Treatment of acute lymphoblastic leukaemia: effect of variation in length of treatment on duration of remission. Report to the Medical Research Council by the Working Party on Leukaemia in Childhood.

Patients with acute lymphoblastic leukaemia (ALL) were allocated at random either to stop maintenance chemotherapy after six 12-week courses or continue with a further six. The main difference between the two groups was in the incidence of bone-marrow relapse within nine months after stopping treatment. Such relapses occurred less in older patients and those with higher leucocyte counts initially than in those who appeared to have the best prognosis--namely, those with typical low-count childhood ALL. No patient given prophylactic irradiation to cranium and spine combined with intrathecal methotrexate suffered meningeal relapses, whereas among those not given such prophylaxis the lack of benefit from continuing treatment was mainly attributable to meningeal relapses.     

Regional immunotherapy has a detrimental effect on the response to combined irradiation and chemotherapy in locally advanced non-small cell bronchogenic carcinoma

Summary Twenty-one patients with stage III M₀ non-oat cell bronchogenic carcinoma confined to the thorax were randomized to receive either intrapleural BCG (10⁷ cfu, Tice strain) or intrapleural saline 3 weeks prior to beginning combined irradiation and chemotherapy. Radiation to the primary tumor and regional nodes was given at a dose of 3,000 rad in ten sessions and was followed in 7–14 days by CAMP chemotherapy (cyclophosphamide, adriamycin, methotrexate, and procarbazine) for a planned duration of 6 months. Isoniazid, 300 mg/day, was given to all patients for 3 months starting 1 week after intrapleural therapy. There were no significant differences in pretreatment prognostic factors or in response to radiation therapy. The patients receiving intrapleural BCG in addition to radiation and chemotherapy had a median survival of 18 weeks, significantly shorter than that for the patients receiving intrapleural saline (54 weeks, P=0.017).Presented in part at the 16th Annual Meeting of the American Society of Clinical Oncology, San Diego, California, May 27, 1980     

Psychological impact of adjuvant chemotherapy in the first two years after mastectomy.

Psychological symptoms were assessed over two years in a randomised trial of three forms of treatment given to women after mastectomy for stage II breast cancer. The treatments were: three weeks'' radiotherapy; one year''s adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil; and radiotherapy followed by chemotherapy. Analysis of the results on an intention to treat basis showed no substantial differences in depression or anxiety among groups at one, three, or six months after the operation. At 13 months, however, patients who had been allocated chemotherapy had significantly more symptoms, especially depression, than control patients treated with radiotherapy alone. Conditioned reflex nausea and vomiting increased considerably during the second six months of chemotherapy and persisted for up to a year afterwards. The psychological morbidity of adjuvant chemotherapy could be substantially reduced if courses of treatment were restricted to about six months.     

Treatment of overt meningeal leukaemia in children: results of second MRC meningeal leukaemia trial.

After induction ofmeningeal remission by a course of intrathecal methotrexate patients were randomly allocated to receive either cranial irradiation or craniospinal irradiation. Patients being treated for their first meningeal relapse were randomised separately from those in their second or subsequent relapse. All eight patients in their first relapse who were given cranial irradiation alone developed further meningeal recurrence (median length of remission 15 weeks) compared with only two out of nine given craniospinal irradiation (median length of remission at least 99 weeks). Four of the nine patients given craniospinal irradiation were alive and without further meningeal relapse two and a half to four years after treatment. Craniospinal irradiation produced no such advantage for patients entering the trial in their second or subsequent meningeal relapse.     

MACOP-B chemotherapy for the treatment of high grade and intermediate grade non Hodgkin's lymphoma.

Between Nov. 1985 and Nov. 1988, sixty-three patients with high grade malignant (hg) and intermediate grade malignant (img) Non Hodgkin's Lymphoma (NHL) were treated with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin). Thirty-seven patients received MACOP-B as an upfront treatment modality, whereas twenty-six patients had relapsed disease and received MACOP-B as a salvage protocol. Four weeks after termination of therapy, 75% of patients with de novo NHL and 72% of the patients with relapsed NHL were in complete remission (CR). In the group of newly diagnosed NHL, 22% achieved partial remission (PR) and 3% no change (NC), whereas in the group with relapsed disease 14% had PR and 14% had progressive disease (PD). At a medium follow-up of 12 months (range 1 month to 33 months), 74% of patients with de novo NHL continued to be in CR whereas the continuous CR rate in patients with relapsed disease was 35%. Overall survival after 30 months of observation for the patient group with de novo NHL was 75% and 40% for patients with relapsed NHL. The mean duration for completion of the projected 12 chemotherapy cycles, given in weekly intervals, was 12.9 and 13.5 weeks in upfront or salvage therapy, respectively. With low incidence of major toxicities, application of drugs on an outpatient basis, and high efficacy, MACOP-B shows substantial advantages for therapy of de novo and relapsed NHL.     

