 Vol.45 n° 4 |
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Paclitaxel and Cisplatin as Salvage Treatment in Patients with Non-seminomatous Germ Cell Tumour Who Failed to Achieve a Complete Remission on Induction Chemotherapy
The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour makers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m² as a 3-hour infusion, followed by cisplatin 100 mg/m², repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine >130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 50%, and nausea and vomiting in 43%.
Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31% in patients with poor prognosis who had not achieved a CR on induction chemotherapy.
Concurrent Cisplatin-Based Radiotherapy and Chermotherapy for locally advanced Cervical Cancer
Background and Methods On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens - cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone - in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 mmol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3).
Results The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than the group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively.
Conclusions Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.
Tobacco and the risk of acute leukaemia in adults
Summary Self-reported smoking histories were collected during face-to-face interviews with 807 patients with acute leukaemia and 1593 age- and sex- matched controls. Individuals who had smoked regularly at some time during their lives were more likely to develop acute leukaemia than those who had never smoked (odds ratio (OR) = 1.2, 95% confidence interval (CI) 1.0-1.4). The association was strongest for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4, 95% CI 1.1-1.7). With respect to the numbers of years smoked, risk estimates were raised in all groups except those who had smoked for fewer than 10 years. Similarly, the odds ratio decreased as the number of years 'stopped smoking' increased, falling to one amongst those who had given up smoking for more than 10 years. No significant linear trends were found, however, with either the numbers of years smoked or the numbers of years stopped smoking. and no significant differences were found between AML and ALL.
The genetics of transitional cell carcinoma: progress and potential clinical application
Our understanding of the genetics of TCC has advanced dramatically during the past few years. Present understanding includes a model for the molecular pathogenesis of the disease and an extensive repertoire of genes and loci known to be genetically altered in TCC, some of which show great promise as predictive markers. This information has been obtained using various approaches which have included the analysis of genes known to be involved in other tumours, and searches for novel genes using techniques to compare bladder tumour and normal genomes. The impetus for these studies is generated by the hypothesis that the phenotype of the bladder cancer cell is determined largely by its genotype. The fruits of such research should include improved methods for diagnosis, prediction of prognosis and disease monitoring and gene targets for the design of novel therapies. This review summarizes current knowledge of the genetics of TCC and describes some examples of the potential clinical utility of this information.
CHOP versus MACOP-B in aggressive lymphoma - a Nordic Lymphoma Group randomised trial
Background: The long-term survival of patients with advanced stage aggressive lymphoma has not improved significantly during the last twenty years. In a randomised trial, the efficacy of MACOP-B, a six-drug weekly chemotherapy regimen, was compared to CHOP, the current standard regimen, in terms of overall and failure-free survival, toxicity and health related quality of life.
Patients and methods: Four hundred five patients with aggressive lymphoma, stage II-IV, age 18-67, were randomised to receive either 12 weeks of MACOP-B or 8 courses of CHOP over 24 weeks. Special emphasis was put in the definition of Ann Arbor stage in extranodal disease. A subset of 95 patients also entered a quality of life study, based on the EORTC QLQ C30.
Results: Thirty-one patients were ineligible. Among the remaining 374 patients, the median age was 52 years. According to the age-adjusted International Prognostic Index, 37% were 'high-intermediate' or 'high-risk' patients. No difference could be demonstrated, either in overall survival (60% at five years in the MACOP-B group and 59% in the CHOP group) or in failure-free survival (47% at five years with MACOP-B and 44% with CHOP). In terms of quality of life, physical function and global quality of life were more impaired in patients receiving MACOP-B, who also exhibited more non-haematological toxicity.
Conclusion: No superiority of MACOP-B compared to CHOP could be demonstrated. CHOP remains the treatment of choice in low-risk patients. At present, intensified or experimental treatment should be reserved for high-risk disease.
How is follow-up after transurethral prostatectomy best performed?
