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M H Cullen

Publications and source records attributed to M H Cullen.

At least 19 recordsLinked to original sources
PubMed1998

A phase II trial of preoperative mitomycin, cisplatin and 5-fluorouracil in adenocarcinoma of the oesophagus.

The effect of neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus has been investigated. Two courses of mitomycin, cisplatin and 5-fluorouracil (MCF) were given, followed by a radiological evaluation of response. Twenty-two of 25 patients completed both courses. Two showed a complete response and 12 a partial response. There was a pathological complete response of the primary tumour in only one patient (although there was residual secondary tumour in a local lymph node). The main toxicity was myelosuppression, with 9/22 patients having the second chemotherapy course delayed. There were three sudden deaths, one due to a pulmonary embolus and two due to complications of infections. Twenty-one patients underwent surgical exploration; there were 18 resections. Although the radiological response rate of MCF (14/25; 56%; 95% CI 37-75) appeared promising, there were no pathological complete responders. Further Phase II trials are needed to identify more efficacious agents and regimens that will yield a pathological response rate of at least 10%, before proceeding to randomized trials of neoadjuvant chemotherapy for adenocarcinoma of the oesophagus.

Adenocarcinoma↗
PubMed1998

A phase II trial of four courses of preoperative chemotherapy in squamous or anaplastic carcinoma of the oesophagus.

We have reported the results of a previous Phase II trial of two courses of neoadjuvant mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2) (MIC) in squamous or anaplastic carcinoma of the oesophagus. In this current study, we have investigated whether there was any clinical benefit in extending the preoperative treatment to four courses for patients who responded after two courses. Response was assessed by barium swallow, which was compared with previous barium swallows performed prior to any treatment and after the second course of MIC. Of an initial 43 patients, 27 (63%) were assessed as responders after two courses of MIC. Twenty of these 27 patients were entered into the study with a view to receiving two further courses of MIC prior to surgery. Seventeen completed four courses. Five patients were complete responders after two courses and remained complete responders after four courses. Twelve patients were partial responders after two courses; six of these became complete responders after four courses, five remained partial responders, and one showed progression. Haematological toxicity and alopecia were increased after extending the number of courses beyond two. On pathological assessment, three patients with a complete response after four courses, and one with a complete response after three courses, had microscopic clearance of tumour. Extension beyond two courses of neoadjuvant MIC gives an improvement in response, as judged by barium assessment, but increases toxicity, cost of treatment and delay before surgery. Although the numbers are small, the results suggest that a worthwhile improvement in the radiological response of squamous or anaplastic oesophageal tumours may be gained by proceeding beyond two courses of MIC. A randomized trial, with larger numbers of patients, is needed to show whether there is any improvement in radiological and pathological response rates and in survival to be gained by the extension of treatment beyond two courses.

Adult↗
PubMed1998

A phase II trial of cisplatin and 5-fluorouracil in adenocarcinoma of the oesophagus.

The effect of brief neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus has been investigated. Two courses of cisplatin and 5-fluorouracil (CFu) were given, followed by evaluation of the response by barium swallow. Twenty-one of 23 patients completed both courses. Two showed a complete response and five a partial response. In only one patient was there a pathological complete response. Toxicity was mild and consisted principally of nausea and vomiting. All patients underwent surgical exploration; resection was completed in 17. There were three hospital deaths (18%). Although CFu has produced two complete responses (on barium swallow) and one complete pathological clearance of tumour, the disappointing total response rate of 7/21 (33%; 95% CI 13-53) or 7/23 (30%; 95% CI 12-49) leads us to believe that further Phase II trials are needed to identify more efficacious agents and regimens.

Adenocarcinoma↗
PubMed1998

Five-year follow-up of a prospective randomised multi-centre trial of weekly chemotherapy (CAPOMEt) versus cyclical chemotherapy (CHOP-Mtx) in the treatment of aggressive non-Hodgkin's lymphoma. Central Lymphoma Group.

