Mantle irradiation alone for clinical stage I-II Hodgkin's disease: long-term follow-up and analysis of prognostic factors in 261 patients.

PURPOSE: To evaluate mantle radiotherapy (MRT) alone as the initial therapy of patients with clinical stage (CS) I-II Hodgkin's disease (HD). PATIENTS AND METHODS: We performed a retrospective study of patients treated with MRT alone for CS I-II supradiaphragmatic HD between 1969 and 1994. Prognostic factor analysis was performed for progression-free survival (PFS) and overall survival (OS). Outcome was also assessed in favorable cohorts defined in the literature. RESULTS: There were 261 eligible patients. The median follow-up period for surviving patients was 8.4 years (range, 1.8 to 27.4 years). The 10-year OS rate was 73%. Multifactor analysis for OS showed that age was the only important prognostic factor. The 10-year PFS rate was 58%. On multifactor analysis for PFS, the most important prognostic factors were clinical stage, B symptoms, histology, number of sites, and tumor bulk. The 10-year PFS rate for lymphocyte-predominant disease was 81% for stage I and 78% for stage II. In favorable patient cohorts defined in the literature, the 10-year PFS rate ranged from 70% to 73% for the whole group and from 71% to 90% in patients with favorable stage I disease, but only from 48% to 57% in patients with favorable stage II disease. On competing-risks analysis, the cumulative 10-year incidence of first site of failure in the para-aortic/splenic region alone was 10.5%. Sixty percent of relapsed patients remain progression-free at 10 years after chemotherapy salvage. CONCLUSION: These results support the use of MRT alone in patients with favorable CS I HD and CS I-II HD with lymphocyte-predominant histology. The remainder of patients with CS I-II HD require more intensive treatment.

Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: a randomized, crossover comparison.

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) administered prophylactically after chemotherapy reduces the duration and severity of neutropenia. This randomized crossover study was designed to assess whether a lower dose of G-CSF is as effective as a standard dose of 5 microg/kg daily. PATIENTS AND METHODS: Patients who received standard-dose chemotherapy regimens expected to cause neutropenia received G-CSF (lenograstim) that started the day after chemotherapy for 14 days or until the absolute neutrophil count (ANC) recovered to greater than 10 x 10(9)/L. The lenograstim dose was randomly allocated to be 2 or 5 microg/kg daily in the first cycle of chemotherapy and crossed over to the alternate dose for the second cycle. The study was designed to accrue 40 assessable patients to provide a power of 80% to detect a difference in duration of neutropenia of 1 day. Fifty-two patients were randomized to treatment and 43 patients completed two cycles of identical chemotherapy. RESULTS: There was little neutropenia irrespective of the dose used. Twenty-three patients (53%) had no grade III or IV neutropenia and 30 patients (70%) had no grade IV neutropenia. Crossover trial methodology was used to assess the difference in outcome caused by the lower dose compared with the standard dose (estimated treatment effect). There was no significant difference in the measures of neutropenia, hospitalization, or other clinical outcomes. The 95% confidence interval (one-sided) for the additional duration of neutropenia caused by the lower dose of lenograstim was 0.43 days or less for grade III or IV neutropenia and 0.34 days or less for grade IV neutropenia. CONCLUSION: Lenograstim 2 microg/kg provides similar protection to 5 microg/kg against neutropenia that complicates standard-dose chemotherapy. The use of a lower dose has important implications for the cost-effectiveness of prophylactic G-CSF therapy.

A randomised double blind crossover study of domperidone and prochlorperazine suppositories for controlling emesis in outpatients receiving chemotherapy.

