T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity.

PURPOSE: Although it has proven difficult to delineate diagnostically reproducible and clinically relevant subgroups, the heterogeneity of diffuse large B-cell lymphomas (DLBCL) is widely acknowledged. In 1992, we reported on six cases that suggested that large B-cell lymphoma rich in stromal histiocytes and T cells may be identified as a distinct clinicopathologic entity within DLBCL. PATIENTS AND METHODS: An integrated clinicopathologic study of 40 cases of this DLBCL subtype is presented. RESULTS: Distinguishing a DLBCL rich in histiocytes and reactive T cells, designated T-cell/histiocyte--rich large B-cell lymphoma (THR-BCL), may be justified from a clinical point of view. The disease typically affects middle-aged male patients who usually present with advanced-stage disease that is not adequately managed with current therapeutic strategies. Whereas proliferation fraction and p53 overexpression, in addition to the clinical variables incorporated in the International Prognostic Index (IPI), significantly correlate with response to treatment and survival in a univariate analysis, only the IPI score identifies relevant prognostic THR-BCL subpopulations in a multivariate model. The morphologic and immunophenotypic profile of the neoplastic B cells in THR-BCL suggests that they may originate from a germinal center ancestor. CONCLUSION: THR-BCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. Experimental therapeutic strategies may be indicated to obtain a more favorable response to treatment in this disease.

Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin's lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods?

PURPOSE: A complete remission (CR) after first-line therapy is associated with longer progression-free survival (PFS). However, defining CR is not always easy because of the presence of residual masses. Metabolic imaging with fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) offers the ability to differentiate between viable and fibrotic inactive tissue. In this study, we evaluated the value of PET in detecting residual disease and, hence, predicting relapse after first-line treatment in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Ninety-three patients with histologically proven NHL, who underwent a whole-body [18F]FDG-PET study after completion of first-line chemotherapy and who had follow-up of at least 1 year, were included. Persistence or absence of residual disease on PET was related to PFS using Kaplan-Meier survival analysis. RESULTS: Sixty-seven patients showed a normal PET scan after first-line chemotherapy; 56 of 67 remained in CR, with a median follow-up of 653 days. Nine of these patients with a residual mass considered as unconfirmed CR received additional radiotherapy. Only 11 of 67 patients relapsed (median PFS, 404 days). Persistent abnormal [18F]FDG uptake was seen in 26 patients, and all of them relapsed (median PFS, 73 days). Because standard restaging also suggested residual disease, 12 patients received immediate secondary treatment. In 14 of 26 patients, only PET predicted persistent disease. From these patients, relapse was proven either by biopsy (n = 8) or by progressive disease on computed tomography or magnetic resonance imaging (n = 6). CONCLUSION: Persistent abnormal [18F]FDG uptake after first-line chemotherapy in NHL is highly predictive for residual or recurrent disease. In relapsing patients, PFS was significantly shorter after a positive scan than after a negative scan.

In vivo cell kinetic measurements in human oesophageal cancer: what can be learned from multiple biopsies?

The importance of intratumour variability of cell kinetics was studied in 60 patients with cancer of the oesophagus. Five biopsies per tumour were taken. The labelling index, S-phase duration and potential doubling time (Tpot) were measured using flow cytometry. The mean Tpot value was 5.56 +/- 4.43 days (+/- 1S.D.) for adenocarcinomas and 4.40 +/- 2.45 days (+/- 1S.D.) for squamous cell carcinomas. These values were statistically significantly different. Although intratumour variation in Tpot measurements occurred, the intertumour variability was more important (P < 0.00001). This feature permits classification of tumours into slow and fast proliferating groups, leaving an intermediate group of tumours that could not be unequivocally categorised. The relative distribution of tumours into these three categories depends on the intratumour and intertumour variability of Tpot, and on the cut-off values used. Increasing the number of biopsies from one to five reduces the number of non-classifiable tumours.

The role of prophylactic spinal irradiation in localized intracranial ependymoma.