BACKGROUND: Weekly alternating regimen known as CAPOMEt is compared to standard cyclical chemotherapy (CHOP-Mtx) in aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Three hundred and eighty-one patients with aggressive NHL were randomised to receive either cyclophosphamide, doxorubicin, vincristine, prednisone and methotrexate (CHOP-Mtx) on a cyclical basis or a weekly regimen incorporating the same drugs with the addition of etoposide (CAPOMEt). RESULTS: After pathological review, 281 patients were deemed eligible. At the census date of 31 March 1994, 158 patients were alive with a median follow up of 5.9 years (minimum 3.0 years). Analysis of all patients and eligible patients showed no significant treatment differences in the rates of complete remission (CR), failure free survival (FFS) or overall survival (OS) between the two arms. The actuarial median OS was 24 months for CAPOMEt compared with 31 months for CHOP-Mtx, with five-year actuarial survival rates of 37% and 43%, respectively. Myelosuppression was significantly more severe with CHOP-Mtx and neurotoxicity was much more common with CAPOMEt. CONCLUSION: Weekly CAPOMEt is equally effective as standard cyclical CHOP-Mtx treatment in aggressive NHL.

Adolescent↗
PubMed1998

Primary chemotherapy after orchidectomy for stage I and II nonseminoma.

The effectiveness of combination chemotherapy in advanced germ cell cancer has led to re-evaluation of treatment approaches in early disease. For patients with stage I nonseminoma it became possible to contemplate an observation policy, relying on chemotherapy to rescue those who relapsed. Subsequently it has been shown that two cycels of adjuvant chemotherapy can prevent relapse in those at high risk. For patients with stage II nonseminoma, a policy of primary chemotherapy postorchidectomy leads to high cure rates, with avoidance of retroperitoneal lymph node dissection, and only a minority of patients requiring lymphadenectomy. The excellent prognosis of these patients increases the importance of minimising risks of any long-term treatment toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Prognostic factors for patients with advanced seminoma treated with platinum-based chemotherapy.

Prognostic factors for 3-year progression-free survival (PFS) were defined in 286 patients with advanced seminoma treated with cisplatin-based chemotherapy at 10 European oncology units (no prior treatment: 236; prior radiotherapy: 50). Previously irradiated patients displayed a 69% PFS as compared to 87% in those presenting with advanced seminoma at the time of diagnosis (P = 0.009). In the univariate analysis, the extent and site of disease before chemotherapy and the level of serum LDH (< 2.0 versus > or = 2.0 x upper limit of normal) correlated with PFS in previously non-irradiated patients, but not in patients with prior radiotherapy. The multivariate analysis was, therefore, restricted to previously non-irradiated patients. The presence of non-pulmonary visceral metastases and a serum LDH level of > or = 2 x normal (N) proved to be independent prognostic factors. Based on these variables, two prognostic models were constructed and validated in an external data set of 166 comparable patients. For clinical use, Model 2 is recommended. The good-prognosis group comprises non-irradiated patients with stage II seminoma and any LDH level at presentation, or stage III and IV patients (with lung metastases only) whose serum LDH level is < 2 x N. These patients display a 94% 3-year PFS. The poor prognosis group includes all other patients with a 56% PFS. With this prognostic model, individualisation of the therapeutic approach may be considered in patients with advanced seminoma and a high risk of chemotherapy-related toxicity.

Adult↗
PubMed1997

Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party.

In a retrospective study, data from 302 patients with metastatic testicular seminoma treated with chemotherapy between 1978 and 1990 in 10 European centres were analysed to evaluate the role, if any, of postchemotherapy treatment with irradiation. The primary endpoint of this study was the progression-free survival rate after chemotherapy with or without additional radiotherapy. This was related to the type of primary chemotherapy, sites and sizes of pre- and postchemotherapy masses, the extent of surgical resection after chemotherapy and the use of radiotherapy. 174 patients had residual disease at the end of chemotherapy. The most important prognostic factors for progression were the presence of any visceral metastases or raised LDH prechemotherapy, and the presence of residual disease at visceral sites after chemotherapy. Approximately half the patients with residual masses underwent postchemotherapy radiotherapy, with selection based predominantly on institutional practice. In patients receiving platinum-based chemotherapy, no significant difference was detected in progression-free survival whether or not radiotherapy was employed. Patients receiving BEP (bleomycin, etoposide and cisplatin) had a progression-free survival rate of 88% (95% CI, 80-96%) uninfluenced by postchemotherapy radiotherapy. In patients with residual masses confined to the abdomen after platinum-based chemotherapy, the absolute benefit to radiotherapy was estimated to be 2.3%. The potential benefit of postchemotherapy radiotherapy is minimal, and so it is concluded that the use of adjuvant radiotherapy to residual masses after platinum-based chemotherapy for metastatic seminoma is unnecessary.