Patients receiving outpatient chemotherapy, without cisplatin, were randomised to receive four doses of either domperidone 60 mg or prochlorperazine 25 mg suppositories every 4 h, starting 30 min before the chemotherapy. They were crossed over for the next chemotherapy cycle. To enable analysis of 100 patients who had received identical chemotherapy in each course, 136 patients were randomised. Patients experienced a higher grade of nausea on domperidone (P = 0.05). Only 18% of patients vomited on domperidone and 14% on prochlorperazine, but the number of vomits was higher on domperidone (P = 0.003) and the duration was significantly increased (P = 0.02). Patients experienced significantly more diarrhoea on domperidone (P < 0.0001), although it was predominantly mild. Patients were significantly more sedated on prochlorperazine on the second course (P = 0.006), but not on the first course (P = 0.9). More patients preferred their second course (P < 0.0001), and were significantly less anxious (P = 0.0002). Patients reported tolerating their treatment similarly for both antiemetics, but more patients preferred prochlorperazine (P = 0.003), mainly due to reductions in nausea and vomiting and other side-effects, particularly diarrhoea.

A randomised double-blind study of high-dose intravenous prochlorperazine versus high-dose metoclopramide as antiemetics for cancer chemotherapy.

High-dose prochlorperazine 0.8 mg/kg administered intravenously 30 min pre and 7 h 30 min post the initial dose of emetogenic chemotherapy was compared to high-dose metoclopramide 2 mg/kg over 20 min every 2 h for five doses starting 30 min prior to chemotherapy in a randomised, double-blind, parallel subjects design study. On the prochlorperazine arm intravenous dextrose placebos every 2 h maintained blinding. Complete suppression of vomiting occurred in 42% on metoclopramide (53% with non-cisplatin regimens) and 36% on prochlorperazine (52% with non-cisplatin-containing regimens) while major responses (2 or less vomits) occurred in 58% on metoclopramide and 54% on prochlorperazine. In patients who vomited after cisplatin, prochlorperazine achieved a significantly shorter duration of vomiting, a median of 5 h compared to 15 h on metoclopramide (P = 0.03). The response rate to prochlorperazine for cisplatin-induced emesis between 12 and 24 h was significantly better than for metoclopramide (prochlorperazine = 0.02). Toxicities were equivalent except for significantly greater sedation and dry mouth on prochlorperazine. Extrapyramidal reactions were recorded equally on both arms but were only severe enough to stop treatment on metoclopramide. The metoclopramide regimen was five times as expensive as prochlorperazine. High-dose prochlorperazine is an active and cost-effective antiemetic.

Salvage radiotherapy for Hodgkin's disease following chemotherapy failure.

PURPOSE: This study aims to: 1) assess failure-free survival (FFS), overall survival (OS), and failure pattern after salvage radiotherapy (SRT) for patients with Hodgkin's disease (HD) who fail chemotherapy (CT); 2) identify patients suitable for SRT as an alternative to more aggressive salvage regimens. METHODS AND MATERIALS: Between 1978 and 1992, 52 patients with relapsed/refractory HD following 26 CT received SRT at the Peter MacCallum Cancer Institute. Patient characteristics at diagnosis were: median age (range 12-63); male-31, female-21; Stage I-4, II-16, III-25, or IV-7. Prior to SRT 27 patients had received the equivalent of both MOPP and ABV(D). The duration of initial complete response (CR) from CT was greater than 12 months in 22 patients. SRT (dose 34-42 Gy) was given to active disease sites. RESULTS: Five-year FFS and OS rates following SRT were 26 and 57%, respectively. Five-year FFS and OS rates of 36 and 75%, respectively, were achieved in patients who relapsed in supradiaphragmatic nodal sites without B symptoms; in a subset of patients with initial Stage I-II disease the FFS and OS rates were 50 and 86%, respectively. On multivariate analysis significant factors for FFS were B symptoms at the time of SRT (p = 0.003), extranodal involvement (p = 0.011) and histology (p = 0.018). For OS significant factors were B symptoms (p = 0.0007), age (p = 0.014) and number of prior CT regimens (p = 0.03). CONCLUSION: The relatively poor results of SRT in terms of FFS justify the use of alternative salvage strategies for most patients with Hodgkin's disease who fail CT. However, SRT offers a low morbidity, potentially curative option for a subset of patients. Our data suggest that patients most suitable for SRT are those with relapse in supradiaphragmatic nodal sites and no B symptoms.

