 Vol.45 n° 2 |
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Subsequent Quality of Life for Children Irradiated for a Brain Tumor Before Age Four Years
Background: We wanted to evaluate survival and functional morbidity following radiation treatment of brain tumors in children less than 4 years old.
Procedures: Outcome was evaluated for 222 children who were less than 4 years old when they were irradiated at University of Toronto Centres, 1958-1995. The status of the survivors with regard to focal neurological defects, vision, hearing, and education at last follow-up was recorded. In 23 adult survivors older than 21 years at last follow-up, information was obtained with regard to higher education, occupation, and living arrangements.
Results: The overall 10-year survival rate was 40%, not significantly different than the 45% for 776 4-16-years-olds with irradiated brain tumor treated at the same institutions. Forty-five percent of the survivors had no major focal neurological, visual, or hearing defects. There were no major differences in the frequencies of these criteria or of schooling between 0-2 and 2-4 year-olds. Among adult survivors, olden than 21 at last follow-up, 26% successfully completed higher education, 31% were in full-time employment, and 37% had never been employed. For medulloblastoma the 5-year survivor rate was 61% for 30 children less than 3 years old and treated from 1975-1995. This compared favorably with recent reports of survival following primary chemotherapy with delayed or omitted radiation treatment.
Summary: Radiation treatment of child with a brain tumor was associated with cure in 1 of every 3 patients. Unfortunately, quality of life for many survivors was not good. Only 1 of every 3 adult survivors was able to have a normal life-style. This shortfall was the result of focal neurological defects, which were present from the time of first treatment, and of the long-term effects of radiation treatment.
Conclusions: The search for less toxic treatment remains appropriate, but is experimental and researchers must recognize that there may be a trade-off between morbidity and mortality.
Treatment of folicular lymphoma
Follicular lymphoma is one of the most common neoplastic lymphoprofilerative diseases encountered in the western world. Intensive scientific scrutiny has led to detailed understanding of the nature of the malignant cell and the specific genetic abnormalities, which are frequently encountered and likely to be etiologic. Clinical research focusing on the treatment of follicular lymphoma continues to reveal new insights into the natural history of the disease. Investigations reported during the past year have focused on a number of important issues with regard to the management of patients with the diseases.
Chemotherapy for ovarian cancer - a consensus statement on standard practice
Background: The management of patients with ovarian cancer is a complex and evolving field. Optimal results from therapy are obtained when patients with ovarian cancer are treated by specialist multidisciplinary teams (Junor et al. 1994).
The earliest stages of ovarian cancer can be treated by surgery alone with excellent results.
The majority of women with ovarian cancer have advanced disease at presentation and require chemotherapy as well as surgery to improve their quality of life and increase survival.
Addition of etoposide to CHOP chemotherapy in untreated patients with high-grade non-Hodgkin's lymphoma
Background: Second-and-third-generation chemotherapy protocols for the treatment of the aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In phase II study we investigated the feasibility and efficacy of the addition of the etoposide to the conventional CHOP regimen.
Patients and methods: Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17-85). Patients received standard-dose CHOP plus etoposide 100 mg/m² i.v. on day and 200 mg/m² p.o. on days 2-3.
Results: The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted tree- and- five year survivals for the group as a whole were 60% and 53%, respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that CHOP-treated patients in a recently completed Nordic study performed during the same time period. Myelosupression (WHO grade 3-4), observed in 87% of patients and infectious complications (WHO grade 3-4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (62%) received 6-8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III and IV at diagnosis were all indicators of a poor survival.
Conclusions: We conclude that CHOP-E treatment is effect in high-grade NHL. However, mainly due to severe myelosupression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.
Key-words: chemotherapy, CHOP, etoposide, high-grade non-Hodgkin's lymphoma, risk factors.
Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission
Background: In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the long-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneic marrow transplantation during the first remission of acute myeloid leukemia.
Methods: Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemia received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplantation. The end points were survival from the time of complete remission and disease-free survival.
Results: In an intention-to-treat analysis, we found no significant differences in disease-free survival among patients receiving high-dose chemotherapy, those undergoing allogeneic marrow transplantation, and those undergoing allogeneic marrow transplantation. The median follow-up was four years. Survival after complete remission was somewhat better after chemotherapy than after autologous marrow transplantation (P=0.05). There was a marginal advantage in terms of overall survival with chemotherapy as compared with allogeneic marrow transplantation (P=0.04).
Conclusions: A postinduction course of high-dose cytarabine can provide equivalent disease-free survival and somewhat better overall survival than autologous marrow transplantation in adults with acute myeloid leukemia.
