Kontynuacja debaty Maciejewskiego dotyczącej radioterapii chorych na zaawansowanego raka gruczołu krokowego: więcej wątpliwości

A recent critical review of clinical trials on radiotherapy for locally advanced prostate cancer by Maciejewski et al. [1] points to a conclusion that most of conventional 5-days-a-week, 2 Gy fraction regimes produce a “plateau effect”. Thus an increase in the total dose above approximately 70 Gy would not improve local tumour control, but could elevate the risk of later complications. Maciejewski et al. propose that radical hypofractionated 3D conformal or dose-intensity modulated radiotherapy with or without 3D HDR boost dose painting may improve the outcome of prostate radiotherapy. The present response describes some unforeseen challenges which may appear while implementing these new treatment strategies in clinical practice, and suggests possible solutions to solve these problems. Also, an alternative viewpoint on the data on dose-response in radiotherapy for prostate cancer is presented. It is postulated that, in addition to tumour hypoxia, distant metastases may create a quasi-plateau in dose-response, when biochemical failures and not loco-regional tumour control are used as the endpoint. Some arguments for the presence of dose response in postoperative EBRT for prostate cancer are presented. This some-what contradictory review of the existing data on radiotherapy for prostate cancer may be considered as a stimulus for further discussion regarding optimization of local therapy. It also illustrates an urgent need for new prospective trials, which would address the clinical and radiobiological ambiguities of theoretical predictions.Maciejewski i wsp. [1], w oparciu o przegląd badań klinicznych dotyczących radioterapii chorych na miejscowo zaawansowanego raka gruczołu krokowego, doszedł do wniosku, że frakcjonowanie konwencjonalne, tj. frakcje 2 Gy podawane przez 5 dni w tygodniu, może prowadzić do tzw. „efektu plateau”. Oznaczałoby to, że podwyższanie całkowitej dawki promieniowania powyżej około 70 Gy nie poprawia odsetka wyleczeń miejscowych, lecz może przyczynić się do wzrostu ryzyka późnych odczynów popromiennych. Maciejewski i wsp. przedstawili przesłanki przemawiające za tym, by do radykalnej radioterapii chorych na raka gruczołu krokowego wprowadzić hypofrakcjonowanie, tj. napromienianie z zastosowaniem wysokich dawek frakcyjnych, posługując się przy tym planowaniem 3 D, modulacją intensywności dawki i wybiórczym podwyższaniem dawki w tych częściach guza, które są niedostatecznie utlenowane. W aktualnej pracy omówiono natomiast trudności, na które można napotkać próbując wprowadzić te nowe schematy leczenia do praktyki klinicznej. Przedstawiono też alternatywny punkt widzenia, dotyczący oceny zależności dawka-efekt w radioterapii chorych na raka gruczołu krokowego: przyjęto bowiem, że gdy miarą niepowodzenia leczenia jest wznowa biochemiczna to „efekt plateau” przy eskalacji dawki może być związany z ujawnieniem się przerzutów odległych. Dokonano ponownej analizy danych klinicznych dotyczących związku dawka-efekt w radioterapii pooperacyjnej. Kontrowersje przedstawione w aktualnej pracy powinny być rozumiane jako bodziec stymulujący do dalszej dyskusji dotyczącej optymalizacji leczenia chorych na raka prostaty. Ilustrują one potrzebę badań klinicznych, które pozwoliłyby rozstrzygnąć wątpliwości przewidywań opartych o przesłanki teoretyczne

The evaluation of 3DRT and IMRT techniques in postoperative radiotherapy for thyroid medullary carcinoma