Objective To evaluate the role of the nurse practitioner (NP) in screening patients for potential discharge after routine transurethral prostatectomy (TURP) or bladder neck incision (BNI) where, although urologists continue to follow such patients, the trend is away from clinic attendance.
Patients and methods The NP telephoned 70 patients 4 weeks after surgery; information about expected post-operative problems, change in symptoms and the need to visit their general practitioner (GP) was recorded. A doctor then saw all patients in a clinic 3 months after TURP or BNI.
Results Complete records were available for 66 patients (TURP 56, BNI 10). Four weeks after their operation. 39 (59%) patients still had one or more significant symptoms but only nine (23%) had consulted their GP. After a telephone interview the NP considered that 38 of the 66 patients were fit to be discharged. At the 3-month outpatient appointment, 37 of these 38 patients were subsequently discharged. Of the remaining 29 patients, 15 (seven with carcinoma of the prostate and eight with significant symptoms) were given follow-up appointments.
Conclusions The persistence of significant symptoms in 12% of patients 3 months after TURP justifies the follow-up of all patients. A telephone interview by the NP at one month is recommended. This could result in safe discharge of more than half the patients and allow follow-up of those who need specialist input.
Cost-effectiveness of faecal occult blood screening for colorectal cancer: results of the Nottingham trial
Colorectal cancer is a major cause of mortality in most industrialised countries. In the USA, 6% of the population will develop the disease during their life-times and 40% of these will die as result of it. Around 140 000 new cases are registered each year [1]. In the European Union during the 1980s, annual deaths from colorectal cancer amounted to around 85 000 [2]. Indeed, the disease is the second leading cause of cancer death in both Western Europe and North America [3]. As with many cancers, risk increases with age.
In the case of two other cancers, breast and cervix, programmes of mass population screening have been adopted as instruments of public health policy in many industrialised countries. In each of these cases, it would appear that the decision-makers concerned felt that the extra costs of screening were more than outweighed by the benefits of early detection and treatment of the disease. Now, equivalent arguments are emerging with respect to colorectal cancer.
Clinical benefits of stabilisation with second line chemotherapy in patients with metastatic colorectal cancer
The options available to treat metastatic colorectal cancer have been expanded recently by the appearance of potent drugs for second line chemotherapy. These have produced sizeable objective responder rates and a generally higher rate of stabilisation. The clinical value of achieving stabilisation in these patients is not well understood. A multi-centre, prospective, descriptive study was undertaken to evaluate health status in 80 patients suffering from metastatic colorectal cancer who were receiving second line chemotherapy. The health-related quality of life (HRQOL) profile and evolution in different health states were compared. Results showed that patients who stabilise on treatment have a very similar profile to that of responders, in contrast to patients whose disease progresses. The different dimensions of HRQOL either improve or remain stable in a higher percentage of patients who have stabilised than in those whose disease has progressed. Lengths and costs of hospital admissions for toxicity or cancer complications are almost three times as high in patients who have progressed as in those who remain stable, which, in turn, are similar to those seen for responders. Stabilisation is shown to be a beneficial result of treatment, not only for the patient but also for the community.
Lung cancer radiation treatment in the elderly
More than 900 000 new cases of lung carcinoma are diagnosed every year in the world, making this malignancy one of the major health problems in western countries [1-3] and more than one third of lung carcinomas occur after 70 years of age [4,5]. Lung cancer represents the most common smoking-related cause of mortality and the percentage of lung cancer in the elderly is expected to increase within the next decade not only as a consequence of increased life expectancy in the general population but also because a great amount of people started smoking in the 1940s and 1950s; those who were still young at the time will have more pack-years than those who started at an older age, therefore, the incidence will continue to increase and especially in older people. [6,7]
As elderly patients with lung cancer undergo radical treatment less frequently than younger patients, the age represents an important clinical parameter in order to make any therapeutic decisions [8-11]. However, it has recently been shown that when the clinical selection is accurate, both the clinical outcomes and the therapy-related toxicity exhibited by elderly patients undergoing standard treatment, are similar to those observed in younger subjects [12,13]. Radiotherapy (both radical and palliative) is the most widely used treatment in elderly patients with non small cell lung cancer [13,14], and when combined with chemotherapy plays an important role also in the management of small cell lung cancer.
