Breast irradiation with brachytherapy: approved techniques and new concepts.

Among surgery and chemotherapy, radiotherapy has an important role in the treatment of breast cancer patients. But not only external beam radiotherapy (EBRT) treatment is an established method for treatment of breast cancer, also brachytherapy (BT) is an approved method. BT is well known for boost irradiation in combination with EBRT, but new indications as re-irradiation for local recurrences or partial breast irradiation offer new aspects in the field of BT for breast cancer treatment. Because of modern CT based 3-D treatment planning systems and the possibility of intensity modulated brachytherapy (IMBT) has getting more potential. In the future for selected patient's re-irradiation of the breast using IMBT after local relapse and second breast conserving surgery might be an alternative instead of mastectomy. Even partial breast BT following breast conservative operation as a new treatment option is getting more and more interesting and is widely investigated in several studies. Due to the approved techniques and the new indications BT is and will be an attractive alternative and extension in the field of breast cancer treatment. But we need five better ten years results for definite conclusions at least.

Determination of field size limitations in stereotactic and intensity modulated radiotherapy.

For dose measurement in small photon fields, different detectors are currently in use: TLD, semiconductor, diamond-detector, film, etc. But for absolute dosimetry, ionization chambers show the most advantages. To meet the basic dosimetrical requirements for lateral electron equilibrium the field size F must not remain under specified values: i.e. 5.2 x 5.2 cm2 for 15 MeV X-bremsstrahlung. As well as increasing the focus-chamber-distance, changing the physical density of the build-up material in the close vicinity of the chamber will be helpful to determine the output factor OF for smaller fields. By means of a correction factor, k(mat), this is taken into account. For a 6 MeV X and a 15 MeV X-bremsstrahlung of linear accelerators the lower limit of the field size F is determined: F > or = 0.8 cm. This value is mainly dependent on the diameter of the focal-spot (phi = 3 mm) of the treatment unit including design characteristics of the treatment head. Beside the dosimetrical aspects, some geometrical parameters have to be considered, when accuracy of dose application should remain on the same level as in medium and large field treatment (4 cm < or = F < or = F(max)). To keep dose-volume errors as low as +/- 10 % (diameter of PTV: 20 mm), the mean total error delta of CT-scanning (delta(p)), planning (delta(pl)), patient positioning (delta(x)), and treatment unit instabilities (delta(m)) should not exceed +/- 0.8 mm.

[High dosage brachytherapy and external irradiation of localized prostate carcinoma--results at the Kiel University Clinic]. / High-dose-rate Brachytherapie und externe Bestrahlung beim lokalisierten Prostatakarzinom--Ergebnisse der Kieler Universitätsklinik.

To evaluate a new therapy protocol for local dose escalation by high dose rate (HDR) brachytherapy for survival, morbidity and prognostic variables in men with localized prostate cancer. The prospectively recorded files of 189 men aged in median 69 years with a mean follow-up of 6 years (12-143 months) receiving curatively intended combined high dose rate (HDR) 192-iridium-brachytherapy (BT) and external beam radiation (EBR) for locally confined prostate cancer were analyzed. Mean age was 68.2 (range 44-84 years). Hundred and twenty-seven patients had T1-2 tumors, and 62 patients had T3-tumors. The total planned dose applied by external beam radiation was 50 Gy in the pelvis, and 40 Gy in the prostate by in-field-dose modification. The HDR-brachytherapy was delivered in two fractions. The dose per fraction amounted 15 Gy. Mean survival was 6 years (range 12-143 months), 76.7% of the patients survived and 86.3% were disease-free. The biochemical non-evidence of disease rate (BNED) was 78%. Univariate survival analysis revealed that low stage (T1-2), low grade (G1-2), normal PSA status after radiation therapy, and no adjuvant hormonal treatment were associated with long survival. However, the stratification for adjuvant hormonal treatment was not according to random. In multivariate analyses PSA status was an independent prognostic factor. The six year results confirm that local dose escalation by HDR-brachytherapy and external beam radiation is curative in men with locally confined prostate cancer. The results are especially in high risk patients encouraging.

[Results of radiotherapy in brain metastasis]. / Ergebnisse der Strahlentherapie bei Hirnmetastasierung.