A review of the clinical literature on ependymoma, published between 1969 and 1989, was carried out to assess the influence of tumor grade and site, tumor control at the primary site, and extent of irradiation on the incidence of spinal seeding after initial treatment. The pooled data show that the incidence of seeding was 8.4% (7/83) for high grade tumors and 4.5% (6/132) for low grade tumors. Seeding occurred more frequently in infratentorial tumors than in supratentorial tumors. For high grade tumors the incidence was 0% (0/26) for supratentorial and 15.7% (6/38) for infratentorial lesions; for low grade tumors the respective incidence was 2.7% (1/37) and 5.5% (4/73). Spinal seeding was 9.5% (15/157) in the event of failure at the primary site compared to 3.3% (4/122) when local control was achieved. The development of spinal metastases was not influenced by the extent of irradiation. For high grade tumors the incidence was 9.4% (5/53) with spinal irradiation and 6.7% (2/30) without prophylactic treatment; for low grade tumors the respective values were 9.3% (4/43) and 2.2% (2/89). These results indicate that tumor grade, tumor localization, and control of the tumor at the primary site are all factors which may influence the risk of spinal seeding. On the present evidence spinal metastases are not prevented by prophylactic spinal irradiation, regardless of tumor grade and site.

Localization errors in mantle-field irradiation for Hodgkin's disease.

The frequency and magnitude of localization errors detected by verification films, during mantle-field irradiation for Hodgkin's disease, were assessed. A total of 216 treatment set-ups was studied. The first verification film, at the start of treatment, showed a localization error of over 1 cm in 13% of cases, leading to a critical margin between the shielding block and the tumor bearing area in 9% of the treatment set-ups. After the first correction, an adequate treatment set-up was obtained in 60% of cases, whereas after two corrections the adequacy rate was 84%. Verification films are therefore very useful in detecting clinically important localization errors and in monitoring and checking subsequent corrections. An additional advantage exists because the first verification film can be used as a final check of the simulation plan itself.

Radiotherapy by multiple fractions per day (MFD) in head and neck cancer: acute reactions of skin and mucosa.

The feasibility of several unusual fractionation schedules in the radiotherapy of head and neck tumors was assessed, especially the acute reactions of skin and mucosa. All schedules were based on the principle of multiple fractions per day (MFD) leading to highly concentrated treatment series, alternating with rest periods. The fraction sizes used were between 1.6-2 Gy, overall treatment time was about 6 weeks, and total dose ranged from 60 to 67.2 Gy. The most important parameter that was modified was the size of the dose given in one treatment series. The first schedule consisted of two unequal radiation series: 48 Gy/12 days, followed by a second series of 19.2 Gy/4 days after a 3- to 4-week interval. All subsequent treatment schedules were divided in equal series: the first in 2 times 30 Gy, the second in 3 times 22.4 Gy, and the third in 4 times 16 Gy. Comparison of acute reactions in skin and mucosa after these irradiations to different dose levels has made it possible to obtain a precise idea of the time course in the development of radiation induced damage and of the dose-effect relationship. Such dose-response curves will be extremely useful in further studies on the dose-modifying effects of sensitizers and cytostatic drugs. Conclusions of this study: 1. In human oral mucosa, the threshold dose for the development of confluent mucositis (patches of 0.5 cm) after fractionated irradiation appears to be around 20 Gy. 2. Intervals of 12 days allow full repair of mucosa damage after a dose of about 20 Gy and repeating the irradiation leads to an identical reaction after second, third or fourth treatments, demonstrating that no cumulative effect exists for acute damage. This phenomenon could be exploited to reduce the acute side effects in radiotherapy. 3. The reactions observed in skin are less pronounced than those of mucosa, possibly due to the dose distribution of high energy photons. The changes are, however, slower to develop and intervals of 2 weeks are insufficient for the skin to fully recover from the radiation damage. Subsequent treatment series led to a cumulative reaction pattern. 4. Finally, a number of treatments were associated with misonidazole, an anoxic cell sensitizer, which did not appear to modify significantly the radiation reactions in either skin or mucosa.

Radiotherapy in multiple fractions per day for prostatic carcinoma: late complications.

The late complications associated with two different irradiation schedules with multiple fractions per day (MFD) used for the treatment of prostatic carcinoma are analyzed in 91 patients. There is a relatively high rate of side-effects with fifteen patients (16.5%) developing severe complications due to the radiotherapy. Complications are generally localized in the urinary system and consist mainly of chronic cystitis and incontinence, with only a few exclusive gastro-intestinal problems. The causative factor seems to be pronounced fibrosis of the normal pelvic tissues.

Effect of simultaneous administration of bleomycin on the acute skin reactions of mice after single and fractionated doses of radiation.

