Late Sequelae of Radiotherapy­The Effect of Technical and Conceptual Innovations in Radiation Oncology.

BACKGROUND: Approximately half of all patients with tumors need radiotherapy. Long-term survivors may suffer from late sequelae of the treatment. The existing radiotherapeutic techniques are being refined so that radiation can be applied more precisely, with the goal of limiting the radiation exposure of normal tissue and reducing late sequelae. METHODS: This review is based on the findings of a selective search in PubMed for publications on late sequelae of conventional percutaneous radiotherapy, January 2000 to May 2020. Late sequelae affecting the central nervous system, lungs, and heart and the development of second tumors are presented, and radiobiological mechanisms and the relevant technical and conceptual considerations are discussed. RESULTS: The current standard of treatment involves the use of linear accelerators, intensity-modulated radiotherapy (IMRT), image-guided and respiratory-gated radiotherapy, and the integration of positron emission tomography combined with computed tomography (PET-CT) in radiation treatment planning. Cardiotoxicity has been reduced with regard to the risk of coronary heart disease after radiotherapy for Hodgkin's lymphoma (hazard ratio [HR] 0.44 [0.23; 0.85]). It was also found that the rate of radiation- induced pneumonitis dropped from 7.9% with conformal treatment to 3.5% with IMRT in a phase III lung cancer trial. It is hoped that neurocognitive functional impairment will be reduced by hippocampal avoidance in modern treatment planning: an initial phase III trial yielded a hazard ratio of 0.74 [0.58; 0.94]. It is estimated that 8% of second solid tumors in adults are induced by radiotherapy (3 additional tumors per 1000 patients at 10 years). CONCLUSION: Special challenges for research in this field arise from the long latency of radiation sequelae and the need for largescale, well-documented patient collectives in order to discern dose-effect relationships, and take account of cofactors, when the overall number of events is small. It is hoped that further technical and conceptual advances will be made in the areas of adaptive radiotherapy, proton and heavy-ion therapy, and personalized therapy.

Quantity-guided drain management reduces seroma formation and wound infections after radical lymph node dissection: results of a comparative observational study of 374 melanoma patients.

BACKGROUND: Lymphatic fistulas are common complications after lymph node dissections in melanoma patients. We investigated whether drain management could improve the patient's outcome. METHODS: Patients who underwent axillary or inguinal lymph node dissection (RALND or RILND) for malignant melanoma were recorded in a prospective database. Two different methods of drain management were compared. Either the drain was removed no later than the eighth postoperative day (period I, 2003-2007) or it was left in place until fluid flow was below 50 ml in 24 h for two consecutive days (period II, 2008-2011). The main outcome criterion was the incidence of seroma punctures after drain removal. RESULTS: 374 patients were analysed. The incidence of seroma punctures significantly decreased in period II. The number of patients with elevated lymphatic secretions rose by 41.3% (RALND) and 38.1% (RILND). With the exception of lymphatic fistulas, we observed significantly more local complications with need for treatment in period I (n = 104, 52%) than in period II (n = 31, 18%). In period II, the hospital stays after both procedures were significantly reduced. CONCLUSIONS: We conclude that quantity-guided drain management leads to a prolonged interval of drainage but is associated with a lower incidence of seroma formation and shorter hospital stay.

Planning study for Merkel cell carcinoma based on the relapse pattern.

PURPOSE: To develop a technique for radiation (RT) of in-transit path ways (IT) in Merkel cell carcinoma. METHOD: In the planning study, IT were ink-marked on the skin during sentinel lymphscintigraphy and wire-marked in planning-CT. Pre- and post-operative planning-CTs were acquired. The clinical target volume (CTV) included tumor bed plus safety margin, IT and draining nodes, the planning volume (PTV) the CTV plus 0.5-1cm margin. VMAT plans with 2-3 arcs were analyzed. RESULTS: A planning study was performed for five pts. including two pts. with primary tumor (PT) in head and neck, 1 pt. each with PT of elbow, forearm and upper leg respectively. Plans showed satisfactory PTV coverage: Dmean 100%±0%, D98% 92.4%±2.24%, homogeneity index (HI) 0.095±0.01, conformation number (CN) 0.84±0.01 and conformality index (CI) 0.95±0.01. CONCLUSION: The planning study confirms feasibility of highly conformal irradiation of IT pathways based on individualized target delineation. Currently, patients referred for non-metastatic MCC are encouraged to enroll in a prospective clinical study that evaluates the feasibility of radiation of IT pathways.

Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity.

BACKGROUND AND PURPOSE: The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity. MATERIALS AND METHODS: Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted. RESULTS: With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance. CONCLUSION: Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.

Regional nodal relapse in surgically staged Merkel cell carcinoma.

PURPOSE: The nodal relapse pattern of surgically staged Merkel cell carcinoma (MCC) with/without elective nodal radiotherapy (RT) was studied in a single institution. METHOD: A total of 51 patients with MCC, 33% UICC stage I, 14% II, 53% III (4 lymph node metastases of unknown primary) were eligible. All patients had surgical staging: 23 patients sentinel node biopsy (SNB), 22 patients SNB followed by lymphadenectomy (LAD) and 6 patients LAD. In all, 94% of the primary tumors (PT) were completely resected; 57% of patients received RT, 51% of known PT sites, 33% (8/24 patients) regional RT to snN0 nodes and 68% (17/27 patients) to pN+ nodes, mean reference dose 51.5 and 50 Gy, respectively. Mean follow-up was 6 years (range 2-14 years). RESULTS: A total of 22% (11/51) patients developed regional relapses (RR); the 5-year RR rate was 27%. In snN0 sites (stage I/II), relapse occurred in 5 of 14 nonirradiated vs. none of 8 irradiated sites (p = 0.054), resulting in a 5-year RR rate of 33% versus 0% (p = 0.16). The crude RR rate was lower in stage I (12%, 2/17 patients) than for stage II (43%, 3/7 patients). In stage III (pN+), RR appeared to be less frequent in irradiated sites (18%, 3/14 patients) compared with nonirradiated sites (33%, 3/10 patients, p = 0.45) with 5-year RR rates of 23% vs. 34%, respectively. DISCUSSION: Our data suggest that adjuvant nodal RT plays a major role even if the sentinel nodes were negative. CONCLUSION: Adjuvant RT of the lymph nodes in patients with stage IIa tumors and RT after LAD in stage III tumors is proposed and should be evaluated prospectively.

Association of single nucleotide polymorphisms in the genes ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with risk of severe erythema after breast conserving radiotherapy.

PURPOSE: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with the risk of severe erythema after breast conserving radiotherapy. METHODS AND MATERIALS: Retrospective analysis of 83 breast cancer patients treated with breast conserving radiotherapy. A total dose of 50.4 Gy was administered, applying 1.8 Gy/fraction within 42 days. Erythema was evaluated according to the Radiation Therapy Oncology Group (RTOG) score. DNA was extracted from blood samples and polymorphisms were determined using either the Polymerase Chain Reaction based Restriction-Fragment-Length-Polymorphism (PCR-RFL) technique or Matrix-Assisted-Laser-Desorption/Ionization -Time-Of-Flight-Mass-Spectrometry (MALDI-TOF). Relative excess heterozygosity (REH) was investigated to check compatibility of genotype frequencies with Hardy-Weinberg equilibrium (HWE). In addition, p-values from the standard exact HWE lack of fit test were calculated using 100,000 permutations. HWE analyses were performed using R. RESULTS: Fifty-six percent (46/83) of all patients developed erythema of grade 2 or 3, with this risk being higher for patients with large breast volume (odds ratio, OR = 2.55, 95% confidence interval, CI: 1.03-6.31, p = 0.041). No significant association between SNPs and risk of erythema was found when all patients were considered. However, in patients with small breast volume the TGFB1 SNP was associated with erythema (p = 0.028), whereas the SNP in XPD showed an association in patients with large breast volume (p = 0.046). A risk score based on all risk alleles was neither significant in all patients nor in patients with small or large breast volume. Risk alleles of most SNPs were different compared to a previously identified risk profile for fibrosis. CONCLUSIONS: The genetic risk profile for erythema appears to be different for patients with small and larger breast volume. This risk profile seems to be specific for erythema as compared to a risk profile for fibrosis.

Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity.

PURPOSE: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity. METHODS AND MATERIALS: Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively. RESULTS: Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32-3.55, p=0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity. CONCLUSIONS: It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.

Sex-specific aspects of tumor therapy.

There is increasing evidence that sex-specific differences in toxicity profiles and outcome after radiotherapy are accumulating in medical oncology, and that treatment strategies may require some modification. Furthermore, sex-specific differences in the sensitivity to genotoxic and therapeutical agents are also of general concern for risk estimation. This review is focussed on the specific influence of sex on these endpoints covering both a clinical and a biological point of view. In this paper, the literature was systematically reviewed with respect to sex-specific differences in tumor and normal tissue sensitivity after exposure to ionizing radiation, as well as to the relevant underlying molecular and cellular mechanisms. Although a number of data on sex-specific differences are available and remarkable differences on clinical, molecular, and cellular levels have been reported, a firm conclusion on any existing sex-specific differences is not yet possible. Future studies are required and should be focussed on this aspect of individual radiosensitivity.

Individual radiosensitivity measured with lymphocytes may predict the risk of acute reaction after radiotherapy.

PURPOSE: We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy. METHODS AND MATERIALS: Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions. RESULTS: Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy. CONCLUSION: Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.

[On the interaction of adjuvant radiotherapy and tamoxifen treatment for breast cancer]. / Zur Interaktion von Strahlentherapie und Tamoxifen beim Mammakarzinom.

BACKGROUND: Tamoxifen (TAM) is well established in the adjuvant therapy of breast cancer. However, the timing of TAM therapy, concurrent or after radiotherapy, is controversial. METHOD: Literature is reviewed with respect to experimental and clinical data on interaction of TAM and radiation on tumor control and radiation side effects. RESULTS: In vitro data support the concept of antagonistic effects of concurrent TAM and radiation on tumor cells, but in animal models a synergistic effect was seen. Considering the modulation of TAM effects by estrogen and growth factor receptors, two-dimensional systems may not be suitable for studying the interaction of TAM and radiation. From a clinical perspective, a tumor-protective effect of TAM therapy concurrent with radiation was not evident. However, prospective studies addressing this question adequately are not available at the time. CONCLUSION: Although some studies indicate an enhancement of lung and subcutaneous fibrosis after TAM therapy, the side effects are mild and at this point do not seem to warrant withholding TAM.

Hyperfractionated-accelerated radiotherapy followed by radical surgery in locally advanced tumors of the oral cavity.

PURPOSE: To evaluate the outcome of hyperfractionated-accelerated radiotherapy and subsequent planned primary tumor resection and radical neck dissection in locally advanced tumors of the oral cavity. PATIENTS AND METHODS: This retrospective analysis evaluates 126 subsequent patients who were treated between 1988 and 1997 for locally advanced tumors of the oral cavity (with extension into the oropharynx in 17 patients), 34 (27%) AJCC stage III and 92 (73%) stage IV. Primary tumor and nodal metastases were irradiated with 1.4 Gy bid to a median total dose of 72.8 Gy (range 58.8-75.6 Gy). Then, planned radical surgery of the primary site according to the initial tumor extent and cervical nodes was performed. Median follow-up of living patients was 6 years (range 1-11 years). RESULTS: 4 weeks after radiotherapy, 14 patients (11%) had complete tumor remission, 92 (73%) partial remission, 15 (12%) no change, and five (4%) progressive disease. Complete resection was achieved in 117 (93%) patients (nine incomplete resections). 5-year locoregional control rate was 62 +/- 9%, overall survival 36 +/- 9%. Surgery-related morbidity occurred in 42 patients (33%; mainly delayed wound healing and fistulae), overall severe treatment-related morbidity in 46 patients (36%). 24/84 relapse-free patients (29%) required a percutaneous gastrostomy or nasal tube > or = 1 year after therapy. CONCLUSION: In this study, the outcome of combined curative radiotherapy and planned surgery of the primary tumor and neck nodes was comparable to reported results of hyperfractionated radiotherapy with or without salvage surgery of the neck nodes with respect to locoregional control and overall survival. Planned surgery carries a substantial risk of morbidity and seems to offer no benefit in comparison to salvage surgery of the neck nodes only. Therefore, salvage surgery is preferred.