PURPOSE: To evaluate the effect of radiation therapy in the treatment of brain metastases. PATIENTS AND METHODS: Fifty-eight patients with brain metastases were irradiated. In 52 patients the post-therapeutic survival time could be evaluated. Most frequent basic tumor entity was lung cancer, followed by breast cancer. Eighteen patients underwent neurosurgery prior to radiation therapy, 23 patients underwent only radiotherapy and in 13 patients an additional chemotherapy was performed. Four patients were treated by all these means. Radiation therapy was done as a whole brain irradiation with a total dose of 40 Gy at single doses of two Gy or 30 Gy at single doses of 3 Gy respectively. RESULTS: There were no radiogenic complications. 42 of 58 patients (72%) showed an improved neurological status. In ten patients radiation therapy had to be abandoned due to deterioration of the patients condition, five patients died in the hospital. Mean survival time for all the patients were 213 days, by subtracting the preterminally treated patients the time improved up to 269 days. The prognosis was dependant of several factors. Main importance had the basic tumor entity itself leading to a mean survival time in breast cancer patients of 347 days in contrary to those with lung cancer and 152 days mean survival time. Good general status, young age and solitary metastasis were positive predictive factors. CONCLUSIONS: Radiation therapy is capable to improve quality of life and to prolong survival after an only short treatment period. Treatment should be initiated quickly and consequently after diagnosis.

[The age-specific results of the adjuvant radiotherapy of breast carcinoma]. / Lebensalterspezifische Ergebnisse der adjuvanten Radiotherapie des Mammakarzinoms.

BACKGROUND: Aim of our work was to evaluate the standards of treatment in elder women with breast cancer and their results of radiation therapy. PATIENTS AND METHODS: In our hospital 218 breast cancer patients were treated in the years 1990 and 1991. Forty-three women were younger than 50 years of age (group I), 92 between 50 and 64 years (group II), 83 elder than 64 years (group III). One hundred and forty-nine patients underwent mastectomy, 65 patients had conservative treatment (Table 5). Four patients were not operable. All of the patients were irradiated uniformly loco-regionally with 50 Gy Co-60-photons, followed by a boost to the tumor bed with 10 Gy with 6- to 12-MeV electrons. Forty-four patients had an additional chemotherapy. RESULTS: The 5-year survival rate was 79.8% (n = 174), the disease free survival was 59.1% (n = 129) (Table 6). The mean rate of local recurrence was 3.6% (n = 8), 4% after mastectomy (n = 6) and 3% (n = 2) with breast conservation. Age group specific 5-year survival rates were 72% (I), 85.6% (II) and 77.1% (III), respectively, disease free survival rates were 48.8% (I), 65.2% (II) and 57.8% (III), respectively. The rates of local recurrence were 9.3% (I), 3.2% (II) and 1.2% (III), respectively. Significant age group specific differences in surgical and radiotherapeutical treatment could not be found. CONCLUSION: The curative chance of treatment has to be used in every age. A treatment of elder patients below the actual valid standards of treatment is not justified.

Neurobehavioral toxicity of total body irradiation: a follow-up in long-term survivors.

PURPOSE: Total body irradiation (TBI) in preparation for bone marrow transplantation (BMT) is a routine treatment of hematological malignancy. A retrospective and a prospective group study of long-term cerebral side effects was performed, with a special emphasis on neurobehavioral toxicity effects. METHODS AND MATERIALS: Twenty disease-free patients treated with hyperfractionated TBI (14.4 Gy, 12 x 1.2 Gy, 4 days), 50 mg/kg cyclophosphamide, and autologous BMT (mean age 38 years, range 17-52 years; age at TBI 35 years, 16-50 years; follow-up time 32 months, 9-65 months) participated in a neuropsychological, neuroradiological, and neurological examination. Data were compared to 14 patients who were investigated prior to TBI. Eleven patients with renal insufficiencies matched for sex and age (38 years, 20-52 years) served as controls. In a longitudinal approach, neuropsychological follow-up data were assessed in 12 long-term survivors (45 years, 23-59 years; follow-up time 8.8 years, 7-10.8 years; time since diagnosis 10.1 years, 7.5-14.2 years). RESULTS: No evidence of neurological deficits was found in post-TBI patients except one case of peripheral movement disorder of unknown origin. Some patients showed moderate brain atrophy. Neuropsychological assessment showed a subtle reduction of memory performance of about one standard deviation. Cognitive decline in individual patients appeared to be associated with pretreatment (brain irradiation, intrathecal methotrexate). Ten-years post disease onset, survivors without pretreatment showed behavioral improvement up to the premorbid level. CONCLUSION: The incidence of long-term neurobehavioral toxicity was very low for the present TBI/BMT regimen.