The effect of bleomycin on the acute mouse foot skin reactions, occurring after irradiation, was investigated. Bleomycin was delivered simultaneously with the irradiation treatment, either by intraperitoneal injection or by subcutaneous continuous infusion. Experiments were carried out to investigate (a) the modification by bleomycin of the response to single doses of radiation (b) the effect of total drug dose on this modification (c) the influence of the drug on repair of sublethal radiation damage and (d) the interference by the drug with compensatory repopulation after irradiation. In none of the experiments could any influence of the drug on these radiation induced reactions and recovery processes be demonstrated. These results are in direct contrast to what we have observed previously for similar types of experiments in another epithelial system, the mouse lip mucosa.

Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy.

Ninety-three patients with primary intracranial ependymoma were treated at the Royal Marsden Hospital, between 1952 and 1988, with postoperative radiotherapy. The survival probability at 5, 10, and 15 years was 51%, 42% and 31%, respectively, and the corresponding progression free survival (PFS) probability, 41%, 38%, and 30%. Tumor grade was the single most important prognostic factor for survival and PFS with gender of lesser prognostic significance. Treatment parameters were stratified for grade. In patients with low grade tumors survival and PFS were better following complete macroscopic excision compared to incomplete surgery. The extent of resection had no significant influence on survival or PFS in patients with high grade tumors. Extent of irradiation did not influence PFS, irrespective of tumor grade, while patients with high grade tumors had marginally better survival following extensive irradiation compared to more limited radiotherapy. The main problem in the treatment of ependymoma remains local progression which was the cause of death in all but two patients. New treatment strategies should focus on improvement of local control, especially in incompletely resected low grade tumors and all high grade tumors. The use of spinal irradiation is unlikely to significantly improve treatment results.

The contribution of magnetic resonance imaging to the three-dimensional treatment planning of localized prostate cancer.

PURPOSE: To investigate whether the use of transaxial and coronal MR imaging improves the ability to localize the apex of the prostate and the anterior part of the rectum compared to the use of transaxial CT alone, and whether the incorporation of MR could improve the coverage of the prostate by the radiotherapy field and change the volume of rectum irradiated. METHODS AND MATERIALS: Ten consecutive patients with localized prostate carcinoma underwent a CT and an axial and coronal MR scan in treatment position. The CT and MR images were mathematically aligned, and three observers were asked to contour independently the prostate and the rectum on CT and on MR. The interobserver variability of the prostatic apex location and of the delineation of the anterior rectal wall were assessed for each image modality. A dosimetry study was performed to evaluate the dose to the rectum when MR was used in addition to CT to localize the pelvic organs. RESULTS: The interobserver variation of the prostatic apex location was largest on CT ranging from 0.54 to 1.07 cm, and smallest on coronal MR ranging from 0.17 to 0.25 cm. The interobserver variation of the delineation of the anterior rectum on MR was small and constant along the whole length of the prostate (0.09+/-0.02 cm), while for CT it was comparable to that for the MR delineation at the base of the prostate, but it increased gradually towards the apex, where the variation reached 0.39 cm. The volume of MR rectum receiving more than 80% of the prescribed dose was on average reduced by 23.8+/-11.2% from the CT to the MR treatment plan. CONCLUSION: It can be concluded that the additional use of axial and coronal MR scans, in designing the treatment plan for localized prostate carcinoma, improves substantially the localization accuracy of the prostatic apex and the anterior aspect of the rectum, resulting in a better coverage of the prostate and a potential to reduce the volume of the rectum irradiated to a high dose.

Breast conserving treatment of Paget's disease.

Between 1971 and 1984, 13 patients with histologically proven Paget's disease were treated conservatively with radiotherapy only. The disease was clinically confined to the nipple or surrounding skin, without signs of an underlying tumor. With a mean follow-up of 58.6 months (ranging between 15 and 118 months), and a median follow up of 52 months, no recurrences locally or at distance were seen. Therefore in these selected cases a mastectomy could be avoided. The results with this breast conserving management suggest a place for radiotherapy in the treatment of Paget's disease limited to the nipple.

Practical implications of backscatter from outside the patient on the dose distribution during total body irradiation.

