Improvements in survival from childhood cancer: results of a population based survey over 30 years

Survival from cancer of children whose cancer was diagnosed during the 30 years 1954-83 was analysed. The study was population based with nearly 3000 cases covering about 30 million child years at risk. When survival during the three decades 1954-63, 1964-73, and 1974-83 was compared striking improvements were observed. For all childhood cancer five year survival increased from 21% in the first decade to 49% in the third decade. During the first and third decades five year survival rates for acute lymphocytic leukaemia increased from 2% to 47%, Hodgkin''s disease from 44% to 91%, non-Hodgkin''s lymphoma from 18% to 45%, Wilms''s tumour from 31% to 85%, and germ cell tumours from 10% to 64%. Twenty patients developed second primary tumours, but otherwise there were few late deaths. Less than 1% of children who survived without a relapse for 10 years subsequently died of their initial cancer.Survival from childhood cancer is no longer rare, and people who have been cured of cancer during childhood should be accepted as normal members of society.     

Musculoskeletal deformities following treatment of Wilms' tumour.

Wilms'' tumour is one of the most common neoplasms of infancy and childhood. Current treatment regimens result in a cure rate of about 80% for localized tumours but may also cause musculoskeletal deformities. Assessment of 21 patients previously treated for Wilms'' tumour showed that all had flank atrophy on the treated side. Radiologic abnormalities included asymmetry of vertebral bodies, vertebral end-plate irregularities, scoliosis, kyphosis, platyspondyly and hypoplasia of the ilium. Although the vertebral changes following radiotherapy for Wilms'' tumour are present from an early age and the potential is great for an increase in spinal deformity with growth, few spinal curves progress past 20 degree. Since one cannot predict which curves will progress, all such patients need careful orthopedic follow-up until skeletal maturity is achieved.     

Wilms' tumour: treatment of 113 patients from 1960 to 1971

The crude 5-year survival rate among children with Wilms'' tumour increased from 54% for those diagnosed from 1960 to 1965 to 81% for the period 1966 to 1971. This resulted from an increased ability to cure metastatic disease and, to a lesser extent, to an increased ability to prevent relapse. It is proposed that, after resection and postoperative irradiation, maintained combination chemotherapy with actinomycin D and vincristine should be used electively to prevent relapse, but that this use should also be selective in order that overall morbidity be minimized. Of urgent priority, therefore, is improved delineation of present-day prognostic factors in children with Wilms'' tumour.     

Population based survival rates for childhood cancer in Britain, 1980-91.

OBJECTIVES--To investigate the survival of children with cancer diagnosed during 1980-91 in order to assess the impact of developments in medical care on a population basis. DESIGN--Retrospective cohort study. SETTING--Great Britain. SUBJECTS--14973 children with cancer diagnosed during 1980-91 and included in the population based National Registry of Childhood Tumours. MAIN OUTCOME MEASURES--Actuarial survival rates. RESULTS--For all cancers combined, two year survival increased from 66% to 76% between 1980-2 and 1989-91, and five year survival increased from 57% to 65% between 1980-2 and 1986-8. Significant increases in survival rates occurred among children with acute lymphoblastic leukaemia, acute nonlymphocytic leukaemia, retinoblastoma, osteosarcoma, Ewing''s sarcoma, rhabdomyosarcoma, and malignant gonadal germ cell tumours. No trend in survival was seen for children with Hodgkin''s disease, central nervous system tumours, neuroblastoma, or Wilms''s tumour. CONCLUSIONS--Nearly two thirds of children who have cancer diagnosed can now expect to survive at least 10 years.     