BRCA1, BRCA2 and their possible function in DNA damage response
The recognition of DNA damage and DNA repair responses are coupled to transcriptional events. This coupling evolved in mammalian cells in order to stimulate DNA repair processes, induce additional repair mechanisms, activate checkpoint functions or apoptosis. In order to repair, recover and survive, mammalian cells must recognize DNA damage and consequently they require the introduction of specific genes and proteins. Some universal, and possibly some other tissue-specific, signal transduction pathways lead to the activation of key transcription factors which then regulate downstream molecular events in the damage response. The regulation of DNA damage repair at the transcriptional level could be a primary response and thus altered gene expression may offer the first detectable molecular events in the process of DNA damage control. BRCA1 and BRCA2 both have transcriptional activator functions and are part of a big nuclear protein complex, which may act as a molecular sensor and signal transducer. The role of the p53 gene in DNA damage response is well established and recently it has been reported that both BRCA1 and BRCA2 gene products actively interact with TP53. Also, there are several studies demonstrating altered damage response in cells mutated for BRCA1 or BRCA2. Clearly, there is a role or perhaps more than one role for the BRCA1 and BRCA2 genes in DNA damage response, but the real question is where to place their action in this very elaborate multistep pathway?
It is estimated that 10% of breast cancer patients develop the disease due to the presence of a breast cancer predisposition gene (Easton and Peto, 1990). Nearly half of these patients are thought to have a mutation in the breast cancer predisposition genes, BRCA1 or BRCA2. The recent isolation of BRCA1 (Miki et al, 1994) and BRCA2 (Wooster et al, 1995) simulated intensive scientific interest. Although a large amount of information is now available, including nucleotide sequence, mutation spectrum, cellular localization and protein structure, the molecular pathway in which BRCA1 and BRCA2 is involved in response to DNA damage remains to be elucidated.
New approaches to systemic treatment of melanoma
Metastatic melanoma is an incurable condition with a median survival of about 6 months. Chemotherapy can result in objective tumour responses but only in a minority of cases and remissions are short-lived, 3-6 months. DTIC is the most active single agent with response rates of 15-20% and although combination chemotherapy can result in higher response rates there is no response duration or survival advantage. Phase II studies have suggested that combining chemotherapy with biological response modifiers may result in higher response rates, in the order of 50% and the results of two large randomized trials investigating this approach are awaited.Adjuvant trials currently focus on interferon and/or vaccine strategies. Further data are required before any adjuvant treatment can be regarded as standard.
Melanoma is becoming an increasingly common disease. In 1995 an estimated 32 100 individuals developed melanoma and 7200 died of this disease in the United States (1). No other tumour is increasing faster in the number of new cases diagnosed. The reasons for this dramatic increase remain unclear, but probably result from a combination of a increased exposure to sunlight, increased amounts of ultraviolet B irradiation reaching the Earth's surface and earlier detection of melanoma.
Fortunately most patients are diagnosed early and surgical treatment of early melanomas results in cure rates of at least 90%. Once vertical invasion is established, there is a rapid decrease in cure rates. Patients with a thick primary melanoma (>4mm) or melanoma metastatic to regional lymph nodes are at high risk of relapse and have a mortality rate of 50-90%.
There have been two large overviews of survival in stage IV melanoma. In 1995 the John Wayne Cancer Institute reported data on 1521 patients who were seen between 1971 and 1993 (2). The median survival of their patients was found to be 7.5 months. A more recent meta-analysis of 5392 patients in 74 studies demonstrated a very similar median survival of 7.9 months (3). Both studies included patients treated with both chemotherapy and biotherapy, and overall survival did not appear to be appreciably different from untreated patients.
These figures highlight the need for better systemic intervention to treat metastatic disease and also effective adjuvant therapy to prevent recurrence and the development of systemic metastases. We review here the current and future prospects for systemic treatment with particular emphasis on the use of biological therapy.
