Radiation treatment of hemato-oncological patients in times of the COVID-19 pandemic : Expert recommendations from the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance.

PURPOSE: The coronavirus pandemic is affecting global health systems, endangering daily patient care. Hemato-oncological patients are particularly vulnerable to infection, requiring decisive recommendations on treatment and triage. The aim of this survey amongst experts on radiation therapy (RT) for lymphoma and leukemia is to delineate typical clinical scenarios and to provide counsel for high-quality care. METHODS: A multi-item questionnaire containing multiple-choice and free-text questions was developed in a peer-reviewed process and sent to members of the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance. Answers were assessed online and analyzed centrally. RESULTS: Omission of RT was only considered in a minority of cases if alternative treatment options were available. Hypofractionated regimens and reduced dosages may be used for indolent lymphoma and fractures due to multiple myeloma. Overall, there was a tendency to shorten RT rather than to postpone or omit it. Even in case of critical resource shortage, panelists agreed to start emergency RT for typical indications (intracranial pressure, spinal compression, superior vena cava syndrome) within 24 h. Possible criteria to consider for patient triage are the availability of (systemic) options, the underlying disease dynamic, and the treatment rationale (curative/palliative). CONCLUSION: RT for hemato-oncological patients receives high-priority and should be maintained even in later stages of the pandemic. Hypofractionation and shortened treatment schedules are feasible options for well-defined constellations, but have to be discussed in the clinical context.

Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Radiotherapy in the treatment of locoregional relapses of breast cancer.

Locoregional recurrences of breast cancer are associated with considerable morbidity and frequently present with concurrent metastatic disease. Yet patients without systemic spread can be treated with curative intent. In a retrospective analysis, the results of treatment of these patients have been evaluated at our institution. Between 1987 and 1996, 113 patients with locoregional breast cancer relapse, without systemic manifestation, received irradiation after local tumour excision. 13 patients (11.5%) had already received radiotherapy as part of their primary treatment. In these cases, only the area involved was treated. In all other patients, the chest wall and the ipsilateral lymph nodes were irradiated. Median dose was 50 Gy (range 20-65 Gy). Median follow-up was 4.4 years. 76 patients (67.3%) presented with chest wall recurrence only, 25 patients (22.1%) with nodal relapse only and 12 patients (10.6%) with combined relapses. 93% of patients had local control of disease after treatment. Local control rate after 5 years was 59%. 63 patients (55.8%) died within the follow-up interval, 45 patients (39.8%) owing to metastases, 4 patients (3.5%) owing to local failure and 8 patients (7%) owing to causes unrelated to tumour. Overall survival after 5 years was 43%. In multivariate analysis, positive hormone receptor status, small tumours on relapse and chest wall relapses alone were associated with improved survival. Radical local therapy is necessary in order to achieve and maintain local control and to prevent secondary dissemination in patients with only local recurrence of breast cancer.

Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92.

PURPOSE: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin's lymphomas (PGI NHL). PATIENTS AND METHODS: Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not. RESULTS: A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses. CONCLUSION: PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.

Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92.

PURPOSE: The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin's lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages. PATIENTS AND METHODS: Whether the treatment included surgery was left to the discretion of each participating center. Radiotherapy (Rx) and chemotherapy were stratified according to histologic grading, stage, and the inclusion or omission of surgery as follows: patients with low-grade PGL were treated with extended-field (EF) Rx (30 Gy). In case of residual tumor after surgery or in case of CT only (in stage IIE after six cycles of cyclophosphamide, vincristine, and prednisone), an additional boost of 10 Gy was given. All patients with high-grade PGL were treated with four (stage IE) or six (stage IIE) cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by EF Rx (stage IE) or involved-field (IF) Rx (stage IIE). Rx dosage corresponded to low-grade NHL. RESULTS: Between October 1992 and November 1996, 106 patients had CT only. The survival rate (SR) after 5 years was 84.4% and was influenced neither by patients' characteristics nor by stage or histologic grade. Seventy-nine patients had CSCT. Their SR was 82.0%. Complete resection of the tumor (R0) was prognostic for the overall survival (P =.0165) as compared with incomplete resection. CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored.