Natural History and Treatment of Wilms's Tumour: An Analysis of 335 Cases Occurring in England and Wales 1962-6

Hospital records and other data relating to Wilms''s tumour were analysed to elucidate both thenatural history of the disease and the effects of treatment, with special reference to actinomycin D. The age of maximum incidence was about 18 months; left-sided tumours were significantly more common than right-sided ones.Prognosis was related to stage of the disease at the initial operation and to the occurrence of metastasis. The three-year survival rate for cases having a nephrectomy was 35%; no child who did not have a nephrectomy survived.Recurrence of the tumour was observed in two-thirds of the cases, almost always within two years of the initial treatment, irrespective of the child''s age. The three-year survival rate for this group was 11%.The effects of radiotherapy and chemotherapy are considered in detail. Very little improvement in survival rate could be ascribed to actinomycin D. The reasons for this and for the variations found in earlier reports on selected cases are possibly the addition of other components of treatment and differences in drug regimens. The findings suggest the need for controlled clinical trials.     

Management of Ontario children with acute lymphoblastic leukemia by the Dana-Farber Cancer Institute protocols.

There is ample evidence of the value of intensive therapeutic strategies in the management of acute lymphoblastic leukemia (ALL), the commonest form of malignant disease in children. Such a program, devised at the Dana-Farber Cancer Institute (DFCI), Boston, and incorporating high-dose L-asparaginase, was adopted in 1984 by the Children''s Hospital at Chedoke-McMaster, Hamilton, Ont., and the Children''s Hospital of Western Ontario, London. We describe the experience of these institutions in the treatment of 82 children with ALL, 19 of whom were switched to the DFCI protocols while in continuing first remission with other treatment programs to complete a minimum of 2 years of maintenance therapy; the remaining 63 children, who had recently diagnosed disease, were consecutively enrolled in the DFCI protocols. Each child was assigned at diagnosis to a category of risk for relapse and treated accordingly. There were no remission induction failures or deaths due to induction therapy among the patients with newly diagnosed disease. There were no differences in total or event-free survival rates between the patients in Hamilton and those in London or between those whose protocols were switched and those who were treated from the beginning with the DFCI protocols. With a median follow-up interval of 144 weeks the total survival rate was 95% and the event-free survival rate 88%. For patients at standard risk of relapse the event-free survival rate was 100%, for those at high risk the rate was 82%, and for those at very high risk the rate was 67%. If infants (all of whom suffered a relapse) are excluded from the last category the rate was 89%. These results were achieved with moderate toxic effects (except for two deaths, one of which was due to a therapeutic misadventure) and suggest that the prospect for cure in children with ALL. may now approximate 80%, a degree of success that demands that consideration be given to reducing total therapy, at least for children with standard-risk disease. Further follow-up will determine whether these high event-free survival rates will stabilize and meet the criteria for cure.     

Effects of childhood cancer on long-term survivors and their families.

Problems experienced by families of long-term survivors of acute lymphatic leukaemia and Wilms''s tumour were investigated to find out the best way of using limited resources to improve management of such patients. All patients had received treatment at Alder Hey Children''s Hospital, and all had completed treatment at least two years before the study. A social worker interviewed the parents of each child. The results showed that various aspects of management needed improvement, including: information given to parents at diagnosis of their child''s illness and during subsequent treatment; continuity of care and multidisciplinary teamwork among those caring for the child; greater understanding by school teachers that such children have the same educational needs as others; wider communication by hospital staff with the child''s other relatives, particularly grandparents; financial help for parents; and marital counselling. To help implement these proposals full-time social workers were attached to the hospital. Preliminary results were encouraging, though it is too early to evaluate the long-term effects of the changes.     

Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner

Activating mutations in the NOTCH1 gene are found in over 50 % of T-ALL cases. Since Notch signaling contributes to the leukemia cell survival and growth, targeting Notch signaling using γ-secretase inhibitors (GSI) has been proposed as a molecularly targeted therapy for the treatment of T-ALL. However, not all T-ALL with NOTCH1 activating mutations respond to GSI treatment. We examined whether GSI could enhance the cytotoxic effect of anti-leukemic agents in the GSI-resistant T-ALL cells although GSI does not have anti-tumor effect as a single agent. GSI significantly increased cell death induced by Vincristine (VCR) but not other anti-leukemic drugs (Methotrexate, Asparaginase, and Cytarabine). The GSI effect in enhancing VCR efficacy was not the result of inhibition of Notch signaling. GSI augmented VCR-induced mitotic arrest, followed by apoptosis. GSI accelerated VCR-triggered loss of mitochondrial membrane potential and caspase-mediated apoptosis. Our finding suggests that GSI has other functions besides inhibiting Notch signaling in T-ALL and incorporating GSI into the conventional regimen containing VCR may offer therapeutic advantage by potentiating VCR treatment in leukemia patients.     

RETROPERITONEAL TUMORS IN CHILDREN—Roentgen Diagnosis

A study was undertaken to determine whether there are any features of retroperitoneal tumors in children that might be demonstrated on roentgenograms to aid in identifying them preoperatively. Study was limited to Wilms'' tumor of the kidney and neuroblastoma.Calcification was found in 57 per cent of the neuroblastomas and in only 12 per cent of Wilms'' tumors. Calcifications in neuroblastomas differed from those in Wilms'' tumors. Calcification in neuroblastoma was more frequent in older children than in the younger ones.The kidney was frequently displaced by both types of tumor. However, the neuroblastoma always displaced the kidney downward, or downward and slightly outward.In most instances, the Wilms'' tumor also displaced the kidney downward and outward, but in some instances upward and medially. This, of course, depended upon the site of origin of the tumor.There was a distortion of the intrarenal structures in 75 per cent of the cases of neuroblastoma and in 71 per cent of the cases of Wilms'' tumor.     

A Statistical Review of Malignant Testicular Tumours Based on the Experience of the Ontario Cancer Foundation Clinics, 1938-1961

For the 827 patients with malignant testicular tumours registered at the Ontario Cancer Foundation''s regional clinics in the period 1938-1961, the probability of surviving for five years after treatment was 59.8%; for the 731 patients who received all or part of their initial treatment at the clinics or were not treated anywhere, five-year survival probability was 62.7%. Most deaths from testicular cancer took place in the first two years after treatment, and 90% of recorded recurrences were diagnosed before the third anniversary. Survival rates were strongly influenced by histological type and extent of disease, and to some degree by age. Survival did not seem to be closely correlated with delay after first symptom, site or size of primary lesion, ectopia, surgical treatment of the abdominal nodes, site or dosage of radiation, or chemotherapy. The survival rates in this series of cases compare favourably with those of other large series.     

健康宣教在小儿狭窄性腱鞘炎围手术期应用价值

目的:对手术疗法治疗狭窄性腱鞘炎的小儿患者采取系统的整体健康宣教,使得患儿疗程缩短,治愈率高,复发率降至最低,功能康复效果良好,提高护理质量。方法:在保守治疗无效的情况下,手术疗法切除部分狭窄腱鞘,围手术期实施系统的全面的功能康复训练及宣教。结果:54例患儿完全治愈,随访3~26个月,无复发及并发症,愈后功能良好。结论:细致、周密的做好围手术期对家长及患儿的双重健康宣教工作,使得护患关系融洽,患者自护能力大大加强,治疗及护理效果满意。     

Nephroblastoma: treatment during 1970-3 and the effect on survival of inclusion in the first MRC trial.

In 1970-3 313 children were diagnosed as having nephroblastoma in Great Britain. From the start of the first Medical Research Council nephroblastoma study in October 1970 until the end of 1973, 98 children (57% of all eligible children) were included in the trial. Of the 313 children, 288 (92%) had a nephrectomy, 248 (79%) received a course of radiotherapy, and 267 (85%) were given at least four days'' chemotherapy. The three-year survival rate was 58%; the rate among children in the trial (77%) was significantly better than that among children who were eligible for the trial but not included (58%). Children who had nephrectomies at specialised children''s and teaching hospitals had a higher survival rate than those treated elsewhere. All children with nephroblastoma should be treated according to well-defined protocols which take into account the age of the child and the stage of the tumour and include a full course of maintenance chemotherapy.     

