Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma.

PURPOSE: To assess myeloablative therapy with autologous bone marrow transplantation (ABMT) in younger patients with follicular lymphoma in the hope of prolonging remission duration and survival. PATIENTS AND METHODS: Since June 1985, 64 patients with follicular lymphoma have received cyclophosphamide (CY) 60 mg/kg x 2 and total-body irradiation (TBI) 2 Gy x 6 supported by ABMT as consolidation of second or subsequent remission. The marrow mononuclear cell (MNC) fraction was treated in vitro with three cycles of the monoclonal antibody (MAb) anti-CD20 and baby rabbit complement before cryopreservation. At the time of treatment, 34 patients were in complete remission (CR), and 30 had residual disease present. RESULTS: The median time to engraftment was 28 days (range, 15 to 46) for both a neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 20 x 10(9)/L. Engraftment did not occur in one patient who died at 12 weeks, and three patients (excluded from the range) have had delayed recovery (> 6 months) of RBCs and platelets. Fifty two patients are alive; three died as a consequence of the transplant procedure, two died in remission from other causes, and seven died of recurrent lymphoma. There was a significant correlation between survival and the total number of episodes of treatment required during the course of the illness (< or = to three v > three, P = .01). With a median follow-up duration of 3 1/2 years, 35 patients continue in remission between 1 and 8 years, and 24 have developed recurrent lymphoma, five with evidence of transformation to high-grade histology. Freedom from recurrence did not correlate with the time from diagnosis, the number of previous treatments, the presence or absence of residual disease at the time of treatment, or during which specific remission the treatment was given (second v > second). However, comparison with an age-matched, remission-matched, historical control group shows a significant advantage in favor of treatment with CY plus TBI plus ABMT (P = .001); currently, there is no difference in survival. CONCLUSION: These results are encouraging, although preliminary; it remains to be established whether this treatment prolongs survival.

Preoperative radiotherapy for esophageal carcinoma.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: MEDLINE and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in MEDLINE, EMBASE and the Cochrane Library on 30th April 2001, two years after original publication. No new trials were found. The search strategy was re-run August 2002 and August 2003 on MEDLINE, EMBASE , CancerLit and The Cochrane Library, and July 2004 and 2005 on MEDLINE, EMBASE and the Cochrane Library. No new relevant trials were identified on any of these occasions. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. AUTHORS' CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Oat cell carcinoma of esophagus: a report of six British patients with a review of the literature.

This paper presents 6 British patients with a diagnosis of oat cell carcinoma of the esophagus. Sixty-six patients have previously been reported in the literature, the majority (30) being British. Approximately two-thirds of these tumors have been reported as pure oat cell carcinoma of the esophagus. Four other histological patterns have been described: oat cell carcinoma with squamous carcinoma in situ; oat cell carcinoma with squamous carcinoma; oat cell carcinoma with adenocarcinoma; and oat cell carcinoma with carcinoid differentiation. A preponderance of males has also been noted, although this series shows a 2:1 female:male ratio. The tumor arises most commonly in the mid or lower esophagus. The cell of origin of these tumors in considered to be the Kulchitsky or APUD cell of neuroectodermal derivation. They may show neurosecretory granules on electron microscopy. Polypeptides have been identified within the tumor cells. One previous report describes a patient with primary oat cell carcinoma of the esophagus and hypercalcemia. A patient with the syndrome of inappropriate anti-diuretic hormone secretion is described in this paper. Survival is poor following radiotherapy, with a median survival of 3 months in this series. On reviewing the records of the Radiation Oncology Unit in Edinburgh, no patient with oat cell carcinoma of the esophagus was reported before 1972. This suggests that awareness of this tumor is increasing and, although rare, its incidence is greater than previously reported.

An evaluation of fast neutron irradiation in the treatment of squamous cell carcinoma in cervical lymph nodes.

Analyses have been made of the response of metastatic cervical lymph nodes following neutron therapy, either as part of a randomized trial or in patients treated electively. In the trial patients, the overall regression and local control rates were similar after photons and neutrons. Mobile nodes, less than 3.0 cm, appeared to respond better to neutron therapy, and node masses greater than 3.0 cm had better control after photon therapy. The differences observed however were not statistically significant. There was a highly significant association between the control of the primary tumor and control of nodal disease. No survival advantage for neutrons was observed in association with apparently better control rates in cervical nodes.

A report of a randomized trial of d(15)+Be neutrons compared with megavoltage X ray therapy of bladder cancer.

The results of a randomized trial of d(15)+Be neutrons compared with 4 or 6 MV photons for the treatment of transitional cell carcinoma of the bladder. Between December 1978 and December 1981, 113 patients were accrued, 53 allocated to be treated by neutrons and 60 by photons. Complete local tumor regression was observed in 64% of patients treated by neutrons and 62% treated by photons. Recurrent cancer was subsequently confirmed in 31% of patients, similar in both treatment groups. There was no significant difference in the control rates by T stage between the two treatment groups. Late morbidity was significantly worse in patients treated by neutrons. Following neutron therapy, 78% of patients had serious late morbidity in at least one tissue compared with 38% in the group treated by photons. Survival was significantly better in the photon treated group 45.3% (+/- 11%) at 5 years compared with 12% (+/- 6%) after neutron therapy.