BackgroundRadical surgical excision is the treatment of choice in all medullary thyroid carcinomas. External beam radiotherapy for medullary thyroid carcinoma is necessary in advanced cases. Unfortunately, a large volume of the head and neck region which has to be irradiated is close to critical structures such as the spinal cord, larynx, and parotid glands, which creates a challenge during radiotherapy planning.AimThe aim of the study is to compare IMRT and 3D plans of patients diagnosed with medullary thyroid carcinoma in terms of CTV coverage and normal tissue sparing.Materials and MethodsA 46-year-old woman with medullary thyroid carcinoma, stage pT4a N1b M0, underwent radical resection, followed by adjuvant radiotherapy to a total dose 60 Gy to the clinical target volume (CTV). Three plans were generated to irradiate the thyroid bed and regional lymph nodes. Two intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DRT) plans were compared in terms of CTV coverage and organ at risk sparing.ResultsUsing the IMRT plans we achieved more homogeneous dose distribution with higher minimal dose and lower maximal dose in the target volume compared to 3DRT technique. Furthermore, mean and maximal dose to critical structures were lower when IMRT was applied compared to 3DRT.ConclusionsIMRT results in improved dose distribution within CTV compared to 3DRT. With the IMRT plan it is also possible to reduce the dose to the organ at risk, especially the larynx, salivary glands and spinal cord

Radiobiological rationale for stereotactic hypofractionated radiosurgery Part II. Normal tissue tolerance — dose constraints

The response of normal tissues/organs to SHRS is more complex than to conventional radiotherapy. Tolerance doses TD5/5 and TD50/5, proposed by Rubin and Casarett, cannot be simply used for SHRS. Instead of LQED2, the BED is advised. The term risk dose (RD) corresponds better than TD to the risk of late morphological and functional disorders (OAR). BED doses show a rapid gradient with increasing distance of the OAR from the tumour GTV. Other risk factors include the dose-volume relationship, OAR organization (serial or parallel) and the ratio of the FSU to the target call. Vasculoendothelial cell damage initiates series of processes resulting in clinical and functional late effect. Using available data and studies, RDmin and RDmax for doses are listed as physical and BED doses for various OAR and dose-volume constraints. The RD values and constraints are rough estimates, since the available SHRS data are sparse and fragmentary, which should be interpreted cautiously and need further clinical validation

Radiobiological rationale for Stereotactic Hypofractionated Radiosurgery (SHRS) Part I. LQED2 or BED formalism

In conventional radiotherapy, 5R’s mechanisms influence tumour cell kill, but in SHRS they do not sufficiently explain the biology of large doses. Indirect cell death is also induced by endothelial damage, stem cell death and antitumour immunity are also activated by a single dose ≥ 12–15 Gy. These three processes defined as extra 3R’s are characterizers in details. Despite some controversies, LQED formalism seems not quite adequate for SHRS. Experimental and a few clinical studies suggest BED formalism as much more useful. Both formalisms are compared and discussed. Clinical reports show a monotonical increase in Tumour Cure Probability (TCP) with higher BED doses. The advantage of SHRS results in significant shortening overall treatment time and in delivery of the BED doses higher than 100 Gy, producing an increase in the TCP, likely unachievable by conventional dose fractionation

Radiobiological rationale for stereotactic hypofractionated radiosurgery Part I. LQED2 or BED formalism

In conventional radiotherapy, 5R’s mechanisms influence tumour cell kill, but in SHRS they do not sufficiently explain the biology of large doses. Indirect cell death is also induced by endothelial damage, stem cell death and antitumour immunity are also activated by a single dose ≥ 12–15 Gy. These three processes defined as extra 3R’s are characterizers in details. Despite some controversies, LQED formalism seems not quite adequate for SHRS. Experimental and a few clinical studies suggest BED formalism as much more useful. Both formalisms are compared and discussed. Clinical reports show a monotonical increase in Tumour Cure Probability (TCP) with higher BED doses. The advantage of SHRS results in significant shortening overall treatment time and in delivery of the BED doses higher than 100 Gy, producing an increase in the TCP, likely unachievable by conventional dose fractionation

Radiobiological rationale for stereotactic hypofractionated radiosurgery Part II. Normal tissue tolerance — dose constraints