Current options in treatment of anthracycline-resistant breast cancer
Breast cancer is a chemosensitive tumour and anthracyclines are one of the most active cyctotoxic agents in chemotherapy treatment. Failure after anthracycline-containing chemotherapy is a poor prognostic factor because of low response rate to salvage chemotherapy. Several factors like P-glycoprotein mediated drug resistance (MDR-I or MRP), glutathione or amplification of topoisomerase II have been found to be involved in anthracycline resistance. No clear benefit for patients treated with 'resistance-modifier' agents like verapamil, dexverapamil or quinidine has yet been demonstrated. Most clinical studies with non-cross resistant cytotoxic agents are laking a strict definition of anthracycline resistance. A strict definition of anthracline resistance implies progressive disease during anthracycline chemotherapuy. Among the cytotoxic drugs only 5-Fluorouracil (given as 24 h continous infusion with folinic acid) and the taxanes produce more than 20% objective remission (RR) in case of anthracycline resistance, whereas the highest response rate was reported for docetaxel (32-57%). Only few randomized studies were performed: docetaxel showed higher anti-tumor activity than methotrexat/5-FU (RR:42% vs 19%, P<0.001) or mitomycin/vinblastine (RR:30% vs 12%; P<0.001) and treatment with paclitaxel (175mg/m²) was in favour to mitomycin (RR 17% vs 6%). In combination chemotherapy most activity have been reported for paclitaxel plus high-dose 5-fluorouracil (given as 24 h continous infusion with folinic acid) (RR:58%) or for docetaxel plus cisplatinum (RR:46%). High-dose regimens with growth factor stem cell support seems to be active in anthracycline-resistant disease but the toxicity is considerable. In conclusion, the taxanes, especially docetaxel as single agent or paclitaxel plus high-dose 5-FU, are the most promising therapeutic options in treatment of anthracycline resistant disease. Further clinical phase II/III studies in breast cancer should include exact definition of anthracycline pretreatment and resistance.
Standards, Options and Recommendations: concomitant radiochemotherapy for cancer of the cervix: a critical analysis of the literature and update of SOR
The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the National Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres (CRLCC) and specialists from French public universities, general hospital and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives: To update, according to the methodology of SOR, the Standards, Options and Recommendations for the management of patients with cancer of the cervix, and in particular, the place of concomitant radiochemotherapy. Methods: Data have been identified by a literature search using Medline (to April 1999) and the personal reference lists of experts. Once the guidelines were defined, the document was submitted for review to independent national and international reviewers and to the medical committees of the CRLCC. Results: The principle recommendations concerning the place of radiochemotherapy in the treatment of cancer of the cervix are: 1) the available data shows a significant increase in local control (level of evidence A) and of overall survival (level of evidence B1) following concomitant radiochemotherapy as compared to radiotherapy alone or the combination of radiotherapy-hydroxyurea. For stages IB, IIA, proximal IIB with bad prognostic factors (tumour size greater than 4 cm and/or invasion of pelvic nodes and/or microscopic invasion of the parametrium) and without lumbo-aortic nodal invasion, concomitant radiochemotherapy can be considered as standard treatment. This benefit is less clear for stages distal IIB, III et IVA without para-aortic nodal invasion (level of evidence C) and must be confirmed (expert agreement); 2) the toxicity of radiochemotherapy is essentially haematologic and gastrointestinal (level of evidence B1) and is greater than that of radiotherapy alone (level of evidence B1); 3) these results have been obtained by the combination pf chemotherapy based on cisplatin alone, or in combination with 5FU. Although of equal benefit, the toxicity of the cisplatin/5FU/hydroxyrea combination was grater than of cisplatin alone in a trial comparing the two protocols. A significantly longer survival have also been obtained by the combination of chemoradiation and adjuvant chemotherapy with epirubicin (level of evidence C). These results must be confirmed; 4) the exact means of delivering the chemotherapy has not been clearly established. In fact, in these trials, some protocols use cisplatin weekly at a dose of 40 mg/m2 and others every three or four weeks at doses ranging from 50 to 75 mg/m2 . Subsequent randomised studies are likely to establish optimal schema for the delivery of chemotherapy when combined with external radiotherapy and brachytherapy.