Is grading of breast fibrosis with mammography feasible?

PURPOSE: To establish a grading system for mammographic fibrosis and correlate it with clinical fibrosis. PATIENTS AND METHODS: Analogous to the LENT/SOMA scale a four-tiered scoring scale of breast fibrosis in mammography (G0 = absent, G1 = barely increased density, G2 = definitely increased density to G3 = very marked density) was established by two observers in a group of 16 patients. Reference mammograms were selected. Independently and blinded to clinical results, three observers scored the fibrosis in mammograms of further 31 patients examined by one radiation oncologist in a cross-sectional follow-up study. Pretreatment parenchyma density was judged according to the American College of Radiology (ACR). Interobserver correlation of mammography scoring as well as correlation of mammography and clinical findings were calculated with Cohen's weighted kappa. All patients had breast-conserving surgery and axillary resection for breast carcinoma T1-2N0-1. The breast was irradiated to a median reference dose of 55 Gy (range 50-60 Gy) with 2 Gy five times weekly or 2.5 Gy four times weekly. Two patients received chemotherapy, 14 patients tamoxifen. Median age was 55 years, median follow-up 8 years (4-15 years). RESULTS: 14 of 31 patients had clinical fibrosis, twelve G1 and two G2. In mammography, mild fibrosis (G1) was seen in 12/12/18 patients (observer 1/2/3) and moderate fibrosis (G2) in 9/10/2 patients. Interobserver correlation for observers 1 and 2 who had developed the score was fair (Cohen's weighted kappa 0.64, 95% confidence interval 0.4-0.88). However, it was weak for observer 3 (0.36 and 0.42, respectively) who relied on reference mammograms only. Independent interobserver correlation of pretreatment breast density was good for all observers (Cohen's weighted kappa 0.73-0.8). The correlation of fibrosis by mammography and palpation was weak (Cohen's weighted kappa 0.32-0.42). CONCLUSION: Grading fibrosis as depicted by mammography is possible, especially if observers prepare by jointly analyzing a training group. It may be useful to study treatment effects, e. g., of fractionation or drugs, because retrospective and repeated analysis is possible. The correlation of mammography with clinical grading should be further evaluated with more objective clinical reference tools.

Radiation-induced plexopathy and fibrosis. Is magnetic resonance imaging the adequate diagnostic tool?