Limited small cell lung cancer: the effect of radiotherapy on local control following response to chemotherapy.

The survival and rate of chest infield relapse was examined in 48 patients with limited disease small cell lung cancer (LSCLC) who had achieved complete (CR) or partial response (PR) following three courses of chemotherapy. During 1985-1986 chemotherapy consisted of carboplatin and etoposide and during 1986-1987, of etoposide, carboplatin, cyclophosphamide, and vincristine (ECCO). After three courses of chemotherapy, chest irradiation (50 Gy in 25 fractions over 5 weeks) was given to encompass the original tumor volume. Complete responders were also given prophylactic cranial irradiation, 30 Gy in 10 fractions over 2 weeks. Overall median survival of all patients receiving chest irradiation was 17 months from commencement of radiotherapy. The infield relapse-free survival at 24 months was 49% (95% confidence interval: 32-66%). Patients who had only achieved a PR at the time of irradiation were more likely to relapse in the chest than complete responders (p = 0.09). We conclude that local relapse remains a major cause of failure in patients with LSCLC in spite of sequential high dose radiotherapy given to patients who have responded to chemotherapy.

Lymphocyte predominant Hodgkin's disease: a clinicopathologic comparative study of histologic and immunophenotypic subtypes.

PURPOSE: To compare the clinicopathologic features of the histologic and immunophenotypic subgroups of lymphocyte predominant Hodgkin's disease. METHODS AND MATERIALS: A retrospective review of 64 patients with lymphocyte predominant Hodgkin's disease treated at the Peter MacCallum Cancer Institute, Melbourne, was performed. Nodular and diffuse histological subtypes were confirmed by review of hematoxylin and eosin paraffin sections. Immunophenotyping with monoclonal antibodies L26 (B-cell origin) and Leu M1 (Hodgkin's phenotype) were available in 36 patients. RESULTS: The estimated freedom from progression and estimated overall survival at 10 years was 74% standard error (SE 5.8%) and 85% (SE 5.2%), non-Hodgkin's respectively. There were no significant differences in freedom from progression or overall survival when nodular and diffuse histology were compared. Similarly the presence of B-cell markers did not influence prognosis. There was only one case of secondary non-Hodgkin's lymphoma. CONCLUSION: Our results are consistent with major reported series displaying no differences between any of the subgroups of lymphocyte predominant Hodgkin's disease.

Results of treating primary tumors of the trachea with radiotherapy.

PURPOSE: To report the efficacy of treatment and to identify prognostic factors that were predictive of survival in primary tumors of the trachea treated with radiotherapy. METHODS AND MATERIALS: The medical records of patients treated at the Peter MacCallum Cancer Institute in the period 1962 to 1995 were reviewed. Forty-two patients were eligible for the study and were treated with radiotherapy. Squamous cell carcinoma (SCC) was the commonest subtype and patients generally presented with long-standing respiratory symptoms. Eleven patients were planned for treatment with at least 50 Gy to the primary, while the rest were treated with lower doses. RESULTS: The estimated median survival for all patients was 5.7 months, with 13% surviving at 2 years. Univariate analysis revealed performance status, weight loss, and lymph node or distant metastatic involvement as significant prognostic factors. Patients planned for treatment with at least 50 Gy survived longer than patients treated with less than 50 Gy, but this was probably due to selection of patients with better prognostic factors for higher dose treatment.

Survival following radiotherapy for post-surgical locoregional recurrence of non-small cell lung cancer.