The Continuing Challenge of Treatment for Non-Hodgkin's Iymphoma in Children
The philosophy of treatment in children's cancers has changed steadily over past 10-15 years as it has become apparent that in many tumour types the chance of cure is very high. One example is non-Hodgking's lymphoma (NHL). In the early 1980s the focus of effort was to try to improve outcome in those patients with non-localized disease in whom standard CHOP-type regimens or more complex multiagent acute lymphocytic leukaemia (ALL) type protocols were of limited value. As will be described later, the stratification of treatment based on histological and subsequently immunophenotypic characteristics and the ability to significantly escalate the doses of chemotherapy transformed the outcome, particularly in B-cell NHL. Currently, as much effort is applied to reducing the early and late sequelae of such treatments as to reducing the relapse rates in the small percentage that fail first-line therapy (Magrath, 1997; Philip at al, 1996; Sandlund et al, 1996). With increased success in the commoner NHL subtypes, interest and effort has been directed towards the less common variants. These are not only biologically intriguing but have thrown up a whole new range of management problems. Their rarity has been a real stimulus to international collaboration which is a prerequisite to improve the understanding of these conditions and optimizing therapy.
Management of Neuroendocrine Tumours
Neuroendocrine tumours (NET) represent a collection of anatomically diverse tumour types derived from common cell lines and unified by the secretion of neuropeptides, whose excess secretion may give rise to distinctive clinical syndromes. They arise from diffuse neuroendocrine cells found in the brain and the pituitary gland, and in sympathetic nervous tissue in the torax, abdomen and pelvis, as well as the entire gut and pancreas. Other common sites include the adrenals, the lungs and the thyroid gland. They may also rarely be found in the ovary, cervix, uterus, prostate and oesophagus. Furthermore most of these tumours contain somatostatin receptors (SSTR); the ability to demonstrate these can be diagnostic as well as therapeutic value. These tumours were previously referred to as APUDomas [1,2], because of their characteristic of amine precursor uptake and decarboxylation (APUD), but they are now more correctly referred to as NET. Differentiation between benign and malignant tumours is difficult histologically; clinical behaviour is the only reliable determinant. This article concentrates on those tumours that behave in a malignant fashion.
Stereotactically Delivered Cranial Radiation Therapy: A Ten-Year Experience of Linac-Based Radiosurgery in the UK
Abstract. In 1989, linear accelerator (linac)-based cranial stereotatic radioation therapy ('radiosurgery') was introduced in the UK at St Bartholomew's Hospital; a new, relocatable stereotatic frame was first used at the same time, allowing fractionated stereotactic radiotherapy. In the first decade of clinical practice using this technology, some 200 patients with blood vessel tumours/malformations have been treated, together with another 200 suffering from other conditions. The usefulness of this technique for cerebral arteriovenous malformations (AVM) has been demonstrated, and also a significant cure rate for AVM of >3 cm diameter (which is larger than for those previously reported after treatment on the gamma unit), albeit attended by a higher complication rate. The epilepsy associated with AVM is much improved by successful radiotherapy. The usefulness of radiosurgery for glomus tumours has been confirmed and new data published on the efficacy of the technique for haemangioblastoma, with new radiation therapy strategies designed for patients with von Hippel-Lindau disease. The acoustic neuroma treatment results have included improvements in hearing (a result not reported in the gamma unit literature), which are ascribed to the lower internal dose gradient within the target volume. Fractionation will, it is argued, also lead to sparing of the special sensory cochlear nerve. The risks of radiosurgery to the brainstem for chordoma of the mid-clivus are reduced by using a 'spacer' technique for the prepontine space. For meningiomas involving the cavernous sinus, conventionally fractionated radiotherapy is recommended when the meningeal base diameter exceeds 3.0 cm and radiosurgery (utilizing fractionation where appropriate) is advised for smaller lesions. Thus far, radiosurgery indications for pituitary adenomas have been restricted to recurrences after conventional radiotherapy, usually those in the cavernous sinus. In therapy for recurrent craniopharyngioma, it is argued that