A reduction in requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer.
Background: A prospective randomized trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer.
Patients and methods: Three hundred nine women (median age 56 years, range 27-70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitoxantrone and methotrexate (+- mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjunt group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements.
Results: The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15 % no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P<0.003). At a median follow-up of 48 months (range 10-70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy.
Conclusion: This randomized trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment whit neoadjuvant chemoendocrine therapy, whit no deterioration in local or distal relapse.
Key words: breast cancer, chemotherapy, mastectomy, neoadjuvant, tamoxifen
ICON2: randomized trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer
Background: A series of meta-analyses of randomized controlled trials raised the question of whether the three-dug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer.
Methods: We carried out an international, multicentre, randomized trial to compare CAP with single-agent carboplatin in women with ovarian cancer requiring chemotherapy. 1526 patients were entered from 132 centres in nine countries. Analyses were by intention to treat.
Findings: 728 patients have died (368/766 allocated CAP vs 360/760 allocated carboplatin) and the survival curves show no evidence of a difference between CAP and carboplatin (hazard ratio 1.00 [95% CI 0.86-1.16]; p=0.98) The results indicate a median survival of 33 months and a 2-year survival of 60% for both groups. We found no evidence that CAP or carboplatin were more or less effective in different subgroups defined by age, stage, residual disease, differentiation, histology, and coordinating centre. CAP was substantially more toxic than carboplatin, causing more alopecia, leucopenia, and nausea. More thrombocytopenia occurred with carboplatin.
Interpretation: Single-agent carboplatin, with the dose calculated by the area-under-the-curve method, is a safe, effective, and appropriate standard of treatment for women with advanced ovarian cancer.
Tamoxifen in the Treatment of Breast Cancer
Breast cancer is the most common cancer in women in the Western world. Because breast cancer is estrogen-dependent, reducing estrogen secretion by oophorectomy, hypophysectomy, or adrenalectomy can cause the cancer to regress. The need for these surgical procedures was reduced by the introduction of Tamoxifen, which acts as an antiestrogen by inhibiting the binding of estrogen to estrogen receptors. Tamoxifen was approved by the Food and drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.
Preliminary Report of the Asian-Oceanian Clinical Oncology Association Randomized Trial Comparing Cisplatin and Epirubicin followed by Radiotherapy versus Radiotherapy Alone in the Treatment of Patients with Locoregionally Advanced Nasopharyngeal Carcinoma
Background: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size Ê 3 cm.
Methods: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m² on Day 1) and epirubicin (110 mg/m² on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (mediam, 71 GY) was delivered to the primary tumor and 60-76 GY (mediam, 66 Gy) to the neck. Two hundred eight-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The mediam follow-up was 30 months for the whole cohort and 41 months for the surviving patients.
Results: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-years RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes > 6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm.
Conclusions: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefor routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.
Key Words: nasopharyngeal carcinoma, neoadjuvant chemotherapy, radiotherapy, relapse free survival, overall survival, recurrence, distant metastasis, cisplatin, epirubucin.
Surgery for gynecologic malignancies
Surgery continues to play a primary role in the investigation and treatment of gynecologic neoplasia. Cold-knife conization is still preferable for diagnosis and treatment of more problematic preinvasive cervical lesions. Newer reconstructive techniques can improve quality of life in exenteration patients.
Efforts continue to reduce morbidity associated with vulvar surgery and groin node dissection. Accurate staging and maximum cytoreduction remain essential goals in primary surgery for ovarian cancers. The utility of secondary surgery for disease assessment or further treatment in controversial. Laparoscopy at presents has a limited role in gynecologic oncology but may be useful for prophylatic oophorectomy in selected individuals.
Gliomas
Introduction:
Central nervous system (CNS) tumors are the most common solid neoplasm of childhood and account for 20% of all malignancies in this age group. Gliomas constitute 40-60% of all childhood primary brain tumors [1]. Low-grade astrocytomas are the most common neoplasms of childhood glial tumors [2]. Astrocytomas are seen more frequently in the supratentorial compartment, although the cerebellar hemispheres are also a common site for astrocytoma [3]. High-grade gliomas also predominantly are in the supratentorial compartment, although brainstem gliomas are common malignancies arising in the infratentorial compartment. In this review we will discuss all histological types of pediatric gliomas including the different anatomical locations, treatment options and prognoses.