Total body irradiation (TBI) sometimes requires the set-up of the patient very close to the wall of the treatment room in order to obtain sufficiently large irradiation fields. Under these conditions, backscattered electrons can become clinically important. In the present study, an attempt was made to quantify the dose contribution to the patient from these electrons. Measurements were performed both in experimental conditions and on patients during their TBI treatment. It is concluded that, with the patient close to the wall, backscattered electrons constitute a significant (up to 20% of the dose obtained under electronic equilibrium at the exit port of the beam) radiation dose which can (under certain conditions) influence measurements of exist dose leading to an overestimation of the midline dose and contribute a superficial irradiation of the patient without therapeutic benefit. This problem can be solved by interposing a 2 cm thick low-Z absorber between wall and patient.

Effect of continuous infusion of bleomycin on the time for completion of repair of sublethal radiation damage in mouse lip mucosa during fractionated irradiation.

The influence of a simultaneous continuous infusion of bleomycin on the time necessary for repair of sublethal radiation damage during fractionated irradiation of mouse lip mucosa was studied. Although there are strong indications that bleomycin interferes with the accumulation and repair of sublethal radiation damage, no significant change in the time course of these repair processes could be demonstrated following various analyses of the experimental results. An interval of at most 4 h between successive irradiations was sufficient to allow for a similar amount of repair of sublethal damage as compared with either 24 h (2 fractions) or 6 h (10 fractions), whether or not radiation was combined with bleomycin infusion.

The effect of small radiation doses per fraction on mouse lip mucosa assessed using the concept of partial tolerance.

The acute effect of small radiation doses per fraction on mouse lip mucosa was investigated in the present study. In order to minimize the amount of additional sparing by regeneration during fractionated irradiations in this rapidly proliferating tissue, the overall treatment time had to be limited to at most 4 days, so that the number of irradiations that could be delivered was limited. Therefore, the concept of partial tolerance, established in the rat spinal cord model, was applied. The present experimental data confirm the validity of using this concept for assessing the effect of small radiation doses on tissues. The results of experiments covering a wide range of fraction sizes show that the isoeffective dose for a given mucosal reaction increases when the dose per fraction is progressively decreased to about 2 Gy per fraction. Further reduction of the size of dose per fraction, however, does not result in a detectable extra increase in the total dose to produce the same level of biological effect. It seems that the dose limit of sparing by fractionation in this rapidly proliferating normal tissue might be situated at larger fraction sizes than 0.6 Gy as estimated on basis of the mathematical linear-quadratic model, using an alpha/beta ratio of 6 Gy measured from data with doses per fraction in the range of 2 to 10 Gy.

The combined effect of bleomycin and irradiation on mouse lip mucosa. 2. Influence on the accumulation and repair of sublethal damage during fractionated irradiation.

The effect on the mouse lip mucosa of different fractionated irradiation schedules (with respectively 1, 2, 4 10 and 20 equal fractions) with and without a simultaneous constant drug regimen (bleomycin 40 mg/kg in a continuous subcutaneous infusion over seven days) was investigated. Lowering the fraction size resulted in a progressive increase of both the dose modification factors (DMF) and the absolute dose reduction (ADR), i.e. from 1.19 and 2.8 Gy respectively for single doses to 1.86 and 21.5 Gy respectively for 20 fractions (at isoeffect level 3.5). The mechanisms involved are most probably a direct cell kill by bleomycin, together with a reduced capacity to accumulate and/or to repair sublethal damage, although the influence of redistribution in the cell cycle during bleomycin infusion can not be excluded. Such large differences in the interaction between chemotherapy and irradiation as a function of the fractionation schedule could lead to a significant underestimate of response if data from single dose or 2-fraction experiments are extrapolated to regimens used in clinical practice.

The combined effect of bleomycin and irradiation on mouse lip mucosa. 1. Influence of timing, sequence and mode of drug administration with single dose irradiation.

The effect of the combination of single dose irradiation and bleomycin on the mucosa of the mouse lip was investigated. Bleomycin was administered either by IP injection or by subcutaneous continuous infusion. With the combined treatment an increased effect was observed compared to irradiation alone. The effect was drug-dose dependent in the range of doses used (5-80 mg/kg) and was similar for both ways of drug administration. There was only a limited influence of timing and sequence of the two agents within a period of 4 days. Since the dose-response curves were shifted in a parallel way, a constant cell killing effect by bleomycin is suggested for all irradiation doses used. This could be due to independent cell kill by the drug, although some mechanism of interaction, such as interference with accumulation of sublethal radiation damage or a true dose modification can not be excluded.