The clinical burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model

OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model''s forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model''s estimates of 96%, 92% and 84%. We also compared the model''s forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model''s estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.     

Conservative Treatment of Chronic Heart Block

A study of 203 patients with chronic heart block treated with oral long-acting isoprenaline showed that 85 (42%) were maintained satisfactorily on the drug for a mean period of 18.2 months. The survival rates at one, two, and three years were 76%, 64%, and 57% respectively. In 115 patients treatment by pacing became necessary to control symptoms, and in these patients the survival rates at one, two and three years were 83%, 72%, and 60%.The two most valuable guides to patients'' response to oral isoprenaline are the response to a trial dose of intravenous isoprenaline and the type of dysrhythmia associated with their Adams-Stokes attacks. Patients with heart failure with slow ventricular rates and those with angina of effort do not respond to treatment with sympathomimetic drugs.The majority of patients with chronic heart block are elderly, and in view of the complexity of pacing systems, and the need for skilled supervision of paced patients, oral long-acting isoprenaline remains of value in the longterm management of chronic heart block, provided patients are carefully selected for this form of therapy.     

A CRITICAL REVIEW OF THE USE OF VINCRISTINE (VCR) AS A TUMOUR CELL SYNCHRONIZING AGENT IN CANCER THERAPY

Vincristine (VCR) has been used clinically in so-called ‘tumour cell synchronization therapy schedules'. These schedules are based on the assumption that cells, arrested in metaphase by low doses of VCR, subsequently re-enter the proliferative cycle synchronously. However, the evidence that tumour cell synchrony can be achieved under clinical conditions or that ‘cell synchronization therapy schedules’ yield a better therapeutic response than other efficient combination schemes, is scanty. Further, even in experimental systems, the efficacy of VCR as a cell synchronizing agent is disputed. Indeed, in some systems, cells arrested in metaphase by low doses of VCR, do not re-enter a normal proliferative cycle at all following arrest. In addition, the complex nature of the VCR—tumour interaction and the heterogeneous nature of the tumour cell populations against which it is used augurs badly for the successful application of cell synchronization therapy schedules.     

Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland.

OBJECTIVE--To compare survival outcome for patients with breast cancer cared for by specialist and non-specialist surgeons in a geographically defined area. DESIGN--Retrospective study of all female patients aged under 75 years in the area treated between 1980 and June 1988 (before breast screening began). Patients were identified from the cancer registry and from pathology records of all hospitals in the area. Specialist surgeons were identified by one author. All other surgeons caring for patients from the area were considered non-specialists. SETTING--A geographically defined population in urban west of Scotland. SUBJECTS--3786 patients with histologically verified breast cancer operated on between 1 January 1980 and 30 June 1988 and followed to 31 December 1993. MAIN OUTCOME MEASURES--Five and 10 year survival rates for specialists and non-specialists; relative hazard ratios derived from Cox''s proportional hazards model adjusted for prognostic factors--age, socioeconomic status, tumour size, and nodal involvement. RESULTS--The five year survival rate was 9% higher and the 10 year survival 8% higher for patients cared for by specialist surgeons. A reduction in risk of dying of 16% (95% confidence interval 6% to 25%) was found after adjustment for age, tumour size, socioeconomic status, and nodal involvement. The benefit of specialist care was apparent for all age groups, for small and large tumours, and for tumours that did and did not affect the nodes and was consistent across all socioeconomic categories. CONCLUSIONS--Survival differences of the magnitude demonstrated have implications for the provision of services for the treatment of women with breast cancer. There is a need to improve equity in the treatment of breast cancer.     