Screening for Prostate Cancer - More Questions than Answers
Whether prostate cancer screening should be applied to the male population or not, remains an extensively debated issue (1, 2). Reference can be made to the favorable results of breast cancer screening and the surprisingly unfavorable results of lung-cancer screening (3). Since 1993 the American Urological Association (AUA) and the American Cancer Society (ACS) have recommended annual prostate-specific antigen (PSA) testing and rectal examinations beginning at age 40 in men belonging to identifiable risk groups (4, 5). In most European countries, particularly in Northern Europe, routine application of screening procedures for prostate cancer is not accepted for a number of reasons: There is limited knowledge about the natural history of prostate cancer diagnosed at screening and the increasing gap between lifetime incidence and mortality suggests that there is a substantial risk of over-diagnosis and subsequent over-treatment. There is no reliable information on the effectiveness of treatment from randomized trials. The benefit of prostate cancer screening, in terms of reducing prostate-cancer-specific mortality, has not yet been shown. Adami and co-workers question whether even a randomized trial of screening for prostate cancer meets the ethical requirements (6). In this article the issues that fuel the prostate cancer screening debate are reviewed.
Is Chemotherapy Beneficial in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma?
Nasopharyngeal carcinoma holds an important place in the debate regarding whether adjuvant chemotherapy is beneficial in the treatment of head and neck cancers. This is because 1) nasopharyngeal carcinoma is a very chemoresponsive tumor, and there are reports of long-standing complete responses for patients with distant metastasis who are given adequate chemoterapies;1-3 2) of all the squamous cell carcinomas of the head and neck, nasopharyngeal carcinoma has the highest incidence (30-40%) of distant metastasis;4 and 3) numerous retrospective or single-arm studies have reported excellent and promising results with the addition of chemotherapy in the treatment of nasopharyngeal carcinoma.5 Because the theoretic basis of neoadjuvant chemotherapy is to enhance locoregional control by tumor debulking or sensitizing the tumor to radiation and to decrease distant metastasis by treating occult micrometastasis, nasopharyngeal carcinoma appears to be the perfect head and neck malignancy for chemotherapy to display its potential, given the considerations just listed.
Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission
We conducted a randomized clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was to evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to receive either PCI (100 patients) or no PCI (111 patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24-30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P=0,25) between the two groups. The 4-year overall survival rate (95% confidence interval) is 22% [15-32%] in the PCI group versus 16% [10-25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI=[0.62-1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P=0.14). The 4-year cumulative rate of brain metastasis is 44% [32-57%] in the PCI group compared to 51% [38-63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brain metastases nor in survival.
Key Words: Prophylactic cranial irradiation; Small-cell lung cancer; Controlled trial
Conformal Radioterapy: A Clinical Review
The term conformal radiotherapy was coined by Shinji Takahashi. Between 1948 and 1963 he published a series of papers on the use of rotation radiography and in 1959 began to apply these principles to radiotherapy: rotation techniques as applied to radiography and radiotherapy of cancer' [1], described the use of moving geared diaphragms and tables to irradiate irregular volumes. He described tree basic techniques, 'rotational body technique', 'column focus' and 'hollow-out technique', which could be used alone or in combination. By applying these techniques to a number of sites including the uterus, rectum, oesophagus, lung, head and neck, and pituitary he was able to demonstrate improvements in local control and reduced in toxicity. However, the evolution of a practical means of delivering conformal radiotherapy had to wait the development of microprocessor technology in the late 1980's [2] and hardware developments such as the multileaf collimator [3,4]. Further developments such as the tree-dimensional (3-D) computed tomographic simulator [5], intensity modulated arcs [6] and tomotherapy [7] offer promise for the future.
Techniques for delivering conformal radiotherapy have been described previously. Other reviews have focused on the possible benefits [8,9]. This review seeks to consider the clinical rationale for conformal radiotherapy and evidence of benefit that has been observed so far. Stereotatic radiotherapy (radiosurgery) is not considered in this article. Where multiple papers have been published from a single institution, reference is given to the most recent only.
Possible mechanisms by which alcohol may influence the development of oral cancer - a review
Although pure ethanol has never been shown to be carcinogenic in laboratory experiments, alcoholic beverages are now recognized as being important aetiological factors in the development of oral cancer. Despite this, the exact mechanism by which alcohol may exert an influence upon the oral mucosa has received less attention. An overview of the association of alcohol and oral cancer, both in combination with tobacco and without, is provided and consideration given to some of the pathways by which alcohol exerts its effect upon the oral mucosa.