Adriamycin in the combined chemotherapy of small-cell lung cancer

The results of combined chemotherapy and chemoradiotherapy of 158 patients with small cell lung cancer are presented. Adriamycin was used as one of the components of the induction chemotherapy of 98 out of the 158 patients. Chemoradiotherapy (nitrosomethylurea, methotrexate, CCNU, adriamycin, vincristine, DTIC, radiotherapy) was performed according to 4 schemes and combined chemotherapy (cyclophosphamide, adriamycin, methotrexate, or CCNU, cyclophosphamide, methotrexate plus adriamycin, vincristine, natulan) was performed according to 2 schemes. The total efficacy (complete and partial regression) of the 6 schemes averaged to 80 per cent. The number of patients with complete regression amounted to 29 per cent. Long-term survival for more than 2 years was observed in 17 per cent of the patients. No signs of metastases or relapses for 5 years were recorded in 6 per cent of patients. Adriamycin is one of the most active antitumor drugs in combined chemotherapy and chemoradiotherapy of small cell lung cancer.     

Chemotherapy in pancreatic cancer: results of a controlled,prospective, randomised,multicentre trial.

Forty patients with inoperable pancreatic cancer were included in a prospective, randomised, controlled trial of multiple chemotherapy. The survival of 19 untreated control patients was compared with that of 21 patients who received an initiation course of intravenous fluorouracil, cyclophosphamide, methotrexate, and vincristine given over five days followed by intravenous fluorouracil and mitomycin given over three or five days at six-week intervals thereafter. Median survival in treated patients was 44 weeks, which was significantly longer than the nine weeks seen in controls. In patients without metastases median survival was 48 weeks in the treated group and 12 weeks in controls. In patients with metastases it was 30 weeks in treated patients and seven weeks in controls. The treatment was well tolerated and seemed to confer a significant prolongation of survival, comparing favourably with previous reports of chemotherapy with or without radiotherapy. If the results are confirmed this regimen may be useful in district general hospital practice.     

Cellular transfer of experimental allergic encephalomyelitis: Altered disease pattern in irradiated recipient Lewis rats

Irradiation of recipient Lewis rats 6–24 hr prior to injection of sensitized lymph node cells (LNC) altered the pattern of transferred experimental allergic encephalomyelitis (EAE). Recipients subjected to total body irradiation in doses ranging from 500 to 1000 rads developed paralysis; nonirradiated control recipients did not do so. Histopathologic changes of EAE, in terms of number of descrete cellular infiltrates, were potentiated in the total body irradiated recipients. Among LNC recipients subjected to regional irradiation (850 rads) of the head or lower spinal column, paralysis was observed only in those animals where the irradiation impinged upon the spinal cord. Cellular infiltrates of EAE were numerically more common in the irradiated region of the neuraxis. The findings are discussed in terms of irradiation rendering the central nervous system of animals and man more vulnerable to autoimmune injury.     

High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): report from the North Thames Cooperative Group.

A randomised study comparing cisplatin 120 mg intravenously with cyclophosphamide 2 g intravenously, each drug being given every month for six months followed by a low dose regimen for a further six months in responding patients, was carried out in 86 patients with advanced epithelial ovarian carcinoma (FIGO stages III and IV). Patients given cisplatin were found to have a longer median survival time than those given cyclophosphamide (19 months compared with 12 months) and a longer median duration of complete clinical response (18 months compared with eight months). The difference in disease free survival was statistically significant even after factors such as age, stage of disease, and the completeness of initial surgery had been taken into account. This study suggests that cisplatin is a more effective chemotherapeutic agent than cyclophosphamide for advanced ovarian cancer and should be the agent of choice in future trials comparing combination chemotherapy with a single agent.     

Multiple fluoroscopy of the chest: carcinogenicity for the female breast and implications for breast cancer screening programs.