Long term survival [> 3 years] has been documented in patients treated with radiotherapy for bronchial stump recurrence following surgery for non-small cell lung cancer [NSCLC]. In this retrospective review of 45 patients with locoregional recurrence of NSCLC we measured survival following radiotherapy according to site of recurrence [bronchial stump or elsewhere] and treatment intent. Estimated median survival for all 45 patients from presentation was 10 months. Ten patients whose disease was confined to the bronchial stump had an estimated median survival of 15 months compared with 9 months for patients with recurrence elsewhere [P = 0.4]. Seventeen patients treated with radical intent [dose > 50 Gy] had an estimated median survival of 16 months, with an estimated 41% alive at two years. The overall survival of patients treated with radical intent is not dissimilar to that of a group of our patients treated similarly with primary radiotherapy for inoperable NSCLC. We conclude that a policy of high dose radiotherapy may be justified in selected patients with recurrent NSCLC.

The influence of induction chemotherapy dose and dose intensity on the duration of remission in acute myeloid leukemia. Australian Leukemia Study Group.

The aim of this study was to assess the influence of dose and dose intensity (DI) of induction and consolidation chemotherapy on relapse rates in 264 de novo patients with acute nonlymphocytic leukemia (ANLL). Patients were randomised to receive cytosine arabinoside (ARAC) 100 mg/m2 continuous infusion for 7 days and daunorubicin (DNR) 50 mg/m2 IV day 1-3 (7-3) or the same drugs with the addition of etoposide 75 mg/m2 IV days 1-7 (7-3-7). Cox proportional hazards regression models were used throughout to identify prognostic factors, including dose delivery parameters, influencing the rate of relapse. Of 152 patients who achieved a complete remission (CR), 104 have relapsed with a median duration of CR of 15.8 months. Actual dose delivered was prospectively documented. Cox regression analysis identified the most significant prognostic factors jointly influencing duration of CR as performance status groups (p < 0.0001), percentage peripheral blasts (p = 0.0015), 7-3-7 arm (p = 0.0075), age < 40 years (p = 0.022) and induction dose ARA-C plus DNR (p = 0.029). In this analysis patients randomized to the 7-3-7 arm had an estimated 43% reduction in the relapse rate and each 10% reduction of doses ARA-C and DNR was associated with an estimated 45% increase in the relapse rate. The number of induction courses, delays in treatment and induction dose intensity did not significantly influence the duration of CR nor did any of the consolidation treatment parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of cytogenetic abnormalities in previously untreated patients with non-Hodgkin's lymphoma.

In this study cytogenetic findings have been correlated with prognosis in 78 previously untreated patients with non-Hodgkin's lymphoma (NHL) presenting between 1983 and 1988. The median follow-up was 7 years (range 2-9 years). There was no significant difference in the duration of survival of 33 patients with only abnormal karyotypes, 35 patients with a mixture of normal and abnormal karyotypes (AN) and 10 patients with only normal karyotypes (NN). This was true for the entire group (p = 0.6) as well as for the subsets of diffuse lymphomas (DL) and follicular lymphomas (FL) (p = 0.6 and 0.4, respectively). Monosomy 14 was the only abnormality in the entire group of patients to be associated with a statistically significant difference in survival duration (p = 0.046). Among the FL patients, trisomy 7 (p = 0.046) and trisomy 12 (p = 0.010) were associated with shorter survival. Presence of t(14;18) did not influence survival in the entire group (p = 0.16), nor in any of the histological subgroups. Among the FL patients with t(14;18), presence of additional cytogenetic abnormalities was not associated with a worse outcome. The lack of consistency of results between various studies is likely to be due to several factors and the prognostic significance of karyotypic abnormalities can only be clarified by large prospective studies employing uniform treatment policies.

A phase II trial of cisplatin and interferon alpha 2b in patients with advanced bladder cancer.

Twenty-two patients with advanced transitional cell bladder cancer were treated in a phase II trial exploring the possible synergy of cisplatin and interferon alpha 2b. Of the 20 evaluable patients, 7 (35%) had a partial response to the treatment, and only 6 patients were able to complete the full planned six cycles of treatment. Response rates, duration of responses, and overall survival of our patients are not superior to those expected by cisplatin alone.