Key Words:
Alcohol; Tobacco; Oral cancer, Oral mucosa
Colorectal cancer screening
Comprehensive evidence-based guidelines for screening and surveillance for colorectal cancer were published in 1997. Backed by compelling scientific data from recently completed controlled trials and case-control studies, these guidelines recommend annual fecal occult blood test screening plus periodic flexible sigmoidoscopy about every 5 years for asymptomatic, average-risk individuals over 50 years of age. Other screening studies published during the past year refine knowledge about how these screening tests detect early cancer and polyps and asses factors that influence compliance with screening recommendations. Preliminary reports suggest revolutionary new methods of screening that may become clinically feasible in the next millennium.
Issues in the treatment of Hodgkin's disease
The treatment of Hodgkin's disease is changing strikingly. In early stages of disease, extended field irradiation to date has been the standard treatment resulting in excellent cure rates. Due however to the recognition of the fatal long-term effects, especially the high rates of second solid tumors, extended field radiation therapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In intermediate stage Hodgkin's disease , where combined modality treatment already is the treatment of choice, extended field irradiation is substituted by involved field irradiation for the same reasons. In advanced stage Hodgkin's disease, eight cycles of standard polychemotherapy (plus additional radiotherapy for large tumor masses and residual lymphomas after chemotherapy) for decades has cured only about 50% of the patients.
While until recently all modifications of the standard chemotherapy regimens could not change the poor outcome of advanced-stage patients, the development of new dose-intensified regimens now for the first time has significantly improved their prognosis. In patients with relapse of Hodgkin's disease after polychemotherapy, long-term survival after salvage chemotherapy is low. Numerous phase II studies suggest an improvement of their poor prognosis by high-dose chemotherapy followed by autologous bone marrow transplantation or peripheral-blood stem cell transplantation. There are still no results of prospective, randomized trials which convincingly demonstrate the benefit of this therapeutic approach, however.
Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials
The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin - or carboplatin - based therapy. Meta-analyses were based on update individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.
Keywords: meta-analysis; systematic review; randomized controlled trials; advanced ovarian cancer; chemotherapy
Health care professionals and patients alike are becoming increasingly aware of the need to make medical decisions on the basis of up-to-date, objective and unbiased research (Chalmers and Haynes, 1994). The most reliable information results from randomized controlled trial (RCTs). Unfortunately, most RCTs, including those conducted in ovarian cancer, have been too small to demonstrate moderate treatment benefits with reliability, and many results have been inconclusive or contradictory. The Advanced Ovarian Cancer Trialists Group (AOCTG) recognized that the best means of synthesizing such randomized evidence is by systematic meta-analysis. In 1988, five meta analysis of chemotherapy in advanced ovarian cancer using update individual patient data were initiated. The first results were published in 1991 (AOCTG, 1991). The AOCTG recognized the importance of updating these results especially for the comparison of carboplatin and cisplatin, in which the data were relatively immature. The comparison of platinum analogues was considered of such clinical importance that further new investigations were initiated to identify whether any particular type of women tumour would benefit more from either cisplatin or carboplatin-based chemotherapy.
Is There a Standard Adjuvant Treatment for Rectal Cancer?
Background: One of the major controversies in oncology today, among oncologists as well as surgeons, is adjuvant treatment for rectal cancer. The current practice differs from Europe to the U.S.A., between institutions within the same country. The question of whether or not to give adjuvant treatment and what regimen should be used is extremely important, as rectal cancer is one of the most frequent cancer types [1]. Thus, an improvement of 5-year survival from, for example, 50 to 60%, corresponds to approximately 100 lives saved in a small country like Norway and approximately 5,000 lives saved in the U.S.A. In addition, successful treatment may reduce suffering from painful recurrences and the need for resource demanding palliative treatment. Establishing an optimal treatment for rectal cancer should, therefore, be a high priority in modern medicine.
I will focus an adjuvant treatment for resectable rectal cancer (Dukes' A, B and C) and will only briefly consider primarily unresectable locally advanced cases. The discussion of standard surgery has been defined. Surgeons have resected rectal cancer for cure for decades, and with large variations in results, in terms of local recurrence rate, survival and complications [2-3]. The surgical techniques employed differ, and its well known that the experience of individual surgeons has a major impact on treatment results [2-5]. Recently, surgeons in many countries made an effort to standardize surgery. This change in surgical approach will also have a major impact on the question of a standard adjuvant treatment. So, what is standard adjuvant treatment today and what will be standard tomorrow?