Abdominal Neoplasms↗
PubMed1997

Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial.

PURPOSE: This prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors. PATIENTS AND METHODS: Between September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles. RESULTS: Of patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response, compared with 227 of 260 (87.3%) allocated to receive CEB (P = .009). There were 30 treatment failures in the 300 patients allocated to BEP and 79 in the 298 allocated to CEB (log-rank chi 2 = 26.9; P < .001), which led to failure-free rates at 1 year of 91% (95% confidence interval [CI], 88% to 94%) and 77% (95% CI, 72% to 82%), respectively. There were 10 deaths in patients allocated to BEP and 27 in patients allocated to CEB (log-rank chi 2 = 8.77; P = .003), which led to 3-year survival rates of 97% (95% CI, 95% to 99%) and 90% (95% CI, 86% to 94%), respectively. CONCLUSION: With these drug doses and schedules, combination chemotherapy based on carboplatin was inferior to that based on cisplatin. This BEP regimen that contains moderate doses of etoposide and bleomycin is effective in the treatment of patients with good-prognosis metastatic nonseminoma.

Adult↗
PubMed1996

A phase I trial to assess the value of recombinant human granulocyte colony stimulating factor (R-MeTHuG-CSF, filgrastim) in accelerating the dose rate of chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma (NHL). The Central Lymphoma Group.

In a multi-centre phase I study we investigated the possibility of reducing the interval between courses of standard CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mgs day 1, and prednisolone 40 mg/m2 days 1-8) from 21 days to 15 days and then 10 days using granulocyte colony stimulating factor (r-MetHuG-CSF (Amgen)-filgrastim) to accelerate neutrophil recovery. Patients received CHOP followed by G-CSF 5 micrograms/kg s.c. from day 2 to the day before the next course (e.g. days 2-14 for the 15-day interval). A total of 28 patients with newly diagnosed intermediate grade or high grade NHL were studied. Four patients were studied at a 21-day interval, six patients were treated at a 15-day interval and subsequently six patients at a 10-day interval. Following analysis of this initial cohort, a further 12 patients were evaluated; four at the 15-day interval, and eight at the 10-day interval. No dose-limiting toxicity was seen in the four patients receiving 21-day CHOP. Dose-limiting toxicity was seen in 4/10 patients treated at the 15-day interval (M:F 7:3, median age 55.5, range 39-67 years). This consisted of infection in two patients, recurrent infection and debility in a third, and mucositis in a fourth. Seven patients experienced one or more infectious episodes requiring antibiotics (median number of episodes: 2, range 1-4). Fourteen patients (M:F 4:3, median age 47.5, range 25-63 years) were treated at the 10-day interval. Dose-limiting toxicity was seen in six patients. This consisted of severe mucositis in three patients, neutropenia and thrombocytopenia on two separate occasions in one patient, and steroid-induced gastritis in two patients. Nine patients had one or more documented infections (median: 2, range 1-3) requiring antibiotics, of which six were severe (WHO grade 3 or 4). One patient died of Pneumocystis carinii (PCP) pneumonia. In summary, G-CSF (filgrastim) will facilitate the shortening of the dosage interval between cycles of CHOP chemotherapy due to accelerated hematological recovery. However, non-hematological toxicity due to the shorter dosage interval is increased and infective episodes are frequent.

Adult↗
PubMed1996

Phase II study of mitomycin, ifosfamide and cisplatin in adenocarcinoma of the oesophagus.

We evaluated the effect of brief neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus. Two courses of mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2;MIC) were given followed by evaluation of response by barium swallow and computed tomography scan. Of 20 patients, 17 completed both courses and 4 (20%) showed a partial response. Toxicity was generally mild and consisted principally of nausea and vomiting. Altogether, 15 patients were surgically explored; resection was completed in 12 patients, 3 of whom died in hospital (25%). Neoadjuvant therapy with MIC offers no advantage over surgery alone.

Adenocarcinoma↗
PubMed1996

Alpha-foetoprotein heterogeneity: what is its value in managing patients with germ cell tumours?