An analysis of the radiation related morbidity observed in a randomized trial of neutron therapy for bladder cancer.

This report is an analysis of the morbidity in the bladder and bowel observed in a randomized trial of d(15)+Be neutrons versus megavoltage photons in the treatment of bladder cancer. Acute reactions in the bladder and bowel were significantly worse after photon therapy. Of the patients treated with photons 45.7% had severe reactions in the bladder compared with 10.6% after neutron therapy (p less than 0.001). Severe acute bowel reactions were observed in 8.5% of the patients after photon therapy compared with 3.8% after neutron therapy (p less than 0.05). Late reactions were significantly worse after neutrons. Severe late reactions in the bladder were seen in 58.5% of patients after neutron therapy and in 40.5% after photon therapy (p less than 0.05). In the bowel they were observed in 53.3% of patients after neutron therapy compared with 8% after photon therapy (p less than 0.0001). The disparity in the degree of early and late complications makes assessment of RBE values difficult. It is estimated that for bladder morbidity the RBE value, for photon dose fractions of 2.75 Gy, is less than 3.3 for early reactions and equal to 3.4 for late effects. The respective RBE values for early and late effects in the bowel are less than 3.4 and 3.8.

Fast neutron therapy for squamous cell carcinoma in the head and neck region: results of a randomized trial.

A randomized trial of fast neuron therapy compared with 4MV photons for patients with head and neck cancer is reported. One hundred and sixty-eight patients were recruited between 1977 and 1984. The minimum follow-up is 2 years. Three patients were withdrawn before treatment began. Eighty-five were allocated to neutron therapy and 80 to receive photon therapy. All patients had squamous cell cancers in one of four primary sites: oral cavity, oropharynx, larynx, and hypopharynx. Local tumor control was similar in both groups: 44.7% after neutrons and 45.0% after photons. Salvage surgery was performed on 18 patients in each treatment group for residual or recurrent cancer. Acute radiation reactions of the mucous membranes were significantly more severe after photons. The number of patients with serious late reactions was greater after neutron therapy but the difference was not statistically significant. There were six deaths related to late morbidity after neutron therapy but none after photon therapy. Survival was better after photon therapy but the difference compared with the neutron group failed to reach statistical significance. When intercurrent deaths are excluded, the difference is less marked. Photon therapy was clearly better in terms of disease-free survival giving a 2-year local disease-free rate of 41.3% (s.e. 5.5%) compared with 29.4% (s.e. 4.9%) after neutrons.

Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group).

PURPOSE: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. METHODS AND MATERIALS: This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. RESULTS: With a median follow-up of 9 years, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p = 0.062). No clear differences in the size of the effect by sex, age, or tumor location were apparent. CONCLUSION: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-->20%).

Neutron therapy for malignant tumours of the salivary glands. A report of the Edinburgh experience.

A group of 28 patients with malignant tumours of the salivary glands have been treated by d(15) + Be neutron irradiation. Nineteen patients had inoperable cancers. Three had gross recurrent cancer and three had measurable residual cancer after surgery. Three patients were treated post-operatively for microscopic residual disease. Seven different histological types of tumour were included. Six out of 8 patients with adenoid cystic carcinomas have lasting local tumour control. 54.5% of the gross tumours were locally controlled. All three of those classified as microscopic residual disease have no evidence of local recurrence. 11/14 cancers given 16.0 Gy or more in 20 fractions in 4 weeks were controlled compared with only 1/8 given a lower dose. 12/19 cancers less than 10.0 cm maximum diameter were controlled. The radiation-related morbidity was similar to that observed after photon therapy.

Fast neutrons in the treatment of head and neck cancers: the results of a multi-centre randomly controlled trial.

The results are presented of a multi-centre randomly controlled trial of fast neutron irradiation and mega-voltage X-rays in the treatment of patients with locally advanced squamous cell carcinoma of the head and neck region. No significant difference was observed in local tumour control rates. Salvage surgery was performed in a similar number of patients in the two groups. Late morbidity was also similar in the two treatment groups. Patients in a subgroup with cancer of the larynx treated by photons had a significantly better survival than those in the neutron treated group.

Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial.

One-hundred-and-seventy-six patients with potentially operable squamous cell carcinoma or adenocarcinoma of the middle or lower thirds of the oesophagus were randomly assigned to preoperative radiotherapy or surgery alone. Patients assigned to the radiotherapy arm received 20 Gy in 10 treatments over 2 weeks, using parallel opposed 4 MV beams. The preoperative radiotherapy was not associated with any significant acute morbidity or any increase in operative complications. The median survival of the overall group of 176 patients was 8 months, and the 5-year survival was 13%. There was no significant difference in the survival of the 90 patients who received preoperative radiotherapy and the 86 who were managed by surgery alone. Proportional hazards analysis identified lymph node involvement, high tumour grade and male sex as significant adverse prognostic features, but the treatment option assigned had no prognostic significance. It was concluded that low dose preoperative radiotherapy offered no advantage over surgery alone.