[Outcome of primary combined radio-chemotherapy in head and neck tumors with simultaneous salivary gland protection by amifostine]. / Ergebnisse der primären kombinierten Radiochemotherapie von Kopf-Hals-Tumoren mit simultaner Speicheldrüsenprotektion durch Amifostin.

AIM: Demonstration and critical evaluation of the use of cytoprotective agents in radiation therapy. PATIENTS AND METHODS: In 1996 9 patients with head and neck tumors were irradiated with a mean dose of 66 Gy and simultaneous application of amifostine. Primaries were in the oropharynx (3), tongue (2), tonsils (2) as well as nasopharynx and soft palate. Parallel carboplatin was administered 6 times with a dose of 100 mg/week and amifostine twice a week with 500 mg over 6 weeks. The evaluation was performed clinically and by sialoscintigraphy (Figure 1). RESULTS: There were no lasting side effects, but episodes of hypotension in 7 of 9 patients and nausea. Radiogenic acute toxicity was nearly uneffected, complaints from xerostomia, however, were diminished. All patients showed increased dermal pigmentation and dermatitis. Sialoscintiraphies 6 months after therapy proved better salivary gland function with correlated better patient condition. CONCLUSION: Amifostine might gain a role in the prevention of lasting radiogenic xerostomia. The required dose is not yet clear. A broader use of amifostine would be favored by lower costs of the substance.

Variability of individual normal tissue radiation sensitivity. An international empirical evaluation of endogenous and exogenous response modifiers.

BACKGROUND: The variability of normal-tissue response is of major concern for radiation therapy. Multiple endogenous and exogenous factors are qualitatively known to alter the acute and late tissue response. Which of them are regarded most important by the European radiation oncologists and what is, empirically, their quantitative influence on the acute or late tissue tolerance? METHODS: In August 1997, we sent a questionnaire to 255 European radiation oncology departments. Among others, the questionnaire asked for endogenous and exogenous factors modifying the tissue response to radiation therapy and their quantitative influence on the acute and late radiation morbidity (TD 5/5). Fifty-five questionnaires (21.5%) were answered. RESULTS: Empirically, the most important endogenous factors to modify the acute tissue tolerance are a) metabolic/other diseases with macro- or microangiopathia (17 answers [a]/32% mean decrease of tissue tolerance), b) collagen diseases (9 a/37%) and c) immune diseases (5 a/53%). As endogenous response modifiers for the TD 5/5 are recognized a) metabolic or other diseases leading to macro- or microangiopathia (15 a/31%), b) collagen diseases (11 a/38%) and c) immune diseases (2 a/50%). Inflammations from any reason are assumed to alter the acute tissue tolerance by (6 a/26%) and the TD 5/5 by (10 a/24%). Exogenous modifiers of the acute tissue response mentioned are a) smoking (34 a/44%), b) alcohol (23 a/45%), c) nutrition/diets (16 a/45%), d) hygiene (9 a/26%) and e) medical therapies (10 a/37%). Exogenous factors assumed to influence the TD 5/5 are a) smoking (22 a/40%), b) alcohol (15 a/38%), c) nutrition/diets (9 a/48%), d) hygiene (5 a/34%) and e) medical therapies (10 a/30%). CONCLUSIONS: Exogenous factors are regarded more important by number and extent on the acute and late tissue response than endogenous modifiers. Both may have an important influence on the individual expression of normal tissue response.

Topographic documentation of acute radiation morbidity.

BACKGROUND: The clinical knowledge on the frequency and severity of acute radiation morbidity is very sparse. With established morbidity recording, only severe side effects are revealed. The lower morbidity (I/II degree) as a major part of the data base is neglected. Another problem may be the lack of interdisciplinary and international compatibility in other systems. For these reasons, our intention was to create an easily acceptable, international and interdisciplinary compatible documentation form for routine use in radiotherapy. METHODS: A detailed topographic documentation sheet for each major topographic site of clinical radiation oncology has been developed (CNS, head and neck, thorax, female breast, abdomen, extremities). It is based upon existing toxicity codes and documentation systems (CTC[WHO], RTOG and EORTC, DEGRO, ADT, KIEL). Furthermore, basic oncological data like TNM, previous surgery or chemotherapy, drugs and more are included. For each topographic body site, one DIN A4 format is required for documentation of a 6 to 7-week treatment course. The toxicity prescription is coded according to the "DEGRO/RTOG Coding System for acute side effects" and to the "EORTC Acute Toxicity Code" to achieve optimal international and interdisciplinary compatibility. RESULTS: Complete documentation of toxicities level 0 to 4 is to be performed within 2 to 5 minutes per week/patient within preformed marks. The clinical performance has proven excellent. Not only level III/IV toxicities are recorded, but also level I/II morbidity. CONCLUSIONS: The topographic documentation system improves recording of acute morbidity in radiation oncology not only by time, but also in quality. Experimental, radiobiological and former clinical data may be proved for their actual plausibility.