A phase II study of cisplatinum and continuous infusion 5-fluorouracil for metastatic melanoma.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.

A phase II trial of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisolone rapidly alternating with doxorubicin and vincristine (CMFP/AV) in advanced breast cancer.

Sixty-seven patients with advanced breast cancer were prospectively entered into a Phase II trial of cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously (i.v.) on day 1, 5-fluorouracil 600 mg/m2 i.v. on day 1, and prednisolone 40 mg/m2 orally on days 1-14 (CMFP) rapidly alternating with doxorubicin 25-30 mg/m2 i.v. on day 8 and vincristine 1.4 mg/m2 i.v. on day 8 (AV). Complete responses (CR) were seen in 7 patients, partial responses (PR) in 25 (CR + PR, 48%), stable disease in 24, and progressive disease in 9. The median time to disease progression was 9.8 months, and the median survival 19.4 months. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia in 50% of patients. CMFP/AV is a well-tolerated, effective regimen in advanced breast cancer but does not appear to be superior to CMFP alone.

The occult head and neck primary: to treat or not to treat?

In patients with cervical node metastases from an unknown primary malignancy, there is unresolved controversy regarding the utility of elective irradiation of putative pharyngeal primary sites as part of the management plan. We analysed the experience of the Peter MacCallum Cancer Institute to assess the risk of withholding mucosal irradiation in relation to the diagnostic algorithm used to exclude a primary lesion at the time of initial presentation. Between 1983 and 1992, 69 patients were seen with metastatic squamous or undifferentiated carcinoma in cervical nodes from an unknown primary site. Neck nodal stage was NX or N1 13%; N2 52%; N3 35%. Nodal disease was bilateral in 12% of patients. Investigations included examination under anaesthesia, with or without random biopsies, in 84%, and CT scanning of the head and neck in 55%. Treatment was by surgery alone in four patients, by radiotherapy alone in 23, and by combined modalities in 40. Two patients received no treatment. Seventeen were treated with palliative intent. The radiotherapy fields provided comprehensive coverage of the pharynx in only eight patients and partial coverage in five. The estimated overall 5-year survival was 36%. Eleven primary tumours were detected between 7 months and 7 years after the initial treatment, of which nine were in head and neck sites. This yielded an estimated incidence of 30% at 10 years, which is similar to the risk of the development of a second primary after the successful treatment of a known head and neck cancer. Only three patients (none of whom had a CT scan as part of their initial evaluation) manifested a primary in an unirradiated pharyngeal site within 2 years of treatment. As the accuracy of imaging improves, the risk of missing an occult primary lesion will decrease further. We conclude that the use of standardized diagnostic investigations incorporating modern imaging substantially eliminates the indication for comprehensive elective mucosal irradiation with its consequent morbidity. The overriding priority in patients who present with advanced neck disease is to secure regional control.

The adequacy of consent forms for informing patients entering oncological clinical trials.

The impact on 100 patients of information and consent forms signed prior to medical oncology clinical trials was evaluated by a survey at a subsequent visit. Only 40 patients believed that the purpose of the form was to explain the treatment. The form was listed as the major source of information by 12 patients while 52 listed a doctor and 26 a nurse. Although 21 patients believed that the form mad them less anxious, 19 patients believed that it made them more anxious. Despite 80 patients reading all of the form, 60 claiming to understand all of it and 68 claiming that in contained adequate information, in tests of recall only 52 patients could name all of their drugs and only 4 all of the side effects. The number of drugs named correlated with how much of the consent form had been read (p = 0.003) and the highest education level achieved by the patient (p = 0.0003). Patients under 55 years had significantly better recall. Patients with a better ECOG performance status were more likely to find the form very helpful. Such forms may not ensure that the requirements for informed consent are satisfied.