Alpha-foetoprotein (AFP) is widely used in the diagnosis, therapeutic monitoring and follow-up of patients with germ cell tumours. On occasion, the interpretation of a raised serum AFP measurement in a patient is confounded by the fact that AFP also increases in a variety of liver and gastrointestinal diseases. AFP exists as a number of isoforms, which can be separated by their differential binding to plant lectins. Thus, AFP-concanavalin A (ConA) binding affords a means of distinguishing between a raised AFP of teratoma or liver aetiology and has recently been reported to possess sensitivity and specificity approaching 100%. We present a patient in whom column chromatographic ConA binding was used as a basis for clinical management decisions for treatment for relapsed germ cell testicular tumour. The presumption of high test specificity led to a delay in the diagnosis of cancer recurrence, from which the patient ultimately died. We conclude that the clinical utility of lectin binding assays currently remains uncertain and further evaluation is warranted.

Adult↗
PubMed1996

Management preferences in stage I non-seminomatous germ cell tumours of the testis: an investigation among patients, controls and oncologists.

Increasingly, treatment choices leading to the same survival outcome can be offered to cancer patients (e.g. mastectomy or conservative surgery in early breast cancer). Two approaches available for post-orchidectomy, stage I patients with non-seminomatous germ cell tumours of the testis (NSGCTT), particularly those at high risk of relapse, include immediate adjuvant chemotherapy (two courses) or surveillance, with chemotherapy (typically four courses) given only on relapse. The aim of this study was to investigate which approach patients prefer. Questionnaires were given to newly diagnosed NSGCTT patients, to patients with previous experience of the two options and to non-cancer controls, including specialist testicular tumour oncologists. Participants were asked to choose between immediate chemotherapy, surveillance or for the doctor to decide, at recurrence risk levels ranging from 10% to 90%. Questionnaires were returned by 207 subjects in nine different groups. The risk thresholds at which subjects' management preference changed, within apparently homogeneous groups, varied greatly, although at least one subject in each group selected adjuvant chemotherapy at the lowest (10%) level of risk. Subjects tended to favour options of which they had previous experience. Cancer patients wanted the doctor to decide more frequently than controls. The wide variability observed makes it difficult to predict which option an individual will select. Personality factors and personal circumstances, other than specific experience and knowledge, are obviously influential. Many patients would prefer their doctor to decide, but variability among oncologists is as great as that among their patients.

Chemotherapy, Adjuvant↗
PubMed1996

Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report.

PURPOSE: This United Kingdom Medical Research Council (UK-MRC) study prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT). PATIENTS AND METHODS: Eligible patients were those identified by the local histopathologist as having features confirmed in MRC surveillance studies to indicate an approximate 50% risk of relapse. Central histopathology review was undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2, bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP). RESULTS: One hundred fourteen eligible cases were enrolled. Median time of follow-up was 4 years, with 93 patients followed-up for at least 2 years. There have been two relapses, including one patient who did not have a germ cell tumor (GCT), according to the reference histopathologist. This patient is alive with active disease, the other has died. There was one death after a cerebrovascular accident during treatment. Assessment of fertility, lung function, and audiometry pretreatment and more than 9 months posttreatment indicated no clinically significant changes. A mean decrease in transfer factor coefficient (KCO) of 15% of the predicted value was noted, but no patient had symptomatic respiratory dysfunction. CONCLUSION: There have been only two relapses among 114 cases of high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy. The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of 104 patients confirmed on histopathology review to have GCT, there has been only one relapse. Adjuvant chemotherapy is free from significant long-term toxicity, offering an effective alternative to surveillance or retroperitoneal lymph node dissection (RPLND) followed by surveillance, and may be preferred by some patients.

Adult↗
PubMed1995

Trials with mitomycin, ifosfamide and cisplatin in non-small cell lung cancer.

In 1988, we reported a Phase II study of mitomycin, ifosfamide and cisplatin (MIC) in inoperable non-small cell lung cancer. The overall objective response rate was 56% in 66 evaluable cases. An improvement in performance status was observed in responding patients and toxicity was acceptable. Consequently we then embarked upon two major, multicentre randomised trials to test this regimen in cases with localised disease (MIC 1--chemotherapy plus radical radiotherapy versus radical radiotherapy alone) and advanced disease (MIC 2--chemotherapy plus palliative care versus palliative care alone). These trials are still in progress with targets of 500 and 300 randomised cases, respectively. The present interim analysis is based on 317 cases randomised in MIC 1 and 193 in MIC 2. The overall response rate (CR + PR) in the MIC 1 trial is 52% with 10% CRs and in the MIC 2 trial is 42% with 5% CRs. Formal symptomatic assessments are monitored in both trials and the present interim analysis indicates symptom improvement in cases randomised to chemotherapy, including patients who fail to achieve an objective PR or CR. Other Phase II studies employing MIC are also reviewed.