fractionation delivered via the relocatable frame will be important, particularly when the disease envelops the optic chiasma. For semicystic/semisolid craniopharyngiomas, the stereotactic delivery of colloidal yttrium-90 into a cystic element is useful, while stereotactic radiosurgery is delivered to the solid component. Staff at this centre consider that radiosurgery for low-grade gliomas, perhaps as boost therapy after conventional fractionation, is worthy of more research. We have been extremely selective in the use of radiosurgery for brain metastases (2% of patients, compared with about 30% in some Gamma Knife units), but future indications may become broader, probably using it as a booster technique after whole-brain conventionally-fractionated radiotherapy. Positron emission tomography scanning, co-registered with magnetic resonance imaging, allows the 'boost' concept in radiosurgery to become a sophisticated and accurate reality. Post-radiosurgical sequelae have been placed within a standard framework classification. New observations are being made with regard to subacute reactions: late-responding intrinsic and extra-axial tumours may swell in the subacute period, prior to shrinkage, and be attended by symptomatic surrounding brain oedema.
Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics
This paper is dedicated to the memory of and achievements of Brian Fox
Summary Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m-2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was 2.6 (range 0.2-16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3-160). In contrast, in 13 subsequent phase I trials with 11 of the initials 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6-56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary.
High-dose chemotherapy: Is it standard management for any common solid tumor?
High-dose chemotherapy with stem-cell support had as its basis the observation of dose-response relationships for many chemotherapeutic agents in laboratory models. The rationale to explore high-dose treatment in the clinic was further enhanced by several retrospective reviews in the 1980s which suggested delivered dose intensity of treatment was an important determinant of patient outcome. The availability of hematopoietic growth factors and technologic advances in the efficiency of stem-cell collection and administration have made the evaluation of exploring high-dose therapy safe and feasible. However, real question remain regarding the apparently superior results of this treatment in the management of solid tumors. This paper reviews the results of high-dose chemotherapy in breast, ovarian and small cell lung cancers. Firstly the evidence for a dose-response relationship to chemotherapeutic agents in the 'standard' dosage range is examined. Secondly results of non-randomized and, where available, randomized trials of high-dose chemotherapy (HDCT) with stem-cell support are summarized and finally conclusions regarding the weight of the evidence for use of HDCT as 'standard' treatment are given. In home of these tumors is there sufficient evidence from randomized trials to consider HDCT a standard to be offered to all patients with a given stage of disease. The apparent benefit of HDCT seen in phase II trials could well be explained by such phenomena as stage shifts and patient selection. Many randomized trials in ovary and breast cancer are either ongoing or presented only as abstracts so final results must be awaited to quantify the benefit, if any of HDCT. It is acknowledged, however, that some practitioners already utilize this treatment. We speculate about the differences in philosophical approaches to cancer treatment which might contribute to early acceptance of novel therapies in the absence of adequate randomized data.
A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex®) with intramuscular formestane in postmenopausal women with advanced breast cancer
Background: This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex®), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability.
Patients and methods: Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted 'blind' of the randomized drug treatment.
Results: Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus 67%, respectively, P=0.0043; oestrone sulphate: 92% versus 67%, respectively, P=0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events.
Conclusions: Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.
Paclitaxel, gemcitabine, and cisplatin in non-resectable non-small-cell lung cancer
Background: Paclitaxel, gemcitabine, and cisplatin are each active in non-small-cell lung cancer (NSCLC), and with different modes of action. Hence, a phase II study combining these drugs were conducted.