Electronical recording and evaluation of acute radiation morbidity.

BACKGROUND: Relatively uniform documentation systems are used for recording of acute side effects in oncology. Object of this work is to illustrate the applicability of electronic data bases for registration and evaluation of acute side effects in radiation therapy. METHODS: Based on topographic documentation sheets, an electronic data base was developed for each major topographic site. Besides general patient related parameters (TNM, previous chemotherapy, surgical interventions, intercurrent diseases and more), the kind and the degree of acute radiation related side effects are documented for each week of radiation and for day 90 (RTOG) as the joint day between acute and subacute tissue reactions. RESULTS: The temporal expenditure for the recording of the general patient related parameters of a patient is less than a minute. The weekly documentation can be performed during the daily routine work and needs approximately 5 minutes per week. The structure of the data base enables for later analyses of acute radiation related morbidity. CONCLUSIONS: Electronic data bases enable a fast and systematic recording and evaluation of acute radiation related side effects. The development of particular registration entities for recording of acute side effects may be a possible application and demonstrates the needs of professional developments.

Pharmacological management of acute radiation morbidity.

BACKGROUND: The acute radiation morbidity may be a serious problem for the patient and may be decreased by pharmacological approaches. MATERIAL AND METHODS: A database research (Medline, Cancerlit, DIMDI, etc.) was performed in order to obtain pharmacological approaches to decrease the acute radiation morbidity. The evaluation was focused on therapeutic principles but not on special drugs. RESULTS: Different approaches may be chosen to protect healthy tissues from the effects of ionizing radiation: 1. administration of cyto- or radioprotective agents prior to irradiation, 2. administration of agents to avoid additional secondary toxicity by inflammation or superinfection during the treatment cycle (supportive care) and 3. administration of rescue agents, such as bone marrow CSFs or hyperbaric oxygen (HBO), after therapy. For radioprotection, there are reports on cellular protection by vitamine E, vitamine C, beta carotene, ribose-cysteine, glutamine, Mgcl2/adenosine triphosphate and WR-2721 (amifostine). In general, preclinical studies show that the combination of pretreatment with amifostine, irradiation, and G-CSF after radiation enhances hematologic recovery. Assessment of these combined effects, including local supportive therapies, merits further clinical investigation. There are data from prospective studies as well as from empirical clinical experience, that radioprotection and clinical supportive care may reduce the treatment related morbidity by 10 to 30% either. CONCLUSIONS: A further improvement of the therapeutic ratio is to be expected by systemically combined application of radioprotectors, supportive care and rescue agents.

[Prevention and therapy of acute radiation-related morbidity of the skin and mucosa. II, Recommendations of the literature]. / Prophylaxe und Therapie akuter Strahlenfolgen an Haut und Schleimhaut. Teil II: Empfehlungen der Literatur.

BACKGROUND: In a German multicenter questionnaire, answered by 89 departments, we had examined the strategies to prevent or to treat the acute morbidity of the skin and mucosa associated to radiation therapy. In this work, the recommendations from the literature are compared to the results of the questionnaire. METHODS: An extensive research on common data information systems (Medline, Cancerlit, DIMDI and others) was performed. The criteria included the organ related morbidity and therapeutic strategies for its reduction. The obtained data were compared to the results from the questionnaire. RESULTS: The study data found by the research often demonstrate small patient numbers and little convincing results. However, as in the questionnaire, the joint principle seems to be the reduction of acute inflammatory tissue reaction by evasion of bacterial and mycotic overgrowth and reduction of exo- and endogenous toxins. CONCLUSIONS: Further studies with more convincing results are required.

[Prevention and therapy of acute radiation injuries of the skin and mucosa. I. Results of a German multicenter questionnaire]. / Prophylaxe und Therapie akuter Strahlenfolgen an Haut und Schleimhaut. Teil I: Ergebnisse einer bundesweiten Erhebung.