The response of normal tissues/organs to SHRS is more complex than to conventional radiotherapy. Tolerance doses TD5/5 and TD50/5, proposed by Rubin and Casarett, cannot be simply used for SHRS. Instead of LQED2, the BED is advised. The term risk dose (RD) corresponds better than TD to the risk of late morphological and functional disorders (OAR). BED doses show a rapid gradient with increasing distance of the OAR from the tumour GTV. Other risk factors include the dose-volume relationship, OAR organization (serial or parallel) and the ratio of the FSU to the target call. Vasculoendothelial cell damage initiates series of processes resulting in clinical and functional late effect. Using available data and studies, RDmin and RDmax for doses are listed as physical and BED doses for various OAR and dose-volume constraints. The RD values and constraints are rough estimates, since the available SHRS data are sparse and fragmentary, which should be interpreted cautiously and need further clinical validation

Short-course radiotherapy as part of total neoadjuvant therapy for locally advanced rectal cancer – a new standard?

Selection of optimal perioperative treatment for rectal cancer remains a subject of controversy. Recently established new rationales for the use of short-course preoperative radiotherapy (SCRT – 25 Gy in 5 fractions), instead of standard long-course preoperative radio-chemotherapy (LCRT-CT), are presented and discussed in the present review. New data suggest that short-course radiotherapy combined with 6 cycles of CAPOX, or 9 of FOLFOX4, at present may be considered the best option for perioperative treatment of high-risk rectal cancer. However, there is a clear need to further optimize preoperative treatment using rapidly evolving markers of treatment response, including microsatellite instability and targetable or predictive tumour mutations

Short-course radiotherapy as a part of total neoadjuvant therapy for locally advanced rectal cancer – a new standard?

Selection of optimal perioperative treatment for rectal cancer remains a subject of controversies.  Recently established new rationales for use of short-course preoperative radiotherapy (SCRT- 25 Gy in 5 fractions), instead of standard long-course preoperative radio-chemotherapy (LCRT-CT), are presented and discussed in the present review. New data suggest that short-course radiotherapy combined with 6 cycles of CAPOX, or 9 of FOLFOX4 may be considered, at present, the best option for perioperative treatment of high-risk rectal cancer. However, there is a clear need to further optimize preoperative treatment using rapidly evolving markers of treatment response, including microsatellite instability and targetable or predictive tumour mutations

78 Wpływ precyzji w wyznaczaniu GTV w planowaniu radioterapii na określenie prawdopodobieństwa miejscowego wyleczenia nowotworu i ryzyka wystąpienia przerzutów

Objętość guza pierwotnego jest uznanym ilościowym wskaźnikiem prognostycznym dla prawdopodobieństwa miejscowego wyleczenia nowotworu w radioterapii (P) i dla ryzyka wystąpienia przerzutów. Większość opracowań klinicznych nie uwzględnia jednak tego wskaźnika, gdyż w rutynowym postępowaniu diagnostyczno – terapeutycznym rejestrowany zwykle jest stopień zawansowania klinicznego nowotworu wg TNM lub FIGO, a nie przestrzenne wymiary guza. W bieżącym opracowaniu wykazano, że objętość guza (której odpowiada obszar GTV-Gross Tumor Volume), może być rutynowo mierzona w oparciu o dane przesyłane z Pracowni Tomografii Komputerowej do Pracowni Planowania Leczenia. Metoda ta nie wymaga dodatkowych nakładów finansowych i zabiera niewiele czasu, gdyż objętość można mierzyć przy okazji wyznaczania GTV. Przedstawiane dane dokumentują, że w grupie chorych z określonym stopniem zaawansowania klinicznego guza pierwotnego T (np. T3) istnieją ogromne (nawet 100-krotne) różnice w objętości guzów u poszczególnych chorych. Wstępne wyniki pracy wskazują też, że precyzja pomiarów objętości guzów w oparciu o dane z nowoczesnego systemu planowania leczenia jest w większości przypadków wystarczająca dla prawidłowej oceny P i R u poszczególnych chorych. Zdaniem autora, rutynowe pomiary objętości guza pierwotnego powinny być włączone do standardu diagnostycznego, niezależnie od oceny stopnia zaawansowania klinicznego nowotworu wg TNM, czy też innych, arbitralnie przyjętych skal