PURPOSE: To investigate magnetic resonance imaging (MRI) features of radiation-induced plexopathy (RIP) and radiation-induced fibrosis frequently associated with RIP. PATIENTS AND METHODS: Seven patients with late radiation sequelae in the supraclavicular region were examined with MRI after a median interval of 7 years (range, 5-18 years) following radiotherapy and 4-7 years after the onset of RIP. Four patients had RIP plus severe soft-tissue fibrosis, two RIP without soft-tissue fibrosis (n = 2/6), and one patient fibrosis without RIP. Patients underwent surgery of breast cancer (n = 6) or chest wall relapse (n = 1) and radiotherapy to the supraclavicular fossa with cobalt with an anterior portal in fractions of 1.7-2.6 Gy to 43-51.6 Gy in 3 cm depth. All patients were relapse-free at the time of MRI. Fibrosis and RIP were scored clinically (RTOG classification). Fibrosis of the supraclavicular and/or axillary region was marked in three and mild in two patients. RIP was mild, marked and severe in two patients each. MRI was performed with a 1.5-T unit including coronal STIR, coronal and transversal T2-weighted, transversal T1-weighted and fat-saturated post-contrast (gadolinium-DTPA) spin echo sequences. RESULTS: The brachial plexus appeared normal in all patients, but subtle changes of adjoining tissue (slight, linear signal intensity in T2-weighted images or contrast enhancement surrounding the plexus) were detected in patients with RIP (n = 4/6) and the patient without RIP (n = 1). However, alterations of the soft tissue (marked signal intensity in T2-weighted sequences) correlated well with the clinical degree of fibrosis and were restricted to areas of marked to severe fibrosis (n = 3/3). CONCLUSION: Reliable MRI signs of RIP could not be identified. The severity of fibrosis closely corresponded to MRI features. The role of MRI in the diagnostic work-up of RIP is, therefore, the exclusion of tumor relapse.

Is there a life-long risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients?

BACKGROUND AND PURPOSE: To contribute to the question whether the risk of radiation-related brachial plexopathy increases, remains constant or decreases with time after treatment. PATIENTS AND METHODS: Between 12/80 and 9/93, 140 breast cancer patients received supraclavicular lymph node irradiation using a telecobalt unit. Total dose was 60 with 3Gy per fraction at a depth of 0.5 cm and 52 with 2.6Gy per fraction to the brachial plexus at a depth of 3 cm. Twenty-eight women received chemotherapy, 34 tamoxifen. Brachial plexopathy was graded using a modified LENT-SOMA score. Actuarial complication-free survival and overall survival were obtained from Kaplan-Meier analysis. The impact of chemotherapy or tamoxifen was tested using the chi2 test. The annual incidence of radiation-related brachial plexopathy was assessed by exponential regression as described by Jung et al. [Radiother Oncol 61 (2001) 233]. RESULTS: Actuarial overall survival was 67.1% after 5 years, 54.0% after 10 years, 49.9% after 15 years, and 44.0% after 20 years. In 19/140 patients, brachial plexopathy grade>/=1 occurred after a median interval of 88 (30-217) months. The percentage of patients being free from plexopathy was 96.1% after 5 years, 75.5% after 10 years, 72.1% after 15 years, and 46.0% after 19 years, respectively. A significant impact of type of surgery, chemotherapy or tamoxifen was not observed. The annual incidence of brachial plexopathy was 2.9% for grade>/=1 lesions and 0.8% for grade>/=3 lesions. The rates did not change significantly with time. CONCLUSIONS: The risk of brachial plexopathy after supraclavicular lymph node irradiation in breast cancer patients remains constant for a considerable portion of the patient's life.

A patient questionnaire for radiation-induced brachial plexopathy.

We analyzed the usefulness of a symptom questionnaire to screen for radiation-induced brachial plexopathy (RIBP) after breast cancer treatment. Four questions addressed distal and proximal paresis: impaired hand functions, problems raising the arm, carrying weights, and lifting objects from a high shelf. Eighty-one relapse-free patients were neurologically examined. Treatment was mastectomy (51%) or breast-conserving surgery (49%), radiotherapy to the supraclavicular +/- axilla with median 60 Gy maximum dose. Sixty-five subsequent control patients had breast-conserving surgery and radiotherapy to the breast only with 55 Gy median dose. Median follow up was 10 and 7.4 years, respectively. Sixteen patients had RIBP, 7 had Radiation Therapy Oncology Group (RTOG) grade 1, 4 grade 2, 3 grade 3, and 2 grade 4 RIBP. Thirty-seven patients had fibrosis and 32 had arm edema. Four patients with RIBP had no fibrosis (n = 2) or fibrosis of the axilla only (n = 2). Specificity of the question "impaired hand functions" for RIBP was 0.66 (95% confidence interval [CI], 0.51-0.78); sensitivity was 0.80 (95% CI, 0.52-0.96). Specificity of the question "raising the arm" was 0.98 (95% CI, 0.9-0.99) and sensitivity was 0.18 (95% CI, 0.04-0.45); the rate of false-positive control patients was 3%. In multivariate analysis, "impaired hand functions" and fibrosis were independent indicators of RIBP (P <0.005). Patients with breast irradiation only stated moderate/pronounced impaired hand functions; and problems carrying weights and lifting objects from a high shelf in 38%, 58%, and 77%, not significantly different from patients with RIBP or the patients with supraclavicular radiation. RIBP is not necessarily associated with fibrosis. The aim of the questionnaire was screening of a population at risk for RIBP. In this group, the question "problems raising the arm" detected severe RIBP with high specificity. Negation of "impaired hand functions" excludes RIBP. Both questions should be included in follow-up questionnaires.