Selection of patients for randomised trials: a study based on the MACOP-B vs CHOP in NHL study.

BACKGROUND: Selection of patients for a clinical trial is affected by awareness of the existence of the trial, interest in the study question and clinical practices and views of the clinicians. AIMS: To investigate the selectivity that may have occurred at Peter MacCallum Cancer Institute (PMCI) during the ANZ Lymphoma Group trial of MACOP-B vs CHOP in non-Hodgkin's lymphoma (NHL). METHODS: NHL patients at PMCI in the study period were assessed against the trial's eligibility criteria. Comparisons were made between eligible (except for consent) non-trial patients and all patients actually randomised into the trial. RESULTS: Of 497 patients presenting during the trial period, 320 (64%) did not meet the specified eligibility criteria, 102 (21%) were unsuitable on other grounds (age and medical) and 75 (15%) were eligible. Of those eligible, 43 (57%) were entered into the trial and 32 (43%) were not. Four non-trial patients had inappropriate application of eligibility criteria and 13 unknown reason. Eligible non-trial patients were similar to trial patients in most patient and tumour characteristics and overall survival. Significantly more non-trial patients had higher stage disease (p = 0.02). More non-trial patients had lower grade histology, but this was not significant. CONCLUSIONS: Physician selectivity occurred with respect to patient entry, but trial and non-trial patients were similar in most characteristics. Eligibility criteria should specify that patients can withstand all trial drugs and patient availability for treatment and follow-up. PMCI trial accural could have been up to 33% greater. These results suggest the trial accrual period could have been 25% shorter. Patient entry into this trial by PMCI clinicians compared favourably with other centres.

Oral methotrexate for superficial transitional cell carcinoma of the bladder.

A total of 22 patients with superficial transitional cell carcinoma of the bladder, uncontrolled cystoscopically and unsuitable for or having failed intravesical therapy, received 50 mg. oral methotrexate per week for 12 months. Of the patients 7 (32%) achieved or remained in complete remission and 5 achieved a partial response, while 4 remained stable, 3 had progression and 3 were not evaluable. Patients who were still alive had a median followup of 2.5 years. Two patients with complete remission had relapse at 16 and 26.4 months, and 5 were disease-free at 34.5, 31.3, 18.6, 17.8 and 16.8 months, respectively. The methotrexate was generally well tolerated but 2 patients discontinued therapy because of dyspnea (1 subsequently died of respiratory failure that was possibly related to the methotrexate) and 1 because of persistent grade 2 mucositis. Grade 3/4 toxicities occurred in 3 patients: 1 each with reversible increases in creatinine and aspartate aminotransferase, and 1 with gastric bloating. There was little hematological toxicity. Reversible skin lesions developed in 4 patients. This oral treatment may provide an effective alternative to intravesical therapy but can be associated with severe toxicity.

Australian Leukaemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma.

The Australian Leukaemia Study Group has performed a randomized trial of interferon alpha-2A (Roferon-A) as a co-induction agent together with intensive combination chemotherapy and as maintenance following completion of 12 cycles of induction treatment. When used as a co-induction agent, interferon-alpha did not improve response rates, time-to-treatment failure, or overall survival. Patients who had interferon together with intensive combination therapy (PCAB: prednisone 60 mg/m2 days 1-5, cyclophosphamide 600 mg/m2 day 1, BCNU 30 mg/m2 day 1, doxorubicin 30 mg/m2 day 1, repeated every 28 d for a total of 12 cycles) had more leucocyte and granulocyte toxicity and received a lower dose intensive of cytotoxic drugs than those patients who received PCAB without interferon. There was a trend towards prolongation of plateau phase which did not reach significance. Interferon, however, did improve the survival of patients who achieved plateau; for those patients interferon was associated with a 33% decrease in the rate of death after adjusting for initial beta-2 microglobulin level.