Adult↗
PubMed1995

Weight gain as an indicator of response to chemotherapy for oesophageal carcinoma.

Patients with oesophageal carcinoma commonly present with dysphagia and weight loss, which may be related to the tumour burden and/or the physical obstruction to the passage of food. In this study we have examined the relationship between weight change and response to chemotherapy in 28 patients undergoing neo-adjuvant chemotherapy for squamous or anaplastic carcinoma. Two pulses of mitomycin, ifosfamide and cisplatin were given 3 weeks apart. Body weights were measured prior to the first pulse and 3 weeks after the second. Patients underwent oesophageal dilatation routinely at diagnostic endoscopy prior to chemotherapy, in order to permit oral nutrition. No dietary modifications were made. Tumour response was assessed on a barium swallow. Patients had a normal spread of weights on presentation. In the non-responding group (n = 9), eight patients lost weight and one gained weight. Of the partial responders (> 50% tumour shrinkage; n = 11), five gained weight, five lost weight and one remained constant. In the complete response group (n = 8), six gained weight and two lost weight. Statistical analysis showed a significant difference (F = 4.61; P = 0.02) between change in weight expressed as a percentage of ideal weight in nonresponders (mean -5.3%) versus partial responders (mean +2.4%), and in non-responders versus complete responders (mean +1.1%). Weight gain during chemotherapy is a good indication of response, although its absence does not preclude a response. In the majority of patients who respond to chemotherapy there will be an increase in weight with improvement in their general condition prior to operation.

Adult↗
PubMed1995

Adjuvant and neo-adjuvant chemotherapy in non-small cell carcinoma.

BACKGROUND: There have been many trials investigating the influence of chemotherapy on survival following surgery or radiotherapy in non-small cell lung cancer. Few have been large enough to detect the sort of differences likely to emerge, given the limited efficacy of chemotherapy. The technique of meta-analysis using individual patient data can allow worthwhile conclusions to be derived from the contradictory data generated by multiple small trials. This paper summarizes published data from randomized trials testing: (1) adjuvant chemotherapy following 'curative' surgery; (2) neoadjuvant chemotherapy prior to surgery in cases of borderline operability; (3) chemotherapy in inoperable, but still localized, disease where standard therapy would be radical radiotherapy. CONCLUSION: All the indications are that combinations including cisplatin confer a small, but real, prolongation of survival. However, meta-analysis is not a substitute for individual trials large enough to detect clinically important differences in survival. Other worthwhile endpoints like symptom control, quality of life and cost cannot be addressed in a meta-analysis. Large, well designed and executed randomized trials are still urgently needed if more time and money is not going to be wasted in the search for better treatments in lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

A phase II study of mitomycin, ifosfamide and cisplatin in operable and inoperable squamous cell carcinoma of the oesophagus.

We have evaluated the effect of mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 (MIC) in two groups of patients with squamous or undifferentiated carcinoma of the oesophagus, as either preoperative or primary treatment. Response was assessed by barium swallow, CT scan, and measurement of metastases where present. Toxicity was acceptable and there were no chemotherapy related deaths. In the operated group, five of 23 patients (22%) showed a complete response (three confirmed histologically) and nine (39%) showed a partial response following two courses of MIC. Resection was completed in 21 patients, with three hospital deaths (14%). Of the 18 patients who were discharged from hospital, eight have died at 4-24 months (median 13) from the start of treatment and 10 are alive at 5-35 months, with known recurrence in one. In the non-operated group, five of 20 patients (25%) showed a response, one complete, following one to four (mean 2.6) courses of MIC. Nineteen patients have died (at median 5 months), and one, who had a complete response, is alive and free from disease at 29 months. Neo-adjuvant therapy with MIC in squamous carcinoma of the oesophagus has shown encouraging early results, with acceptable toxicity.

Aged↗