The time course of development of late side effects after irradiation of the prostate with multiple fractions per day.

BACKGROUND AND PURPOSE: A group of patients with prostate cancer was irradiated in the early 1980s with a TID schedule, resulting in a very high frequency of side effects. The time course of development of severe late complications was evaluated. MATERIALS AND METHODS: We retrospectively reviewed the records of 91 patients with prostate cancer, irradiated on a linear accelerator or a cobalt unit between 1980 and 1983. They received a split-course irradiation with multiple fractions per day (MFD) up to a nominal dose of 60 Gy. The rate of development of severe late urological and gastrointestinal complications, grade 3 or more according to the RTOG scoring system, was analysed. RESULTS: The 5-year actuarial incidence of urological complications was 51%. After a lag time of a few months, patients develop "first events' at a nearly constant rate of 10% for 5 years after treatment. Subsequent events ("all events') seem to continue to appear even after 5 years. The actuarial incidence at 5 years of gastrointestinal complications was 14%, with no new events developing later than 3 years after treatment. CONCLUSIONS: The irradiation schedule used resulted in an unacceptable high incidence of late side effects, probably due to incomplete repair between fractions. MFD fractions to the pelvis should be avoided, unless sufficient time in between fractions can be allowed. Moreover, the fact that after this treatment schedule with very pronounced biological effects, new severe complications continued to develop up to 5 years after therapy, indicates that sufficiently long follow-up time has to be respected when investigating new radiation techniques for pelvic tumours.

The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.

PURPOSE: (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. PATIENTS AND METHODS: The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LN's on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy (V(lung(20))), were calculated. RESULTS: Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LN's, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV (P=0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29+/-18% (+/-1 SD) (P=0.002) and of the V(lung(20)) of 27+/-18% (+/-1 SD) (P=0.001). CONCLUSION: In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

Repopulation kinetics in irradiated mouse lip mucosa: the relative importance of treatment protraction and time distribution of irradiations.

The repopulation kinetics of the irradiated lip mucosa of mice has been investigated. Split-dose experiments showed that, in this tissue, repopulation starts within 3 days after the first irradiation and increases exponentially within 10 days. To assess the relative importance of protraction and distribution of irradiations as a function of time, 10 fractions were given in (1) 3 days (three irradiations per day with a 4-hr interval), (2) 11 days (daily fractions), or (3) two short courses, each consisting of five fractions given in 1.5 days separated by a rest period of 8 days, with an overall time of 11 days. The results show that by protracting the treatment from 3 to 11 days (with daily irradiations) repopulation accounts for recovery of approximately 13 Gy. Delivering the radiation in two short courses separated by a rest period leads to an additional recovery of approximately 5 Gy. The most plausible explanation for this observation is that repopulation is much more efficient during the rest period between the two courses than during continuous daily irradiation. Although the regimen of two short courses with a rest period spares the acute reaction, it will not enhance the late tolerance. Before thorough knowledge about the repopulation kinetics of the tumors can be gained, caution should be observed for indiscriminate use of split-course multiple-fraction-per-day (MFD) regimens for treating various tumors.

Mitomycin C for metastatic prostate cancer: final analysis of a randomized trial.

BACKGROUND: Almost all patients that undergo hormonal manipulation for metastatic prostate cancer will ultimately progress because of hormone resistance. Therefore we assessed the effect of early addition of intravenous Mitomycin C to orchiectomy in patients with newly diagnosed metastatic prostate cancer. PATIENTS AND METHODS: 178 patients with histologically proven and previously untreated metastatic prostate cancer were included in a prospective, randomized multicenter trial. Randomization was done centrally between orchiectomy alone and orchiectomy with Mitomycin C. 148 patients were evaluable. RESULTS: At the final analysis 139 patients have deceased. The remaining 9 patients are still alive, but all present progression. There was no statistically significant difference in the real time to progression, or in the estimated cancer related and overall survival between both groups. Mean time to progression was 29 months in group 1 (orchiectomy alone), and 26 months in group 2 (orchiectomy and Mitomycin C) (p = 0.64). Mean time to cancer related death was 32 months and mean overall survival was 31 months in both groups. CONCLUSIONS: Mitomycin C has no beneficial effect when used in conjunction to orchiectomy in patients with newly diagnosed metastatic prostate cancer.