Long-term results after combined modality treatment for non-metastatic osteosarcoma

Since the introduction of multimodality treatment, the prognosis of patients with high-grade non-metastatic osteosarcoma has significantly improved. A retrospective review was performed to assess the long-term results of this approach in a single centre setting, and to investigate the impact of potential clinical prognostic factors. Between 1985 and 1993, 35 patients with stage II-A and II-B osteosarcoma underwent preoperative chemotherapy (high-dose methotrexate), wide surgery, and adjuvant chemotherapy (cisplatin-doxorubicin/bleomycin-cyclophosphamide-dactinomycin) (modified T-10A protocol). There were 19 males and 16 females. Median patient age was 17 y (range 12–42). Primary tumour sites were the extremities (83%) and axial bones (17%). In spite of an unfavourable grade 3–4 histologic response rate to high-dose methotrexate of 12%, 31 (88%) patients were able to undergo limb-sparing surgery and 28 (80%) were rendered disease free after the planned therapy. Median follow-up was 8 y. The actuarial overall survival and disease-free survival rates were 64% and 49% at 5 y, and 59% and 49% at 10y, respectively. Tumour size and primary site were significant prognostic factors for survival in univariate analyses. In conclusion, long-term survival after combined modality treatment can be achieved in more than 60% of patients with localised osteosarcoma, including non-appendicular lesions. Limb-sparing surgery is a realistic goal for most cases. The prognostic value of tumour necrosis and the efficacy of neoadjuvant chemotherapy should be interpreted according to individual high-dose methotrexate scheduling.     

Primary Treatment Response Rather than Front Line Stem Cell Transplantation Is Crucial for Long Term Outcome of Peripheral T-Cell Lymphomas

Outcome of systemic peripheral T-cell lymphomas (PTCL) is unsatisfactory and no controlled clinical study guides the therapy. Phase II studies suggest to consolidate response achieved after front-line treatment with stem cell transplant (SCT). We retrospectively evaluate the impact of front-line SCT consolidation in a single Center cohort of 209 patients treated during the last two decades. Median age was 49 years (range 15-85) with a prevalence of male sex (61%), advanced stage (68%) while IPI was >2 in 44%. Primary treatment was MACOP-B (39%) CHO(E)P (39%), intensive regimens (18%) or others (4%). Complete response to primary treatment (i.e. before SCT) was 60% (5% partial remission). Forty-four patients further proceeded to SCT while 92 did not receive consolidation. Outcome of primary responders was good, with a 3-year overall survival of 74% (82% in ALCL ALK+ and 69% for the other histologies). By multivariate analysis a better overall survival was significantly associated with IPI<2 (P=0.001), primary response (P=0.000), and ALCL ALK+ (P=0.012). The multivariate analysis performed on responders, showed that only IPI was predictive of a better survival while ALCL ALK+ and undergoing SCT were not. Response to primary treatment rather than post-remission programs is the crucial determinant of PTCL outcome.     

Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin

Between 2% and 9% of patients with cancer present with metastatic nonsquamous cell carcinoma of unknown primary origin. Traditionally, a series of investigations is undertaken to locate the primary origin of the tumour, although many of these tests are often painful or distressing to patients, unsuccessful in locating the primary site and costly to the health care system. Moreover, even if a tumour is found it usually cannot be treated surgically. However, a small number of cancers of unknown primary origin can be cured, arrested or effectively palliated with systemic treatment. This study compares the costs and outcomes of the current practice of comprehensively searching for the primary tumour with those of an alternative, limited approach that identifies only the primary tumours for which relatively effective systemic therapy exists. Decision trees were constructed for the two diagnostic approaches and their associated therapeutic options. Costs and probabilities were integrated with published data on the survival of patients with each type of cancer. The results indicate that the comprehensive diagnostic strategy may increase 1-year survival rates from 11.0% to 11.5%. On the basis of Ontario cost data it is calculated that the additional costs of a comprehensive search for 1000 patients will range from approximately $2 million to $8 million, depending on the subsequent treatment strategy.