Consequential Late Effects Research Articles

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation

IntroductionThe phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. Ipsilateral Breast Tumour Relapse (IBTR)Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4–3.1), 1.7% (1.2–1.6) after 27 Gy and 1.4% (0.2–2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. Normal tissue effectsThe 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. Radiobiological considerationsThe design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/β estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. ConclusionThe 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

Consequential late effects up to >10 years following primary and postoperative radiotherapy for prostate cancer

Consequential late effects up to >10 years following primary and postoperative radiotherapy for prostate cancer

Consequential Late Effects up to 10 years Following Primary and Postoperative Radiotherapy for Prostate Cancer

To evaluate the impact of acute toxicity on chronic problems following primary (pRT) and postoperative radiotherapy (opRT) for prostate cancer. Patients treated in the years 2003-2008 were surveyed prospectively using a validated questionnaire (EPIC, Expanded Prostate Cancer Index Composite) before the beginning of RT, at the last day, two months, 1-3 years, 5-8 years and 9-13 years after the end of RT. A score difference of 5 points is regarded as clinically significant, >20 points as a clinically large quality of life (QoL) change. Only patients treated up to 70.2-72Gy (pRT) and 66.0-66.6Gy (opRT) in 1.8-2.0Gy fractions were included. Patients were required to respond to the questionnaire before and at the end of RT, additionally at least one questionnaire >1 year after RT, resulting in 287 patients (n = 185 pRT and n = 102 opRT). The response rate to the questionnaire after 1-3 years was 85% (n = 245), after 5-8 70% (n = 201) and after 9-13 years 55% (n = 157). Significant differences before the start of RT between pRT and opRT were lower urinary (mean bother score of 87 vs. 82; p = 0.02) and sexual (mean bother score of 61 vs. 39; p<0.01) scores for opRT. However, larger changes at the end of RT were found for pRT (urinary score: 21 vs. 13 points; p<0.01; sexual score: 11 vs. -2 Punkte; p<0.01; negative change = QoL improvement). After 10 years, urinary scores declined less (5 vs. 14 points; p = 0.04), sexual scores declined more (18 vs. -2 points; p = 0.01) following pRT vs. opRT. For patients with a bother score decline >20 points in the bowel domain (Bdiff>20) and urinary domain (Udiff>20) at the last day of RT, the respective bowel baseline scores were similar both for pRT and opRT, urinary baseline scores only for opRT. However, patients with pRT and Udiff>20 had significantly higher baseline scores (85 vs. 79; p<0.01). For patients with Bdiff >20, both the difference in relation to baseline levels and the absolute bother scores 10 years after RT remained significantly worse in comparison to patients with smaller acute changes (71 vs. 93 10 years after pRT; p<0.01; 82 vs. 91 after opRT; p = 0.07). The same effect was found for patients with Udiff>20 in the urinary domain, statistically significant up to 5 years after pRT, but only up to 2 months after opRT. In comparison to opRT, significantly larger acute, but smaller chronic urinary changes resulted. Acute toxicity during radiotherapy has a significant impact on chronic problems as consequential late effects, especially in the bowel domain. These acute bowel score changes cannot be predicted by baseline problems before the beginning of treatment.