Long-term follow-up results of irradiation alone or combined with surgery in stage I-IV carcinoma of the uterine cervix.

OBJECTIVE: Evaluation of side effects and prognostic factors for survival in cervical carcinoma treated with radiation therapy +/- surgery. MATERIAL AND METHODS: From January 1986 to June 1995 277 female patients with cervical carcinoma were treated by irradiation in the Department of Radiation Oncology of the University of Münster. Out of them 224 patients were evaluable for clinical features. 20 of them did not undergo complete radiation series and 14 patients received irradiation for recurrent disease, therefore 190 patients (n = 103 pts. with primary irradiation, n = 87 pts. with postoperative irradiation) were analyzed for survival/therapeutic features. RESULTS: 5-year-disease-free survival rates after primary irradiation: (FIGO I number of patients too small); FIGO II (n = 33 pts.) 52%; FIGO III (n = 44 pts.) 39.5%; FIGO IV (n = 18 pts.) 26%. 5-year-survival rates after postoperative irradiation: pT1 (n = 43 pts.) 87.4%; pT2 (n = 37 pts.) 47%. As significant prognostic factors for disease specific survival after irradiation alone the hemoglobin bloodlevel at the beginning of radiation therapy, tumor stage according to FIGO, tumor size and irradiation of the paraaortic region were revealed. As significant prognostic factors for disease free survival after postoperative irradiation were seen: interval between surgery and the beginning of radiation therapy, tumor invasion of parametria, postoperative stage, involvement of lymph nodes and lymph-/hemangiosis. The documented side effects among all patients corresponded to data found in literature. CONCLUSIONS: Prognostic factors for disease free survival in our patients corresponded to the results of other studies. Acute and chronic side effects after irradiation were within the usual range. Especially in case of additional irradiation of the paraaortic region we could not find an accumulation of side effects. An elevation of disease free survival rates in patients with cervical carcinoma probably could be obtained by improving positional techniques for irradiation or changing fractionation schedules.

Patterns of microsatellite polymorphism in the range-restricted bonobo (Pan paniscus): considerations for interspecific comparison with chimpanzees (P. troglodytes).

The endangered great ape, Pan paniscus (bonobo) has the smallest range of the African apes. Virtually nothing is known about the genetic diversity or genetic structure of this species, while substantial amounts of polymorphism have been reported for the bonobo's widespread congener, the chimpanzee (P. troglodytes). Given its restricted range, what is the extent of genetic variation in the bonobo relative to the chimpanzee, and is the bonobo genetically depauperate? To investigate patterns of genetic polymorphism, bonobos of wild origin were genotyped for 28 microsatellite loci. The mean number of alleles per locus (5.2) and the mean observed heterozygosity (0.52) in bonobos were similar to variation observed in a wild chimpanzee community (P. t. schweinfurthii). The rarer bonobo is not genetically depauperate and may have genetic diversity comparable to the eastern chimpanzee subspecies. Bonobos have approximately 55% of the allelic diversity and 66% of the observed heterozygosity exhibited by all three chimpanzee subspecies sampled across equatorial Africa. Resampling techniques were used to quantify the effects of sample size differences and number and choice of loci between bonobos and chimpanzees. The examination of these variables underscores their importance in accurately interpreting interspecific comparisons of diversity estimates.

Operative and conservative management of primary gastric lymphoma: interim results of a German multicenter study.