Patients and methods: Treatment was paclitaxel 110 mg/m2 and cisplatin 60 mg/m² day 1 and 15, with gemcitabine 800 mg/m² day 1, 8, and 15, every four weeks. Patients had previously untreated NSCLC, measurable disease, age 18-70 years, performance status £ 2, and no brain metastases.
Results: Among 49 patients, 6 (group 1) received chemotherapy as described above, while 43 patients (group 2) did not receive gemcitabine day 8. In group 1, all experienced grade 4 neutropenia and four achieved a partial response (67%). In group 2, neutropenia grade 4 occured in 58%, with one episode of febrile neutropenia and no toxic death. No other grade 4 toxicities occured, while grade 3 toxicity occured with respect to thrombocytopenia (9%), nausea/vomiting (12%), neurotoxicity (12%), and nephrotoxicity (7%). There were 3 complete and 20 partial responses (response rate 54%, 95% confidence limits 38%-69%), median response duration 29 weeks (range 10-66+), median time to progression 28 weeks (range 4-66+), median survival 46 weeks (4-89+) and one-year survival rate 42%.
Conclusion: This regimen of paclitaxel, gemcitabine, and cisplatin has neutropenia as dose limiting toxicity, but septicemic episodes were rare and toxic death did not occur. The regimen appears safe and with a noteworthy activity both in terms of response rate, time to progression, and survival.
Allogeneic bone marrow transplantation in aggressive non-Hodgkin's lymphoma (excluding Burkitt and lymphoblastic lymphoma): a series of 73 patients from the SFGM database
The place of allogeneic bone marrow transplantation (BMT) in the treatment of aggressive non-Hodgkin's lymphoma (NHL) remains controversial. We conducted a retrospective study of French experience in allografting NHL between 1984 and 1994. To improve the homogeneity of the study population, cases of low-grade, Burkitt and lymphoblastic NHL were excluded. 73 patients were included in the analysis. Median age at transplantation was 35 years (range 9-61 years); 64 patients were in stage IV and 45 had bone marrow involvement at diagnosis. At the time of transplantation, 46 patients had sensitive disease (25 in complete remission: CR).
The overall survival (OS) and progression-free survival (PFS) rates were 41% and 40% respectively at 5 years (median follow-up of survivors 90 months). The probability of disease progression was 30% at 5 years, and only one relapse occurred after 15 months. 32 patients died of transplantation-related complications. In multivariate analysis, pretransplant complete remission was the main factor associated with longer survival (OS at 60 months of 76% among the 25 patients in CR at transplant and of 23% among the 48 patients not in CR at transplant). Neither acute nor chronic graft-versus-host disease (GvHD) influenced the relapse rate.
In conclusion, in this high-risk population the overall results of allogeneic BMT were encouraging, despite a high transplant-related mortality rate. We believe this procedure should be studied further in prospective controlled trials.
Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer
Of the 1421 patients, 725 received TOR and 696 TAM. Response rates were 24.0% and 25.3%, respectively (p = 0.675) with 95% confidence interval (95% CI) for the difference -5.3 to 3.4. Of the 1157 patients in the pivotal studies, 75% had progressed and 50% expired. Median treatment times were 4.9 months in TOR and 5.3 months in TAM groups (p = 0.762, hazard ratio 0.98 with 95% CI 0.87-1.11). Median survival times were 31.0 (TOR) and 33.1 (TAM) months (p = 0.758, hazard ratio 0.98 with 95% CI 0.83-1.15). All results are consistent with the criteria of statistical equivalence between TOR and TAM. More patients in TAM (20%) than in TOR (14%, p = 0.007) discontinued the treatment prematurely but overall the treatments were well tolerated. As the treatments were equally effective all data were analyzed together for predictive factors. High tumor ER concentration, long disease free time, soft tissue metastases, few metastatic sites, and good performance status all independently predicted longer survival (p < 0.001). Previous adjuvant tamoxifen predicted shorter survival (p = 0.008). Objective response to treatment or disease stabilization for at least 12 months both predicted prolonged survival (p = 0.001).