Normal tissue tolerance

Effects of radiation exposure are observed in virtually all normal tissues. Early reactions occur primarily in turnover tissues (e.g., bone marrow, epidermis, mucosae of the gastrointestinal tract), where proliferative impairment results in progressive hypoplasia and eventually complete loss of functional cells, after a tissue dependent but dose independent latent time. These early radiation reponses are regularly preceded and accompanied by vascular and inflammatory reactions. In contrast, late reactions are based on combined parenchymal, vascular, and connective tissue changes; very late effects are dominated by vascular sequelae. In most instances, a significant involvement of the immune system can also be demonstrated for chronic radiation sequelae, and a contribution of neural changes is discussed. The orchestrated response of all tissue components results in loss of function within the exposed volume. Importantly, latent times of late effects are inversely dependent on dose. Hence modern, highly conformal treatment techniques with relatively low and inhomogeneous doses in the organs at risk (OAR) require very long follow-up intervals with a precise assessment and documentation of the complication endpoints for characterisation of the treatment-induced morbidity profile. Consequential late effects (CLEs) develop through interactions between early and late effects in the same organ; they follow the radiobiological principles of the early reactions. The clinical manifestation of radiation responses is defined by several parameters, summarized as the “R’s of radiobiology”. First, each individual symptom or endpoint of radiation-induced morbidity follows an individual dose-effect relationship (intrinsic ‘R’adiosensitivity), in many instances related to the dose within specific subvolumes of the individual OAR, rather than e.g., the mean organ dose. The biological effectiveness of a certain (total) dose is modulated by exposure conditions: Changes in dose fractionation protocols (‘R’recovery) predominantly impact on late responding tissues, while overall treatment time (‘R’epopulation) predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure (i’R’adiated volume”) are related to tissue architecture. In mainly ‘tubular’ or ‘serial’ organs (e.g., gastrointestinal tract, but also vasculature), local exposure affects function in downstream compartments. In contrast, in predominantly ‘parallel’ organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. However, all organs in fact are composed of tubular and serial components. Translational studies into damage processing (molecular ‘R’adiopathology), starting immediately after the onset of radiation exposure, but proceeding for long and very long time intervals even at subclinical levels, intra- and intercellular signals and signalling pathways may be identified that are relevant or even specific for the clinical manifestation of morbidity endpoints. These can serve as a basis to identify (early) biomarkers of the individual risk for specific tissue reactions and endpoints, and also for establishment of strategies to prevent/mitigate tissue effects after exposure.

Normal tissue tolerance

: Effects of radiation exposure are observed in virtually all normal tissues. Early reactions occur primarily in turnover tissues (e.g., bone marrow, epidermis, mucosae of the gastrointestinal tract), where proliferative impairment results in progressive hypoplasia and eventually complete loss of functional cells, after a tissue dependent but dose independent latent time. These early radiation reponses are regularly preceded and accompanied by vascular and inflammatory reactions. In contrast, late reactions are based on combined parenchymal, vascular, and connective tissue changes; very late effects are dominated by vascular sequelae. In most instances, a significant involvement of the immune system can also be demonstrated for chronic radiation sequelae, and a contribution of neural changes is discussed. The orchestrated response of all tissue components results in loss of function within the exposed volume. Importantly, latent times of late effects are inversely dependent on dose. Hence modern, highly conformal treatment techniques with relatively low and inhomogeneous doses in the organs at risk (OAR) require very long follow-up intervals with a precise assessment and documentation of the complication endpoints for characterisation of the treatment-induced morbidity profile. Consequential late effects (CLEs) develop through interactions between early and late effects in the same organ; they follow the radiobiological principles of the early reactions. The clinical manifestation of radiation responses is defined by several parameters, summarized as the “R’s of radiobiology”. First, each individual symptom or endpoint of radiation-induced morbidity follows an individual dose-effect relationship (intrinsic ‘R’adiosensitivity), in many instances related to the dose within specific subvolumes of the individual OAR, rather than e.g., the mean organ dose. The biological effectiveness of a certain (total) dose is modulated by exposure conditions: Changes in dose fractionation protocols (‘R’recovery) predominantly impact on late responding tissues, while overall treatment time (‘R’epopulation) predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure (i’R’adiated volume”) are related to tissue architecture. In mainly ‘tubular’ or ‘serial’ organs (e.g., gastrointestinal tract, but also vasculature), local exposure affects function in downstream compartments. In contrast, in predominantly ‘parallel’ organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. However, all organs in fact are composed of tubular and serial components. Translational studies into damage processing (molecular ‘R’adiopathology), starting immediately after the onset of radiation exposure, but proceeding for long and very long time intervals even at subclinical levels, intra- and intercellular signals and signalling pathways may be identified that are relevant or even specific for the clinical manifestation of morbidity endpoints. These can serve as a basis to identify (early) biomarkers of the individual risk for specific tissue reactions and endpoints, and also for establishment of strategies to prevent/mitigate tissue effects after exposure.

Radiobiology of tissue reactions.