What is standard? The introduction of a standard adjuvant treatment for rectal cancer (as with other standard treatment) should, in general, be based on available documentation from at least two or three high quality independent randomized trials (or a meta-analysis). Moreover, the benefit of the treatment should be clinically significant in terms of survival, recurrence rate or quality of life, the side-effects should be tolerable and the costs acceptable. On this background, I will discuss adjuvant treatment for rectal cancer.
Cladribine in the Treatment of Advanced Relapsed or Refractory Low and Intermediate Grade Non-Hodgkin's Lymphoma
Background: Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies.
Methods: The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks.
Results: Twenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient intermediate grade diffuse large cell lymphoma , and three of six patients who had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea.
Conclusions: Cladribine is an active single agent in the treatment of patients with refractory of relapsed advanced stage indolent lymphoma, with major responses in one third of patients.
Selective use of PET scan in the preoperative staging of NSCLC
Positron emission tomography (PET) is a imaging technique which identifies abnormalities by utilising their metabolic properties rather than their anatomical density. In this study, we evaluated the place of PET scanning for the characterisation of additional abnormalities discovered on routine, preoperative CT evaluation of patients with proven NSCLC. A total of 21 patients underwent PET scanning using fluorodeoxyglucose (FDG). In these patients routine CT scans had found 26 concomitant lesions which were in lung, adrenal gland, liver, kidney, spleen and pleura. FDG uptake was positive at the primary site in all patients. FDG uptake in 13 of the concomitant lesions suggested malignancy. Malignancy was confirmed at all of these foci by histology in eight (six at thoracotomy, fine needle aspiration biopsy (FNAB) and open biopsy) and by clinical and radiological follow-up for 1-15 months in five. In 13 lesions, PET suggested benign disease. Histology reported no evidence of malignancy in five and the six foci followed on clinical and radiographic follow-up for 2-16 months had no evidence of malignancy. PET was falsely negative in only one site where malignancy was proven by thoracotomy. PET failed to detect the remaining lesion which was an unassociated primary kidney tumour in a patient with Li-Fraumeni syndrome. The accuracy of PET scanning in the assessment of those additional lesions found on CT evaluation of otherwise operable NSCLC was found to be 96% with a sensitivity of 93% and specificity of 100%. These results indicate that PET is useful to characterize additional lesions found on CT scan of patients with NSCLC.
Key Words: PET scan; Staging of lung cancer
Doxorubicin Cardiotoxicity in Children: Comparison of a Consecutive Divided Daily Dose Administration Schedule With Single Dose (Rapid) Infusion Administration
Background: Doxorubicin cardiotoxicity remains a serious problem in children with malignancy. The present study was undertaken to determine if the administration of consecutive divided daily doses of doxorubicin would significantly reduce the likelihood of cardiotoxicity in children compared with a single dose administration regimen.
Procedure: One hundred thirteen children (60 boys and 53 girls) received doxorubicin either by single dose infusion or by a consecutive divided daily dose schedule. The divided dose patients received one third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single dose schedule received the cycle dose as a 20-minute infusion. The mean doxorubicin dose was 341 mg/m². Patients were followed up for 4-180 months. There were 60 boys and 53 girls in the series.
Results: Fifteen patients developed cardiacdysfunction, eight of whom died of progressive cardiac failure. There was no significant difference in the incidence of cardiac dysfunction between the divided and single dose infusion groups. More girl than boys developed cardiac dysfunction and more girls died of progressive cardiac failure; this difference was not statistically significant. The median time to development of cardiac failure was 2 months.
Conclusions: The divided dose regiment did not alter the incidence of cardiotoxicity. Other schedules should therefore be investigated. Our data suggest that, at similar cumulative doses, girls are more likely to develop cardiac dysfunction than are boys. If the sex-related difference.
Impact of Hospital Volume on Operative Mortality for Major Cancer Surgery
Context: Hospitals that treat relatively high volume of patients for selected surgical oncology procedures report lower surgical in-hospital mortality rites than hospitals with a low volume of the procedures, but the reports do not take into account length of stay or adjust for case mix.
Objective: To determine whether hospital volume was inversely associated with 30-day operative mortality, after adjusting for case mix.
Design and Setting: Retrospective cohort study using the Surveillance, Epidemiology, and End results (SEER)-Medicare linked database in which the hypothesis was prospectively specified. Surgeons determined in advance the surgical oncology procedures for which the experience of treating a larger volume of patients was most likely to lead to the knowledge or technical expertise that might offset surgical fatalities.