PURPOSE/OBJECTIVE: Biology and appropriate management of gastrointestinal (GI lymphomas are matters of an ongoing controversial debate. To evaluate histological features, sites of involvement and management of primary GI-lymphomas, a prospective multicentric study was initiated in 10/1992. Aim of study was the further standardization of operative and conservative treatment modalities. MATERIALS AND METHODS: Study started 10/1992 and was closed 11/1996. A total of 381 evaluable patients had been accrued then. Standardized diagnostic workup included endoscopic and radiological evaluation of the complete GI-tract as well as a central histological review. Diagnosis was established after Lewin, stage classification was made after Musshoff, and histological classification was made after Isaacson. Treatment decision concerning operative or conservative management was due to the initially acting physician. Patients with resection of low grade lymphoma received total abdominal irradiation 30 Gy + 10 Gy boost to incompletely resected areas. After resection of high grade lymphoma CHOP chemotherapy (4 cycles for stage IE, 6 cycles for higher stages) after McKelvy was followed by total abdominal irradiation 30 Gy for stage IE respectively involved field irradiation 30 Gy for higher stages with 10 Gy boost to incompletely resected areas. Primary conservative- treatment consisted of six cycles COP chemotherapy after Bagley for low grade lymphomas stage > IE and total abdominal irradiation 30 Gy + 10 Gy boost to involved areas for all stages. Patients with high grade lymphomas received 4 x CHOP followed by total abdominal irradiation 30 Gy + 10 Gy boost to involved areas or 6 x CHOP plus involved field radiation therapy with 40 Gy. 257 patients are considered for analysis due to exclusion criteria of the study, 190 of them were suffered from gastric lymphoma. Their median observation time is 29 months, maximum observation time is 68 months. RESULTS: Sites of involvement were stomach in 73.4%, small bowel 9.6%, ileocoecal region 6.9%, and other sites 3.2% More than one GI site was involved in 6.9%. Gastric lymphomas achieved a survival probability of 89% after 3 years. Though surgical and conservative treatment was not randomized, outcome was analyzed in gastric NHL stages I and II (histologic subtype not considered showing no significant influence). At 3 and 5 years survival is 88% in resected cases vs. 94% and 86% in conservatively treated patients (p = 0.350). Analyzing only stages I + II(1) surgery also seems of no advantage even considering only RO-resections. There was one acute gastrointestinal bleeding under primary chemotherapy for a high grade lymphoma. Toxicities of grade III and IV WHO were rarely seen during treatment. All other acute toxicities were not more than grade II WHO. CONCLUSION: Conservative treatment in this setting is feasible. The operative approach seems not to be advantageous compared to conservative treatment and should be critically reconsidered.

Analysis of failures after whole abdominal irradiation in gastrointestinal lymphomas. Is prophylactic irradiation of inguinal lymph nodes required? German Multicenter Study Group on GI-NHL, University of Muenster.

BACKGROUND: To evaluate failures and to investigate the need for prophylactic inclusion of the inguinal lymph nodes in case of whole abdominal irradiation in gastrointestinal lymphoma. PATIENTS AND METHOD: In October 1992 a prospective study on primary gastrointestinal lymphoma was initiated to evaluate management strategies. Treatment consisted either of conservative management comprehending radiotherapy +/- chemotherapy or radio-/chemotherapy sequential to primary surgery, depending on the physician's decision. Until November 1996, 382 patients were enrolled. Out of them we analyzed 92 patients who received a whole abdominal irradiation, in 21 cases with prophylactic inclusion, in 71 cases without inclusion of inguinal lymph nodes. RESULTS: After a median follow-up time of 36 months in 92 patients with whole abdominal irradiation 9 patients developed relapse of gastrointestinal lymphoma (8 local failures, 1 distant failure). In these cases the analysis of radiation therapy shows low tumor doses or small field sizes. No significant difference in the relapse rates is shown between the 21 patients with inclusion of the inguinal lymph nodes in the abdominal radiation fields (3 recurrences approximately equal to 14.3%) and the 71 patients without enclosure of the inguinal lymph nodes (6 recurrences approximately equal to 8.5%). CONCLUSION: General prophylactic enclosure of the inguinal lymph nodes in the case of whole abdominal irradiation in gastrointestinal lymphoma seems to be unnecessary.

Pre- and postoperative investigations of hepatic glucose production and leucine turnover in Cushing's disease utilizing stable isotope techniques.