BACKGROUND: The acute radiation related morbidity is an essential factor for the patient's outcome in radiotherapy. The prophylactic and therapeutic management of acute side effects has a wide clinical range between different radiation oncology departments. In this work, it was to evaluate the remedies, which are used for prevention and therapeutic management of acute radiation related morbidity of the skin and mucosa (mouth, pharynx, esophagus, small and large bowel, rectum and vagina). METHODS: A questionnaire was sent to 130 radiotherapeutic departments in Germany in July 1995. The questionnaire had been designed with 22 open questions concerning the preventive and therapeutic management of acute radiation related morbidity of skin and mucosal sites. It has been correlated to the scoring system of the RTOG/EORTC and its German modification according to Seegenschmiedt and Sauer. The evaluation was performed anonymously. RESULTS: From 130 questionnaires, 89 (68.4%) were sent back till August 1995. All of them were evaluable. The recommendations showed a broad spectrum for each site. Especially the oral mucositis was treated in many different ways and combinations. The prevention and therapy of complicating superinfections seem to be the joint principle of most of the recommendations. CONCLUSIONS: The management of the acute radiation related morbidity has a wide clinical spectrum among different radiation therapy centers. Systematic prospectively designed investigations are necessary in order to achieve a further reduction in the radiation related acute morbidity. Therefore, a multicenter collaborative working group has been founded.

[Survival of exclusively irradiated patients with NSCLC. Significance of pretherapeutic hemoglobin level]. / Uberlebenszeiten ausschliesslich bestrahlter NSCLC-Patienten. Die Bedeutung des prätherapeutischen Hämoglobinwerts.

BACKGROUND: In a retrospective study files of 96 non-operated, non-small-cell lung cancer (NSCLC) patients receiving radiation therapy were statistically analysed. A correlation of the pre-therapeutical haemoglobin level and the survival of patients after a primary radiation therapy has been described by some authors, but it is an open question whether there is any dose-modification in the treatment schedule, related to different prognostic subgroups of patients, that makes sense. PATIENTS AND METHOD: We have analysed the files of 96 primary radiated patients to evaluate the pre-therapeutical haemoglobin level as well as sex, age, histopathology, total dose and fractionation. The analysis of Karnofsky-status or patient condition was not performed as there was a lack of sufficient data in the patient files. RESULTS: Histopathology, sex, age as well as total dose and fractionation of the radiation treatment were similar in the cohort building 3 groups: Hb < 11 g/dl, Hb between 11 to 15 g/dl and Hb > 15 g/dl. The investigation resulted in the observation, that lower levels of initial serum haemoglobin concentration compared to levels over 15 g/dl are negative prognostic factors. Higher initial haemoglobin concentration is a high significant positive prognostic factor (p = 0.0001). The applied total dose (> 30 Gy, > 50 Gy, > 55 Gy) was not a significant prognostic factor in this patient material, where two thirds of the patients had an advanced cancer (stage IIIB or stage IV). CONCLUSIONS: We conclude that initial haemoglobin concentration is a significant prognostic factor for NSCLC patients treated by radiation therapy. Further investigations are necessary to determine whether a dose escalation can improve the outcome of a subgroup of patients with high-normal haemoglobin levels.

[Late results of radiotherapy of soft tissue sarcoma]. / Spätergebnisse nach Strahlentherapie des Weichteilsarkoms.

PURPOSE: To evaluate the effect of radiation therapy in the treatment of soft-tissue sarcomas. MATERIALS AND METHODS: Between March 1970 and January 1990, 58 patients with soft-tissue sarcoma were referred for radiation therapy. The most frequent histologic diagnoses included fibrosarcoma (n = 15), neurofibrosarcoma (n = 5) and rhabdomyosarcoma (n = 5). Central tumor sites in the trunk (n = 31) were much more frequent than in the head and neck region (n = 14) or the extremities (n = 13). Thirty-nine of 58 primary tumors were bigger than 5 centimeters. Forty-five patients were irradiated after surgery, 5 patients prior to surgery; in 8 cases only radiation therapy was used. Radiation therapy was performed with Co-60 photons and an average total dose of 58 Gy, fractionated in single doses of 2 Gy. The treatment results were obtained by actual follow-up examinations. RESULTS: Twenty-three of 58 patients survived at least 5 years (39.9%). Of 15 patients with R0 resection 11 were alive after 5 years (73.3%). Local tumor control was achieved in 34 of 58 patients (58.6%). Low 5-year-survival rates were associated with dedifferentiation of the primary tumor (three survivors in 10 patients with G3 tumor), tumor diameters over 5 cm (13 survivors of 39), R2 resection (3 survivors of 16) and tumor sites in the body trunk (11 survivors of 31). CONCLUSIONS: (1) The best results of radiation therapy were achieved after R0 resection of the primary tumor. (2) Tumors in the trunk are prognostically worse because of bigger tumor diameters due to later diagnosis.