Tissue effects of radiation exposure are observed in virtually all normal tissues, with interactions when several organs are involved. Early reactions occur in turnover tissues, where proliferative impairment results in hypoplasia; late reactions, based on combined parenchymal, vascular, and connective tissue changes, result in loss of function within the exposed volume; consequential late effects develop through interactions between early and late effects in the same organ; and very late effects are dominated by vascular sequelae. Invariably, involvement of the immune system is observed. Importantly, latent times of late effects are inversely dependent on the biologically equieffective dose. Each tissue component and--importantly--each individual symptom/endpoint displays a specific dose-effect relationship. Equieffective doses are modulated by exposure conditions: in particular, dose-rate reduction--down to chronic levels--and dose fractionation impact on late responding tissues, while overall exposure time predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure are related to tissue architecture. In 'tubular' organs (gastrointestinal tract, but also vasculature), punctual exposure affects function in downstream compartments. In 'parallel' organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. Forthcoming studies must address biomarkers of the individual risk for tissue reactions, and strategies to prevent/mitigate tissue effects after exposure.

Consequential late effects after radiotherapy for prostate cancer - a prospective longitudinal quality of life study

BackgroundTo answer the question if and to which extent acute symptoms at the end and/or several weeks after radiotherapy can predict adverse urinary and gastrointestinal long-term quality of life (QoL).MethodsA group of 298 patients has been surveyed prospectively before (time A), at the last day (B), two months after (C) and >one year after (D) radiotherapy using a validated questionnaire (Expanded Prostate Cancer Index Composite). A subgroup of 10% with the greatest urinary/bowel bother score decrease at time D was defined as patients with adverse long-term QoL.ResultsSubgroup and correlation analyses could demonstrate a strong dependence of urinary/bowel QoL after radiotherapy on urinary/bowel QoL before radiotherapy. In contrast to absolute scores, QoL score changes (relative to baseline scores) did not correlate with pretreatment scores. Long-term changes could be well predicted by acute changes. Patients reporting great/moderate bother with urinary/bowel problems at time C reported to have great/moderate bother at time D in ≥ 50%, respectively. In a multivariate analysis of factors for adverse long-term urinary and bowel QoL, score changes at time C were found to be independent predictors, respectively. Additionally, QoL changes at time B were independently predictive for adverse long-term bowel QoL.ConclusionsConsequential late effects play a major role after radiotherapy for prostate cancer. Patients with greater and particularly longer non-healing acute toxicity are candidates for closer follow-up and possible prophylactic actions to reduce a high probability of long-term problems.

Glucagon-Like Peptide-2 Improves Both Acute and Late Experimental Radiation Enteritis in the Rat

Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study. Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure. In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers. GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.

Concurrent Chemoradiotherapy in the Management of Squamous Cell Cancer of the Oropharynx: Current Standards and Future Directions

The use of radiotherapy and concurrent chemotherapy has been explored in the management of squamous cell head and neck cancer for more than 3 decades. Even the earliest phase II and phase III studies, which used conventional radiotherapy and single-agent chemotherapy with drugs such as fluorouracil, bleomycin, and cisplatin, suggested a survival benefit from this approach. Validation of concurrent chemoradiotherapy as a community standard occurred in 1996, with the initial report from INT 0099, a randomized trial comparing radiotherapy alone with concurrent radiation and single-agent cisplatin, followed by adjuvant fluorouracil and cisplatin in patients with advanced nasopharyngeal cancer (1). This study, subsequently published in 1998, demonstrated a highly significant progression-free and overall survival advantage for patients treated with the combinedmodality regimen, and this regimen was rapidly accepted as a standard of care for advanced nasopharyngeal cancer. Also in 1998 came a report from a large meta-analysis of updated, individual data assessing the role of chemotherapy in squamous cell head and neck cancer (2). Patients from randomized trials conducted between 1965 and 1993 were included. This analysis, subsequently published in 2000, reviewed results from 63 separate trials involving 10,741 patients, comparing locoregional treatment with or without chemotherapy. Although no overall survival benefit was seen for treatment schedules using either induction or adjuvant chemotherapy,ahighlysignificantsurvivalbenefitwasidentified for concomitant chemotherapy and radiation. A hazard ratio of 0.81 (95% Confidence Interval (CI), 0.76‐0.88) with a p value of <0.0001 and an 8% 5-year survival benefit was observed, even from these older studies. Although oropharynx cancer often predominated in these clinical trials, they were, in general, not site specific. Nonetheless, this meta-analysis further justified the use of concurrent chemoradiotherapy as a standard nonoperative treatment for this disease. Results from a North American Intergroup trial of chemoradiotherapy in patients with unresectable head-and-neck tumors were first presented in 2000 and were published in 2003 (3). This study compared radiotherapy alone with radiotherapy and single-agent cisplatin and a third arm using a split course of radiotherapy and concurrent combination fluorouracil and cisplatin. As seen in nasopharynx cancer, the concurrent chemoradiotherapy arm using single-agent cisplatin proved superior to radiotherapy alone, with a projected 3-year survival improvement from 23% to 37% and a median survival improvement from 12.6 to 19.1 months (p = 0.014). The third treatment arm, which used a split course of radiotherapy, did not prove to be statistically different from the other two arms, an observation attributed to the scheduled break in radiotherapy delivery on this arm of the trial. This Intergroup study firmly established concurrent chemoradiotherapy with single-agent cisplatin as a treatment standard for unresectable head and neck cancer. Although it was not a site-specific study, primary tumors in the oropharynx predominated in the study population. During this same period, several other smaller single- and multi-institution trials were also published, comparing various combinations of concurrent chemotherapy and radiotherapy with radiotherapy alone as definitive treatment for this disease. In general, they were also not site-specific studies. The results, however, were very consistent. The addition of concurrent chemotherapy to radiotherapy reproducibly improved both survival and locoregional control.