Individual radiosensitivity measured with lymphocytes may be used to predict the risk of fibrosis after radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: To analyse the relationship of individual cellular radiosensitivity and fibrosis after breast conserving therapy. A new model was used describing the percentage of patients developing fibrosis per year and per patient at risk. PATIENTS AND METHODS: In a retrospective study, 86 patients were included, who had undergone breast conserving surgery and irradiation of the breast with a median dose of 55 Gy (54-55 Gy) given at 2.5 Gy/fraction (n=57) or 2 Gy/fraction (n=29). Median age was 62 years (range 44-86) and median follow-up was 7.5 years (range 5-17). Patients were examined for fibrosis according to the LENT/SOMA score. For analysis, fibrosis was classified as grade 0 and grade 1 (G0-1) or present grade 2 and grade 3 (G2-3). The time to complete development of fibrosis was determined by analysis of yearly mammograms. Individual cellular radiosensitivity was determined by scoring lethal chromosomal aberrations in in vitro irradiated (6 Gy) lymphocytes using metaphase technique. Patients with low/intermediate cellular radiosensitivity were compared with patients with high cellular radiosensitivity using actuarial methods. RESULTS: Ten patients developed fibrosis at 1-8 years after radiotherapy. Individual cellular radiosensitivity was described by normal distribution of lethal chromosomal aberrations, the average was 5.47 lethal aberrations per cell (standard deviation (SD) 0.71). Cellular radiosensitivity was defined as low/intermediate (< or =6.18 lethal aberrations) in 73 patients and high (>6.18 lethal aberrations; mean+SD) in 13 patients. In both groups, the actuarial rate of fibrosis-free patients decreased exponentially with time after radiotherapy. Patients with high cellular radiosensitivity showed a 2.3-fold higher annual rate for fibrosis than patients with intermediate and low radiosensitivity (3.6 versus 1.6% per year). CONCLUSIONS: In breast cancer patients, high individual cellular radiosensitivity as determined by the number of lethal chromosome aberrations in in vitro irradiated lymphocytes might be associated with an enhanced annual rate of fibrosis.

Cosmesis from the patient's and the doctor's view.

