concerned the possible enhanced dose to the lungs and the heart. Conclusion: In a multi-centre trial an easy irradiation technique applicable in a large number of centres should be provided. A quality assurance programme allows early detection of possible problems with treatment planning and delivery. The analysis of the dummy run data showed that if the recommendations of the Quality Assurance Committee are applied, both standard and alternative IM-MS irradiation techniques produce acceptable dose distributions.

Early mycosis fungoides: can the diagnosis be made reliably?

The diagnosis of early mycosis fungoides is often regarded as difficult or impossible due to the lack of clear-cut histopathologic criteria. Many authors have published observations of histologic features seen in biopsies of patients with mycosis fungoides and have offered parameters that may be helpful in diagnosis. In the study, undertaken by members of the EORTC Cutaneous Lymphoma Study Group, the proposed histologic features are tested for sensitivity and specificity. This commentary discusses some of the historical issues and the value of the EORTC study pertaining to the diagnosis of early mycosis fungoides.

Ductal carcinoma in situ revisited

Since our review appeared in The Breast, further information from randomized studies has become available. The EORTC data have been published and are summarized in Table 1. This was a randomized trial assessing the value of radiotherapy after breast conserving surgery. The results demonstrate a significant advantage for radiotherapy both in terms of ductal carcinoma in situ (DCIS) and invasive recurrence. There was a significant excess of contralateral cancers in the irradiated group. The benefits of radiotherapy in the NSABP study was greatest in patients at high risk of recurrence. Marked/moderate comedo necrosis, solid tumour type, moderate/marked lymphoid infiltrate and multifocality were all found to be significant predictors for breast recurrence in patients treated by wide excision alone or wide local excision plus radiotherapy. Uncertain/involved margins and poor unclear grade were of borderline significance (Table 2). 1 The results relating grade to local recurrence from the EORTC study have been presented but have not been separated into groups who did or did not have radiotherapy but have not shown a relationship between degree of differentiation of DCIS and local recurrence, which is surprising (Table 3). The most recent publication from the NSABP treated patients with DCIS by wide local excision and radiotherapy and randomized them for tamoxifen, 20 mg a day for 5 years. 2 Although this study showed a significant reduction in all breast cancer events there were only significant reductions in ipsilateral invasive disease and contralateral DCIS. Surprisingly there was no apparent effect on ipsilateral DCIS and contralateral invasive cancer (Table 4). The effect of tamoxifen was also much greater in patients whose disease was incompletely excised. The role of tamoxifen in DCIS which has been widely excised remains uncertain

Cytogenetic and Southern blot analysis to demonstrate clonality and to estimate prognosis in patients with myelodysplastic syndromes

We examined the bone marrow of 109 patients with myelodysplastic syndrome (MDS) at the time of diagnosis and during the course of the disease by means of Southern blot analysis and/or cytogenetic studies to detect and evaluate clonal markers, their implications for the prognosis of the disease, and the response to treatment. The patients either were enrolled in an EORTC study and received low-dose Ara-C with (n=31) or without (n=21) growth factors, according to the study protocol, or were treated supportively (only one patient received regular chemotherapy for concomitant lymphoma). Full or at least partial remission was achieved by 34% of the treated patients (n=54). In 57% (53 of 93) of all patients a clonal marker of either kind was detected by Southern blot analysis and/or cytogenetic examination. Clonal chromosomal aberrations were found in 45% (35 of 77) of the cases examined at diagnosis, with solitary del(5q) aberrations occurring in 10% of the cases and complex aberrations in 18%, trisomy 8 or monosomy 7 being a frequent finding. Of all patients, 49% (28 of 57) were characterized by one or more gene rearrangements (e.g., Ig-JH, TcR-beta, M-bcr, GM-CSF, G-CSF, or IL-3) at diagnosis. In five of 21 cases (24%) studied in hematological remission of the disease chromosomal aberrations were still detectable, and in seven of 23 (30%) a gene rearrangement persisted. We also found six cases with multiple clones exhibiting different susceptibilities to treatment and thereby indicating the oligoclonal character of this disease. Clinical evaluation revealed that the prognosis of the respective patients was directly related to the particular clonal markers detected at diagnosis: Risk groups were subdivided according to the karyotypes, with a solitary del(5q) aberration meaning a favorable, a normal karyotype an intermediate, solitary aberrations without del(5q) a poor, and complex karyotypes a very poor prognosis. We showed that densitometry helps to increase the sensitivity of Southern blot analysis by quantifying the amount of altered DNA, which often increases shortly before or at progression of MDS. Overall, there was a high level of concordance of both clonality examinations with the clinical course of the disease and the response rate. Therefore, we recommend cytogenetic studies and Southern blot analysis to detect clonal markers at diagnosis of MDS, to detect oligoclonality and clonal evolution, or to quantify the amount of clonal DNA, which appears to be a sensitive tool for evaluating the prognosis and response to therapy in MDS.

Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy — A phase III EORTC study

Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy — A phase III EORTC study

Stereotactic one-time irradiation (radiosurgery). The methods, indications and results

Stereotaxy is a method to determine a point in the patient's body by an external coordinate system which is attached to the patient. Radiosurgery uses this method for precise delivery of a high single radiation dose to the patient. The aim is to destroy the tissue in the target and to spare surrounding unaffected normal tissue by a steep dose gradient. Three techniques of percutaneous radiosurgery are available: radiosurgery with ion beams with a cyclotron, spherical arrangement of cobalt-60 sources, the so-called gamma knife, and an adapted linear accelerator. The availability and the good clinical experience lead to a wide spread use of linear accelerator for radiosurgery in recent years. A subsequent development is fractionated stereotactic radiotherapy which combines the precision of radiosurgery with the radiobiological advantage of fractionation. Only a few indications for radiosurgery are proven by statistically valid studies. One of these is the treatment of small arteriovenous malformation, where obliteration rates of 80% to 100% are reported with only minor toxicity. However, the obliteration rate is reduced significantly in large arteriovenous malformations. A local control rate of 90% is obtained after radiosurgery of brain metastases which is comparable to the results of microsurgical resection followed by adjuvant whole brain radiotherapy. An ongoing EORTC study evaluates the role of adjuvant whole brain radiotherapy after radiosurgery. The survival of the patients with brain metastases is limited by the existence of progressive extracerebral disease. The role of radiosurgery in the treatment of benign tumors is currently evaluated in clinical studies which include: vestibular schwannomas, meningiomas, chordomas and chondrosarcomas and pituitary adenomas. Most of the published studies include only small tumors because radiosurgery is limited by the risk of radionecrosis of adjacent normal tissue, which shows a steep dose volume response relationship. Recent developments of stereotactic radiotherapy include the use of mini-multileaf-collimators and clinical studies on stereotactic radiotherapy of extracranial targets. Stereotactic irradiation is a well established treatment technique for intracranial tumors and arteriovenous malformations. Methods are available that allow optimization of dose distributions to irregularly shaped tumors for single dose as well as fractionated stereotactic irradiations by linear accelerator. Therefore the therapeutic potential of this technique has increased and enables also the extracerebral application in controlled clinical studies.

Oxaliplatin in ovarian cancer

Oxaliplatin in ovarian cancer

Chemoprevention of head and neck and lung (pre)cancer.

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.