Carcinoembryonic antigen as a prognostic indicator in the radiotherapeutic management of rectal cancer.

Carcinoembryonic antigen (CEA) levels have been assessed retrospectively in a group of 32 patients with inoperable or recurrent carcinoma of the rectum treated with radiotherapy. Complete clinical regression of pelvic disease was only achieved in patients with pre-treatment CEA levels less than 30 ng/ml when no metastases were present. Pre-treatment CEA assay has a place as a prognostic indicator in the radiotherapeutic management of inoperable or recurrent carcinoma of the rectum.

Treatment of advanced carcinoma of the vulva with chemoradiotherapy - can exenterative surgery be avoided?

Thirty-seven patients with advanced FIGO stage (17 stage III, 20 stage IV) carcinoma of the vulva whose extent of disease would have required extenterative surgery were treated with chemoradiotherapy (CRT). Radiotherapy was given as a split course (2500 cGy mid-plane dose in 10 daily fractions, repeated 1 month later) to the first seven patients. Subsequently radiotherapy was given as a continuous course (4500 cGy mid-plane dose in 20-25 daily fractions). Chemotherapy included mitomycin c as an intravenous bolus and 5 fluorouracil as a continuous intra-venous infusion over 4-5 days, with variations in timing and dose according to the type of radiotherapy course. Fifteen (47%) complete and 11 (34%) partial responses were seen at 3 months after completion of treatment. Of the 15 patients with complete response, 10 remained disease-free for a median of 24 months (range 6-36 months). The median sur-vival for complete and partial responding patients was 15 and 11 months, respectively (range 2-37 months). Acute toxicity included moist perineal desquamation, diarrhea and myelosupression. One death secondary to neutropaenic sepsis occurred in the split course group. WHO grade 3 radiation enteritis occurred in one patient (14%) in the split course and two patients (6%) in the continuous CRT groups. Using CRT, very high response rates have been obtained with relatively low toxicity. There is a useful role for CRT in the treatment of patients with locally advanced recurrent disease although its place in the management of extensive primary disease requires further evaluation.

Tarsal metastases in a patient with rectal cancer.

Bone metastases from colorectal cancer are uncommon and usually present late in the natural history of metastatic disease. This case report describes a 48-year-old man who developed an unusual distribution of bony metastases with multifocal osteolytic tarsal metastases 50 months after excision of a rectal carcinoma. An open biopsy was required to establish the diagnosis, exclude osteomyelitis and allow palliative radiotherapy to be given.

A phase I study of mixed (neutron and photon) irradiation using two fractions per day in the treatment of high-grade astrocytomas.

A Phase I study of the treatment of 50 patients with high-grade astrocytomas by mixed schedule (neutron and photon) irradiation given in 12 fractions over 4 weeks is reported. The neutron and photon fractions were separated each day by 2-3 h. A total neutron dose of 6.36 Gy (8% gamma) and 20.40 Gy of photons was prescribed. Treatment was well tolerated and there was no clinical evidence of radiation-related morbidity in the brain. The median survival was 6.9 months, similar to that expected after photon irradiation alone. A multivariate analysis of prognostic variables in presented.

Report of a randomised pilot study of the treatment of patients with supratentorial gliomas using neutron irradiation.

A randomised pilot study is reported of d(15)+Be neutrons compared with 4 MV photons in the treatment of patients with astrocytoma. Sixteen patients were treated by photons and 18 by neutrons. Both treatments were well tolerated by patients. The median survival after photons was 11 months and after neutrons, 7 months. It was demonstrated that four of nine patients treated by neutrons had evidence at autopsy of radiation-induced brain damage. All had residual cancer. No patient treated by photons had signs of radiation-related morbidity. The trial was, therefore, discontinued prematurely.

The results of a randomised trial of mixed-schedule (neutron/photon) irradiation in the treatment of supratentorial Grade III and Grade IV astrocytoma.

A randomised trial is reported of mixed-schedule (neutron/photon) irradiation compared with photon therapy for patients with Grade III or Grade IV astrocytoma. Thirty-one patients were allocated to be treated by the neutron/photon regime and 30 patients by photons. The median survival was 4 months in the mixed-schedule group and 8 months in the photon group. The survival rates were not significantly different. All patients who died had evidence of residual brain tumour. None had signs of radiation-related morbidity.

Preoperative radiotherapy for esophageal carcinoma.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in Medline, Embase and the Cochrane Library on 2nd May 2000, one year after original publication. No new trials were found. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Preoperative radiotherapy for esophageal carcinoma. Oeosphageal Cancer Collaborative Group.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Successful chemoradiotherapy for anal cancer despite previous radical radiotherapy for gynaecological malignancy.

Repeat radical irradiation of the pelvis is generally not undertaken because of concerns regarding normal tissue damage; in particular to small bowel, bladder and bone. Two patients with carcinoma of the anal canal are presented who had previously been treated by radical pelvic radiotherapy for gynaecological malignancy. Both were re-treated with radical radiotherapy to the pelvis with concomitant chemotherapy. A complete remission of anal cancer was achieved in both patients with minimal acute and late toxicities.