185 Consequential vs generic late effects

185 Consequential vs generic late effects

143 oral Consequential late effects in altered radiotherapy for head and neck cancer — incidence and risk factors

143 oral Consequential late effects in altered radiotherapy for head and neck cancer — incidence and risk factors

39 Amelioration of late radiation effects in mouse urinary bladder by modulation of acute symptoms — experimental evidence for consequential late effects

39 Amelioration of late radiation effects in mouse urinary bladder by modulation of acute symptoms — experimental evidence for consequential late effects

Therapeutic outcome and relation of acute and late side effects in the adjuvant radiotherapy of endometrial carcinoma stage I and II

Background and purpose: Adjuvant radiotherapy is the standard treatment for endometrial carcinoma. However, until now there has been no clear indication that radiotherapy in that setting improves survival. This calls for critical assessment of the relation between the expected benefit and the number and severity of postradiotherapeutic side effects. Material and methods: In a retrospective study 159 consecutive patients with stage I and II endometrial carcinoma were treated with external radiotherapy and vaginal brachytherapy after hysterectomy and bilateral salpingoophorectomy (no surgical lymph node staging). Recurrence rates, survival and side effects were evaluated, in particular with regard to the relation of acute and late toxicity. Results: Five percent of all patients developed a recurrence either in the abdomen or at distant locations. No pelvic relapses were diagnosed. Five-year relapse-free survival was 92% for stage IA+B, 84% for stage IC, and 79% for stage II disease. Acute toxicity was seen in 65.4% of patients, all grade 1 or 2, late toxicity grade 1 or 2 in 18.8%, grade 3 or 4 complications in 1.8%. The estimated 5-year freedom from late toxicity was 76.8%. Seventy-seven percent of all patients with treatment interruptions or premature end of therapy experienced late injury. In ten of 33 patients with late sequelae there was no free interval between early and late toxicity. No relation of radiation technique/fractionation and the rate of side effects was noticed. Conclusions: Adjuvant radiotherapy leads to excellent pelvic control, with few serious complications. Major acute toxicity shows significant correlation with the incidence of severe late injury, which we suggest to classify in part as consequential late effects.

Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity

Purpose. Toxicity of an accelerated 7 days per week fractionation schedule (arm A) was evaluated and compared with a conventional 5 days per week treatment (arm B) in a randomized trial. Materials and methods. Forty-four patients with squamous cell carcinoma of the head and neck in stage T 2–4N 0–1M 0 were included in the study. Total dose and dose per fraction of 2.0 Gy given once-a-day at 24 h intervals were the same in both arms of the trial. The only difference was the overall treatment time being 5 weeks in arm A and 7 weeks in arm B. Results. Analysis of severe mucosal reactions shows significant difference between arm A and B, with regard to both maximum score and duration of severe mucositis. Confluent mucositis (score > 15 according to the Dische system) lasting longer than 3 weeks developed in 48% of patients in arm A and only in 5% in arm B. In group A seven (30%) late effects (osteo- and soft tissue necrosis) occurred during 7–12 month follow-up with two reactions (10%) in group B being suspected as late effects. There was significant association between acute reactions and late effects in arm A, suggesting that the late effects are consequential. Conclusion. The high incidence of severe acute reactions and consequential late effects suggests that the accelerated treatment in arm A (using daily fractions of 2.0 Gy, 7 days per week) gives unacceptable toxicity.