Impairment of glucose tolerance and muscle wasting indicating a disorder of glucose metabolism are characteristic features of Cushing's syndrome. We have examined glucose and amino acid metabolism in eleven patients with pituitary dependent Cushing's disease in comparison to nine healthy controls. Furthermore, the therapeutic effect of selective pituitary microsurgery was studied by repeated stable isotope measurements of hepatic glucose production and leucine turnover rates. Eight patients remitted after surgery and 3 had persistent disease. All patients were investigated prior to surgery and again 1 week and 3 months after the operation with (6,6-2H2)-glucose and (5,5,5-2H3)-leucine by means of a primed (4 mg/kg.min and 0.27 mg/kg.min), continuous (0.05 mg/kg.min and 0.005 mg/kg.min) infusion. In Cushing's disease, both the preoperatively elevated mean glucose production rate (2.34 +/- 0.63 mg/kg.min) and the reduced mean leucine turnover (0.213 +/- 0.025 mg/kg.min) were found to be linked with hepatic insulin resistance and an insulin-induced reduction in protein breakdown combined with a reduced protein synthesis. Mean glucose production and leucine flux both normalized after surgery in the remitting patients (2.18 +/- 0.15 mg/kg.min and 0.244 +/- 0.047 mg/kg.min 3 months after the operation). The metabolic disorders thus were reversible following successful correction of hormonal oversecretion by transsphenoidal surgery.

Results of LSA2-L2 therapy in 26 children with non-Hodgkin's lymphoma.

Twenty-six children with non-Hodgkin's lymphoma (NHL), 17 boys and nine girls, were treated with the LSA2-L2 protocol. Seven children had stage I or II, 16 Stage III and three Stage IV according to Murphy's staging system. Eight children had their primaries in peripheral lymph nodes, eight in the abdomen, six in the mediastinum and four in other sites. All tumors were classified histologically according to four different classifications. Overall disease-free actuarial survival is 53.6%. Complete responders show a disease-free survival of 77.8%. Fourteen children survived for 9-56 months. Included are all seven children with Stage I or II who survive irrespective of histologic type of the tumor. Of the remaining 12 children in Stage III or IV three children died in remission and nine of progressive disease. Eight of these nine patients did not attain complete remission. Whereas four of five children with the convoluted type of NHL survive, four of five patients with the Burkitt's type (small noncleaved follicle center cell lymphomas) died of progressive disease. According to Rappaport's classification, four of six children with diffuse undifferentiated lymphoma (DUL) are dead due to tumour progression. Considering the classification of lymphoblastic lymphomas introduced by Nathwani et al., 23 five of seven children suffering from lymphoblastic lymphomas but only two of eight children with nonlymphoblastic lymphomas belong to the survivors. Therefore histologic findings do hold prognostic significance in our series of children with NHL.

[Treatment of orbital rhabdomyosarcoma (author's transl)]. / Zur Therapie des Rhabdomyosarkoms der Orbita.

From March 1973 to December 1981 embryonal rhabdomyosarcoma of the orbit was diagnosed in 5 children. In two children exenteration was done after a previous local radiotherapy. In one child the exenteration of the orbit was done after a primary chemo- and radiotherapy because of local progression of the tumor. In two children the exenteration was avoidable by this therapy. In four of these five children this was followed by vincristine, actinomycin D and cyclophosphamide for 16 to 24 months. After the diagnosis these four children survived until now from 3 1/2 to more than 8 years. They are free of treatment and free of disease. Seven months after diagnosis one child died with an acute respiratory distress syndrome (at post mortem: hyaline membranes). In patients with rhabdomyosarcoma of the orbit it is justified to avoid the mutilating exenteration by primary chemotherapy followed by irradiation of the reduced manner. If exenteration becomes subsequently necessary the chance for survival is not diminished in our opinion.

[Diagnostic and therapeutic problems of nasopharyngeal carcinoma in childhood (author's transl)]. / Diagnostische und therapeutische Probleme des Nasopharynxkarzinoms im Kindesalter anhand von drei Patienten.