The risk of radiation carcinogenesis has been established for breast tissue from experience with total body irradiation and multiple fluoroscopy of the chest with the patient prone. The doubling dose has been estimated to lie between 20 and 50 rads. Before undertaking radiologic screening programs for breast cancer, therefore, it is necessary to determine whether exposures below this range are safe. Of 792 women who had had tuberculosis and were followed for a minimum of 20 years, 451 had had multiple fluoroscopy while supine; 341 had not had fluoroscopy. The first group received a total radiation dose to the breast averaging 17 rads (141.5 fluoroscopies); the incidence of breast cancer in this group was not increased. Had fluoroscopy been performed with the patient prone the total radiation dose would have averaged 308 rads. The difference is thought to explain the increased incidence of breast cancer attributable to fluoroscopy given with the patient prone. Mid-breast exposure with mammography or xeroradiography varies between 3 and 6 rads. Repetitive screening would, therefore, appear safe provided total exposure did not exceed 20 rads. With this restriction there would appear to be no reason to curtail screening of women for breast cancer.     

Symptomatic epilepsy associated with intracranial calcifications in children with acute lymphoblastic leukemia (ALL)

Acute and long-term sequels of central nervous system (CNS) prophylaxis with irradiation and intrathecal chemotherapy in children suffering from acute lymphoblastic leukemia (ALL) include vasculopathies, leucoencephalopathies, intracranial calcifications, intellectual and neurological impairment. We report two children at the age 5 and 8 years who manifested partial motor or complex seizures and intracranial calcifications 2-4 years after the diagnosis of ALL had been established. The occurrence of these disorders was much earlier than reported in the literature. Both children received prophylactic CNS treatment with irradiation and intrathecal methotrexate (MTX). Their brain CT scans and EEG had been normal before the first epileptic seizure was registered. Children are now seizure free on carbamazepine, and a boy with complex partial and myoclonic seizures is also on valproate and vigabatrine. Symptomatic epilepsy associated with intracranial calcifications and persisting EEG changes might occur as side effects of ALL treatment.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Investigations into sister chromatid exchange in patients under cytostatic therapy

Summary In vivo sister chromatid exchange (SCE) determinations were carried out in patients with Psoriasis vulgaris under methotrexate therapy and patients with histologically verified bronchial carcinoma under cyclophosphamide, methotrexate or a combined chemotherapy. A pronounced increase in SCE rate was only found after cyclophosphamide treatment.Abbreviation Cyclo cyclophosphamide - MTX methotrexate - FU fluorouracil - Pred prednisolone - VB vinblastine - VC vincristine - BM bleomycin     

Allogeneic marrow transplantation after total lymphoid irradiation (TLI): effect of dose/fraction, thymic irradiation, delayed marrow infusion, and presensitization.

BALB/c mice infused with 30 x 10(6) C57BL/Ka bone marrow (BM) cells 1 day after treatment with fractionated total lymphoid irradiation (TLI) (17 fractions of 200 rads each) became stable mixed chimeras without clinical graft-vs-host disease (GVHD). Mice given 18 fractions of 100, 50, or 25 rads each followed 1 day later by C57BL/Ka BM did not become chimeric, indicating that a critical cumulative radiation dose is required for this effect. Animals given TLI with lead shielding placed over the thymus also developed stable chimerism without GVHD. Thus susceptibility to tolerance induction and protection from GVHD after TLI and allogeneic BM transplantation is not due to alteration of the thymic microenvironment by fractionated irradiation. A delay of 7 or 21 days between completion of TLI and BM administration resulted in a high incidence of graft rejection. Sensitization to minor histocompatibility antigens of the BM donor strain by blood transfusion either before or during TLI resulted in marrow graft rejection in a high percentage of animals.     

Intrathecal Chemotherapy in Burkitt's Lymphoma

Meningeal involvement with Burkitt lymphoma cells constitutes the most challenging therapeutic problem in the management of Burkitt''s tumour. The results of intrathecal chemotherapy with methotrexate or cytosine arabinoside in 55 episodes of malignant pleocytosis in 38 patients with Burkitt''s tumour are described. The response was complete in nearly all patients after the administration of either agent. Cerebrospinal fluid (C.S.F.) remissions were more prolonged in patients receiving intrathecal methotrexate or cytosine arabinoside daily for four days as opposed to a 10-day schedule. A controlled randomized trial of “prophylactic” intrathecal chemotherapy in patients without malignant cells in the C.S.F. on admission showed no protective effect against the subsequent development of malignant pleocytosis. Future therapeutic approaches are considered in the light of these results.     

Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells

Background aimsThe purpose of this study was to observe the clinical effect and safety of umbilical cord mesenchymal stem cells (UC-MSCs) in treating spinal cord injury (SCI) by intrathecal injection.MethodsFrom January 2008 to October 2010, we treated 22 patients with SCI with UC-MSCs by intrathecal injection; dosage was 1 × 10⁶ cells/kg body weight once a week given four times as a course. Four patients received two courses, one patient received three courses and all other patients received one course. American Spinal Injury Association scoring system and International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale were used to evaluate neural function and ability to perform activities of daily living.ResultsTreatment was effective in 13 of 22 patients; nine patients had no response. Among patients with incomplete SCI, the response to treatment was 81.25%; there was no response to treatment among six patients with complete SCI. Five patients with a response to treatment received two to three courses of therapy, and effects in these patients were further enhanced. In most patients in whom treatment was effective, motor or sensory functions, or both, were improved, and bowel and bladder control ability was improved. In 22 patients 1 month after therapy, algesia, tactile sensation, motion and activity of daily living scale were significantly improved (P < 0.01). During therapy, common adverse effects were headache (one case) and low back pain (one cases); these disappeared within 1–3 days. No treatment-related adverse events occurred during a follow-up period ranging from 3 months to 3 years.ConclusionsUC-MSC therapy by intrathecal injection is safe and can improve neurologic function and quality of life in most patients with incomplete SCI.     

Bacille Calmette-Guérin as maintenance therapy for non-Hodgkin's lymphoma.

Following complete remission of non-Hodgkin''s lymphoma by chemotherapy, irradiation or both, 44 patients were studied to assess the value of bacille Calmette-Guérin (BCG) as maintenance therapy. Patients with stage LI, EI or EII disease were allocated at random to receive BCG or no further maintenance therapy, and those with stage LII, LIII, EIII or IV disease received BCG therapy or orally administered cyclophosphamide. BCG had no effect on the duration of remission or the overall survival from the time of randomization. However, after the first recurrence there was a significant improvement in survival in the patients who had received BCG maintenance therapy.     

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m² methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m². Seven days later intravenous methotrexate, 120 mg/m² was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m² with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m² (median 200 mg/m²). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m² caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.     

Combined treatment of rituximab,idarubicin, dexamethasone,cytarabine, methotrexate with radiotherapy for primary central nervous system lymphoma

The overall response rates and long‐term survival of primary central nervous system lymphoma (PCNSL) are still significantly inferior to the results achieved in similar subtypes of extranodal non‐Hodgkin's lymphoma. It is clearly necessary to investigate new therapeutic methods on PCNSL. We encountered three patients histologically documented PCNSL as diffuse large B‐cell lymphoma (DLBCL). They were treated with R‐IDARAM which comprised rituximab, idarubicin, dexamethasone, cytarabine and methotrexate. Patient 1 received stereotactic brachytherapy (SBT) prior to chemotherapy performed with iodine‐125 seeds (cumulative therapeutic dose 50 Gy). After six cycles of R‐IDARAM at 3‐weekly intervals, radiotherapy was applied at a dosage of 2000–4000 cGy in conventional schedule (180 or 200 cGy/day) to whole brain or spinal cord in all patients. Complete remission (CR) was achieved after first two cycles of R‐IDARAM in all patients. All three patients remained in CR at the time of this report with a median duration of follow‐up of 23 months (ranging from 13 to 41 months). Three patients have been alive for 41, 13, 16 months respectively until now. The patient with the longest survival time was the one given SBT prior to chemotherapy. This study suggests that R‐IDARAM combining with radiotherapy maybe a high effective regimen in PCNSL patients especially those with primary central nervous system DLBCL. A comprehensive treatment combining internal radiotherapy by SBT, modified R‐IDARAM and followed reduced external radiotherapy may be a new treatment concept for PCNSL with higher efficiency and lower toxicity.     

Supervoltage Radiation Therapy—Use of the Linear Accelerator for Treating Ovarian Adenocarcinoma

In a study of patients treated thus far by supervoltage radiation from the Stanford linear accelerator, the following conclusions were reached:Homogenous radiation in doses of 4,000 rads may be delivered to the upper abdomen and 5,500 rads to the lower abdomen and pelvis for the treatment of ovarian cancer by the proper utilization of modern super-voltage radiation sources.Patients with Stage 2 and Stage 3 lesions are best treated by total hysterectomy and bilateral salpingo-oophorectomy followed by total pelvic irradiation.Stage 4 disease was seldom controlled by high dose radiation therapy to the entire peritoneal cavity.An unusual histologic pattern has been found in the liver of three patients who died three to nine months after 4,000 to 5,000 rads had been given in a period of five or six weeks.