156 Accidental over irradiation in breast cancer patients

In the Department of Radiation Therapy Vicenza Hospital, in Italy, where the author was working at the time, in September—october 1989 18 breast cancer patients (pts) were treated with electrons of a linac CGR Saturne 20: 12 after limited surgery (stages T1–2 N0 in 9 and T1–2 in 3 pts) and 6 after radical mastectomy (T2–3 N1–2 in 3 treated with radical mastectomy, I pt had inflammatory carcinoma and 2 local recurrence, both 5 years after radical surgery). Median age was 50 years (range 38–65). Because of an ionization chambers breakdown, the electron doses were higher (from 78% to 148%) than proposed (50 Gy/25f and boost of 10 Gy/5f). Twelve/18 pts had 25–30 fractions, 3/18 23–24 f, 2/18 22 f and 1/18 19 f. (At the end of radiotherapy erythema was noted as follows (ROTG score): grade 1 in 1 pt, grade 2 in 12, grade 3 in 4 and not indicated in 1. Since no dosimetric control was done during the two months, the total dose for each pt is unknown. A dosimetric control was asked for because of consequential late effects (i.e. worsening or persistence of erythema several weeks after the completion of radiotherapy) in pts treated with electrons. In the same period no abnormal affect was noted with photons (18 MV). Late effects were: skin necrosis requiring plastic surgery in 12/18 (6/12 pts had mastectomy after limited surgery); rib fractures in 11/18; pulmonary fibrosis in 12/18; pericardial or cardiac damage (all had left breast cancer) in 5/18. Until now 2 pts died: one for epidenuoid carcinoma in 1991, the other for metastatic disease in January 1995 (in 1988 she had had controlateral breast cancer: T1 N1 as the second cancer). No correlation was found between late effects and electron energy or number of fractions. In conclusion: there is no correlation between early and late radiation effects, consequential late effects can give radiation therapists a hint of doses higher than prescribed; a periodic programmed linear accelerator control of energies and doses is mandatory. In the Department of Radiation Therapy Vicenza Hospital, in Italy, where the author was working at the time, in September—october 1989 18 breast cancer patients (pts) were treated with electrons of a linac CGR Saturne 20: 12 after limited surgery (stages T1–2 N0 in 9 and T1–2 in 3 pts) and 6 after radical mastectomy (T2–3 N1–2 in 3 treated with radical mastectomy, I pt had inflammatory carcinoma and 2 local recurrence, both 5 years after radical surgery). Median age was 50 years (range 38–65). Because of an ionization chambers breakdown, the electron doses were higher (from 78% to 148%) than proposed (50 Gy/25f and boost of 10 Gy/5f). Twelve/18 pts had 25–30 fractions, 3/18 23–24 f, 2/18 22 f and 1/18 19 f. (At the end of radiotherapy erythema was noted as follows (ROTG score): grade 1 in 1 pt, grade 2 in 12, grade 3 in 4 and not indicated in 1. Since no dosimetric control was done during the two months, the total dose for each pt is unknown. A dosimetric control was asked for because of consequential late effects (i.e. worsening or persistence of erythema several weeks after the completion of radiotherapy) in pts treated with electrons. In the same period no abnormal affect was noted with photons (18 MV). Late effects were: skin necrosis requiring plastic surgery in 12/18 (6/12 pts had mastectomy after limited surgery); rib fractures in 11/18; pulmonary fibrosis in 12/18; pericardial or cardiac damage (all had left breast cancer) in 5/18. Until now 2 pts died: one for epidenuoid carcinoma in 1991, the other for metastatic disease in January 1995 (in 1988 she had had controlateral breast cancer: T1 N1 as the second cancer). No correlation was found between late effects and electron energy or number of fractions. In conclusion: there is no correlation between early and late radiation effects, consequential late effects can give radiation therapists a hint of doses higher than prescribed; a periodic programmed linear accelerator control of energies and doses is mandatory.