Between 1974 and 1978 three children with a nasopharyngeal carcinoma (stages: T3N3MO, T4N2MO, T4N1MO) were treated with primary radiotherapy (tumor dose: 45-67 Gy). Local control was achieved in two children, one of these (T4 primarily) had a local relapse five months after diagnosis. Only one of the three children had radiotherapy to the neck region. This child developed lung and mediastinal metastases with hypertrophic osteoarthropathy twelve months after diagnosis. In the other two children lung metastases were observed two and seven weeks after the diagnosis respectively. In these two radiotherapy of metastases and chemotherapy were considered more important than radiotherapy of the neck region. All three children showed disappearance or considerable reduction of lung metastases due to radio- and chemotherapy. Yet, all three died of progressive disease within a few months. Early diagnosis of nasopharyngeal carcinoma in children will only be possible when pediatricians are more aware of this disease, also in our regions. Radiotherapy should be done only with megavoltage equipment using extensive radiation fields for the primary tumor area and elective radiation of the neck region. The use of additional primary chemotherapy is suggested for stages T3/T4. This mode of management may help to prevent distant metastases.

[Treatment of Wilms' tumor (author's transl)]. / Therapie des Wilms-Tumors.

Uniform treatment based on the therapeutic approach of the 1st and 2nd US National Wilms' Tumor Study was decided on in March 1976 by paediatricians, surgeons, urologists and radiotherapists in Austria. Wilms' tumour was diagnosed in 34 children between 1 january 1976 an 29 february 1980 (stage I: n = 11, stage II: n = 8, stage III: n = 8, stage IV: n = 7). Parents of two children refused treatments; both children have since died of metastases. Of the remaining 32 children 29 (90.6%) are alive, 10 for more than 4, 15 for more than 3 and 19 for more than 2 years after diagnosis. 21 children are without need of treatment. Three children have died, one due to postoperative complications, one due to haemorrhagic chickenpox, but free of tumour, and one after insufficient treatment. Two of the five children with a recurrence between 2 1/4 to 15 months after diagnosis had been treated inadequately in the initial phase. The tumour free survival rate in 74.2%. Two children with early occurring or recurrent lung metastases have survived for 53 1/2 and 54 months up to now.

[Comparative evaluation of hydroxyproline in urine and in serum as a possible clinical parameter for radiation-induced destruction of connective tissue due to fractionated radiation therapy (author's transl)]. / Vergleichende Untersuchung über die Wertigkeit von Hydroxyprolin im Urin und im Serum als klinischer Parameter der radiogen bedingten Bindegewebsdestruktion unter fraktionierter Strahlentherapie.

In the course of postoperative fractionated radiation therapy hydroxyproline was evaluated as a biochemical parameter of radiation damage in 60 patients with different tumour diseases. At different times before, during and after therapy, hydroxyproline in serum was evaluated according to the method of Dabew and Struck, hydroxyproline in urine according to the test combination "hypronosticon" (Organon-Technika). There was no correlation to be found between hydroxyproline in serum or urine, clinical course of disease and radiation dose. Possible explanations were discussed.

Effect of cyclophosphamide or x-rays on spontaneously occurring metastases from tumors transplanted into the tails of mice.

A spontaneous metastases model in mice is being used to test the efficiency of various treatments in eliminating metastases. Solid tumors were transplanted into the tails of mice and removed by tail transection when they had grown to a 4- to 5- or 6- to 7-mm mean diameter. Subsequently, 70 to 95% of mice not given other treatment developed metastases in the lungs or in regional lymph nodes (lumbar sacral region), or in both sites. The present paper reports the effects of whole-body or partial-body treatment on these metastases. The treatments, which started at the time of surgical transection of the tail, included a range of single or fractionated doses of cyclophosphamide (CTX) or X-rays given either to the whole body or locally to the lungs only. CTX reduced the incidence of metastases in both sites although the incidence of lung metastases was reduced by smaller doses of CTX than that of the lumbar sacral metastases. Whole-body irradiation of 6 grays (600 rads) had no effect on the incidence of metastases, whereas local irradiation of the lungs with single doses of 14.5 or 20 grays reduced the number substantially, as did 95 mg or more of CTX per kg. Thus, CTX or radiation reduced the incidence of lung metastases in a system where metastases developed from cells seeded from a primary tumor rather than from a cell suspension injected into the tail vein.