Patients: All 5013 patients in the SEER registry aged 65 years or older at cancer diagnosis who underwent pancreatectomy, esophagectomy, pneumonectomy, liver resection, or pelvic exenteration, using incident cancers of the pancreas, esophagus, lung, colon, and rectum, and various genitourinary cancers diagnosed between 1984 and 1993.
Main Outcome Measure: Thirty-day mortality in relation to procedure volume, adjusted for comorbidity, patient age, and cancer stage.
Results: Higher volume has linked with lower mortality for pancreatectomy (P=.004), esophagectomy (P<.0001), liver resection (P=.04), and pelvic exenteration (P=.04), but not for pneumonectomy (p=.32). The most striking results were for esophagectomy, for which the operative mortality rose to 17,3% in low-volume hospitals, compared with 3.4% in high-volumes hospitals, and for pancreatectomy, for which the corresponding rates were 12.9% vs 5.8%. Adjustments for case mix and other patient factors did not change the finding that low volume was strongly associated with excess mortality.
Conclusions.- These data support the hypothesis that when complex surgical oncologic procedures are provided by surgical teams in hospitals with specialty expertise, mortality rates are lower.
The remission status before and the PCR status after high-dose therapy with peripheral blood stem cell support are prognostic factors for relapse-free survival in patients with follicular non-Hodgkin's lymphoma
It was the aim of our study to examine the clinical significance of t(14;18)-positive cells in samples from 47 patients with follicular non-Hodgkin's lymphoma (NHL) who underwent high-dose therapy with autologous peripheral blood stem cell (PBSC) transplantation. At the time of PBSC mobilization, 25 patients were in first remission, while 22 patients had a history of previous treatment failure. At the same time, 43 patients had polymerase chain reaction (PCR)-positive cells in samples from bone marrow (BM) and/or peripheral blood (PB). Independent of the remission status, high-dose cytarabine and mitoxantrone with granulocyte colony-stimulating factor (G-CSF) support were administered for PBSC mobilization. Following high-dose conditioning therapy which consisted of cyclophosphamide (200 mg/kg) and hyperfractionated total body irradiation (TBI, 14.4 Gy) or BEAM (carmustine, etoposide, cytarabine, melphalan), 34 patients received PCR-positive and 13 patients received PCR-negative autografts. After a median follow-up time of 20 months (range; 6-50) post-transplantation, 33 patients were a remission, while 14 patients had relapsed after a median time of 14.5 months (range, 10-42). Using the Andersen-Gill proportional hazards regression model for the analysis of relapse-free survival, we found that PCR-positive findings in samples form BM and/or PB at any given time-point after transplantation were associated with an increased estimated hazard ratio of 4.5 in comparison with a PCR-negative finding (P=0.013). On the other hand, patients included while they were in first remission had a smaller estimated hazard ratio of 0.3 when compared with patients with a history of previous treatment failure (P=0.048). For the latter group of patients, this translates into a significantly smaller probability of relapse-free survival in comparison to patients who were in first remission at the time of PBSC-mobilization (P=0.012).
In conclusion, the remission status of the patients before autografting and the PCR status as assessed on the occasion of follow-up examinations are significant prognostic parameters for relapse-free survival in patients with follicular lymphoma undergoing high-dose therapy with PBSC autografting.
Keywords: blood stem cell transplantation; minimal disease; non-Hodgkin's lymphoma (NHL); polymerase chain reaction (PCR); t(14;18) translocation
Emerging treatments for epidemic (AIDS-related) Kaposi's sarcoma
Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection.
KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden.
These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.
Surgical management of the neck in squamous cell carcinoma of the floor of the mouth
Nodal involvement in squamous cell carcinoma considerably lowers survival rates. Despite its importance, neck management has still not been adequately explored. The Authors have retrospectively reviewed the records of 112 cases. Unilateral N+ were treated with a homolateral therapeutic and a controlateral prophylatic neck dissection; bilateral N+ were treated with bilateral therapeutic neck dissection. On first observation the majority of cases (66.1%) were T1-2. N+ patients accounted for 45.5%. Among N- patients, 21,3% of occult nodal metastases were observed. The 5-year survival rate was 52.7%. With N+ lesions, a radical neck dissection should be performed; the dissection should be performed bilaterally. With N- lesions a prophylatic modified radical neck dissection is recommended in T2-4 lesions.
Key Words: Oral cancer; Floor of the mouth; Nodal metastases; Neck dissection.
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Revista Brasileira de Cancerologia - Volume 45 n°2 Abr/Mai/Jun 1999