PURPOSE: Long-term cosmesis from the patient's perspective is compared to the doctor's appraisal. Factors that determine judgment of cosmesis are analyzed. Also, a patient questionnaire was designed to screen for normal tissue reactions and is evaluated. METHODS AND PATIENTS: With structured questions, patients rated their satisfaction considering cosmesis, the difference in overall appearance, and specific changes of the breast. Two doctors rated cosmesis and radiation late effects (LENT/SOMA). Ratings were compared, and the relative impact of single items was studied. Two hundred eighty-seven patients with unilateral breast carcinoma were examined after a median follow-up of 8 years. They were treated between 1981 and 1995 with lumpectomy and radiotherapy of the breast with 1.8-2.5 Gy fractions with a median total dose of 55 Gy (range: 50-65 Gy). RESULTS: One hundred sixty-one patients rated cosmesis as satisfying, 73 patients rated it as acceptable, and 25 patients as poor. Eighty-nine patients noted severe changes of appearance. Severe firmness and extensive scars were the most frequent complaint; the most important single item for judging cosmesis as poor was highly visible scars. Generally, doctors rated cosmesis less favorably (satisfactory, 150 patients; poor, 43 patients). Severe fibrosis was more important than discoloration of the breast or scars. Correlation between patients' and doctors' rating of cosmesis was modest (Cohen's weighted kappa 0.29), whereas the doctor's rating correlated well (0.55). Specificity and sensitivity of the questionnaire item for severe fibrosis (using doctors' judgments as gold standard) was 0.8; Cohen's weighted kappa was 0.34 (95% confidence interval: 0.21-0.48). CONCLUSION: Rating of cosmesis is subjective. Patients' satisfaction with cosmesis is greater than the doctors' and is determined not only by radiation late effects, but also by factors unrelated to the appearance of the breast. Severe fibrosis may be detected by a patient questionnaire.

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA) scores were compared in a group of breast cancer patients. The impact of the classification system on grading late effects was evaluated. MATERIALS AND METHODS: Telangiectasia, skin pigmentation, and fibrosis were scored according to both LENT/SOMA and RTOG criteria. The results were compared with respect to up- or downgrading and correlated (Spearman's rho). Other side effects were recorded using LENT/SOMA criteria. Interobserver variability was calculated with Cohen's kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent breast-conserving therapy between 1981 and 1995 were examined. The median dose of radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31 patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were used. Two doctors examined 45 patients jointly. RESULTS: Of all patients, 20% had telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77% retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearman's rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy were observed in 226 patients using LENT/SOMA criteria. Interobserver variability was similar for both classification systems and ranged from Cohen's kappa 0.3 (retraction) to 0.91 (telangiectasia). CONCLUSIONS: LENT/SOMA criteria seem to be the better tool in grading and recording late radiation toxicity compared with the RTOG scale. There was some upgrading with the RTOG score when skin toxicity is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of the LENT/SOMA scoring system should be considered to standardize reporting of late radiation morbidity.

Radiotherapy after high-dose chemotherapy and peripheral blood stem cell support in high-risk breast cancer.

PURPOSE: To assess the toxicity and efficacy of radiotherapy with respect to locoregional control after adjuvant high-dose chemotherapy for patients with breast cancer. At first, radiotherapy was withheld because of toxicity concerns, but it was introduced in 1995 because of reported high locoregional relapse rates. METHODS AND MATERIALS: Between 1992 and 1998, 40 patients with Stage II-III high-risk breast cancer received adjuvant high-dose chemotherapy consisting of thiotepa, mitoxantrone, and cyclophosphamide and peripheral blood stem cell support after four cycles of induction chemotherapy. The chest wall or breast, as well as the supraclavicular nodes, were irradiated with electrons and photons to a median dose of 50.4 Gy in 20 patients. Six additional patients received only supraclavicular irradiation to a median dose of 50.4 Gy. Acute toxicity was scored clinically. Pulmonary function tests were performed in 14 irradiated patients before high-dose chemotherapy and 1.1-4.4 years (median 1.6) after irradiation. The median follow-up time of living patients was 33 vs. 67 months in irradiated (n = 26) and nonirradiated (n = 14) patients, respectively. RESULTS: G2 and G3 hematologic toxicity occurred in 1 patient each. No clinical pneumonitis or clinical impairment of lung function was observed. After 1-2 years, the lung function tests showed only minor changes in 4 patients. The 3-year locoregional control rate was 92% in the irradiated patients vs. 58% in the nonirradiated patients (p = 0.049, actuarial analysis). CONCLUSION: In this series, adjuvant radiotherapy after adjuvant chemotherapy for breast cancer appeared well tolerated, with improved local regional control and without significant side effects. Longer follow-up and more patient accrual, as well as Phase III trials, are necessary for confirmation.