TOR 60 mg/day and TAM are equally effective and well tolerated in the treatment of advanced breast cancer in postmenopausal women. Probability of survival may be predicted based on patient characteristics and on the initial response to the treatment.
Ceftriaxone plus Once Daily Aminoglycoside with Filgrastim for Treatment of Febrile Neutropenia: Early Hospital Discharge vs. Standard In-Patient Care
Background: In febrile neutropenic patients, ceftriaxone plus an aminoglycoside is effective for the treatment of infection, while filgrastim reduces the extent and duration of neutropenia. Because the once daily dosing regimen of this combination permits ambulatory treatment, there is a need to test criteria for early hospital discharge. Methods: Hospitalized adult patients with febrile neutropenia (following chemotherapy) considered to be potentially treatable on a follow-up out-patient basis were entered into this open-label, multinational study. Patients received a once daily combination of ceftriaxone for ³ 5 days, aminoglycoside for ³ 2 days, and filgrastim until the absolute neutrophil count was ³ 1.0 x 109/l for 2 days. Those initially responding to therapy (reduction of fever by ³ 1ºC within 72h, and clinical improvement) were randomized into standard in-patients or follow-up out-patient treatment groups, the latter patients being discharged from hospital early, after meeting defined criteria. Results: 105 patients were enrolled, of whom 21 initial non-responders were not randomized. Efficacy was evaluable in 80 patients. Success (resolution of fever and symptoms, maintained for 7 days after cessation of therapy, and eradication of infecting pathogens) was similar among in-patients (40/42, 95%) and out-patients (34/38, 89%). The duration of hospitalization was shorter for out-patients than in-patients (median of 4 vs. 6 days, respectively). No hospital readmissions were necessary in out-patients. All other efficacy parameters assessed were comparable in both groups, as was tolerability/safety. One potentially drug-related death was reported. Conclusions: Patients who satisfy prospectively defined criteria for early discharge can be treated safely on an out-patient basis with a regimen of once daily ceftriaxone plus an aminoglycoside with filgrastim. In addition to reducing healthcare costs, it may improve patients' quality of life.
Preliminary results of the alternating administration of natural interferon-a and recombinant interferon-g for metastatic renal cell carcinoma
Objective To evaluate the efficacy and toxicity of the alternating administration of natural (n) interferon (IFN)-a and recombinant (r) IFN-g for metastatic RCC.
Patients and methods The study comprised 24 patients (median age 60 years, range 42-77), 20 of whom were evaluable for response and all 24 evaluable for toxicity. Initially, nIFN-a was administered subcutaneously on days 1 and 3, and rIFN-g on day 2, for 1-2 weeks in the evening or at night, both at doses of 3 UM. If this regimen was tolerated, nIFN-a and nIFN-g were administered at the same doses on days 1, 3 and 5 and on days 2 and 4, respectively.
Results There were three complete remissions and two partial remissions, giving a total response rate of 25%. All responders (complete plus partial remission) had undergone nephrectomy. Multiple lung metastases completely disappeared from four responders. The median and maximum time to remission in the responders were 2 and 7 months, respectively. The survival time of the responders was significantly longer than that of those not responding (stable and progressive disease, P = 0.0202). Toxicities were mostly limited to WHO grades 1 and 2, with grade 3 leucopenia and grade 4 hepatic dysfunction in only one patient each. These toxicities were transient and there were no treatment-related deaths.
Conclusion The alternating administration of nIFN-a and nIFN-g is an effective treatment for metastatic RCC. This treatment is particularly suitable for patients who have undergone nephrectomy and have lung metastases.
Cisplatin, Radiation, and Adjuvant Hysterectiomy Compared with Radiation and Adjuvant Hysterectomy for Bulky Stage ib Cervical Carcinoma
Background Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer.
Methods Women with bulky stage IB cervical cancers (tumor, ³ 4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later.
Results The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0,51 (95 percent confidence interval, 0.34 to 0,75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P = 0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent).
Conclusions Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.
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Revista Brasileira de Cancerologia - Volume 45 n°4 Out/Nov/Dez 1999