Dose–volume effects for normal tissues in external radiotherapy: Pelvis

Radiotherapy and Oncology 93 (2009) 153–167

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Systematic review

Dose–volume effects for normal tissues in external radiotherapy: Pelvis Claudio Fiorino a,*, Riccardo Valdagni b, Tiziana Rancati b, Giuseppe Sanguineti c a

Medical Physics Department, San Raffaele Scientific Institute, Milan, Italy Prostate program, Scientific Directorate Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy c Radiotherapy Department, The John Hopkins University, Baltimore, MD, USA b

a r t i c l e

i n f o

Article history: Received 23 February 2009 Received in revised form 11 August 2009 Accepted 11 August 2009 Available online 16 September 2009 Keywords: Toxicity in radiotherapy Prostate Gynecological Rectum Bladder NTCP Dose–volume models in radiotherapy Dose–volume histograms Intensity-modulated radiotherapy Optimisation in radiotherapy

a b s t r a c t A great deal of quantitative information regarding the dose–volume relationships of pelvic organs at risk has been collected and analysed over the last 10 years. The need to improve our knowledge in the modelling of late and acute toxicity has become increasingly important, due to the rapidly increasing use of inverse-planned intensity-modulated radiotherapy (IMRT) and the consequent need of a quantitative assessment of dose–volume or biological-based cost functions. This comprehensive review concerns most organs at risk involved in planning optimisation for prostate and other types of pelvic cancer. The rectum is the most investigated organ: the largest studies on dose–volume modelling of rectal toxicity show quite consistent results, suggesting that sufficiently reliable dose–volume/EUD-based constraints can be safely applied in most clinical situations. Quantitative data on bladder, bowel, sexual organs and pelvic bone marrow are more lacking but are rapidly emerging; however, for these organs, further investigation on large groups of patients is necessary. Ó 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 153–167

The rapidly increasing use of inverse-planned intensity-modulated radiotherapy (IMRT) is pushing the research in the quantitative assessment of dose–volume relationships of organs partially irradiated during external beam radiotherapy. After the first parametrization of dose–volume effects based on the experience from the 2D radiotherapy era reported by Burman et al. [1], the availability of 3D dose–volume information dramatically increased the amount of quantitative data. These efforts translated into both the proposal of reliable dose–volume constraints able to reduce toxicity, and the development of normal tissue complication probability (NTCP) models properly fitting these data in a usable way. Although the pelvic region is one of the most investigated areas, critical reviews, mainly focused on single organs [2–5], have been only sporadically published in the recent years. The current review covers most organs and normal structures potentially involved in planning optimisation for prostate and other cancers arising within the pelvis. Of the normal structures, the rectum, being the most investigated one, receives the greatest attention. On the other hand, quantitative information and modelling regarding bladder, bowel, sexual functions and pelvic bone

marrow are rapidly emerging and, although less established, will be critically presented. Literature was reviewed based on PubMed and MEDLINE database searches (up to January 2009), including abstracts of meetings and papers in press: for each section/subsection, key title words were used and possibly combined with other more general keywords (such as radiotherapy, dose–volume effects, NTCP and DVH). Bibliography of ‘‘key” papers was also used to find additional references. Publications generally dealing with pelvic toxicity without any correlation with dose–volume effects were generally disregarded, being outside the aim of the review. When large amount of the literature was available (as for the rectum and bowel), summary tables were prepared: when appropriate, most valuable publications were selected based on clear criteria (such as number of patients, definition of rectum extension, clarity of the end-point and homogeneity of the investigated population).

Rectum Late bleeding: dose–volume relationships

* Corresponding author. Address: Servizio di Fisica Sanitaria, Istituto Scientifico Ospedale San Raffaele, Via Olgettina 60, 20132 Milano, Italy. E-mail address: fi[email protected] (C. Fiorino). 0167-8140/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.08.004

Due to both the large number of patients with prostate cancer and the impact of rectal bleeding on the quality of life of long-sur-

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viving patients, rectal bleeding has been extensively investigated and reported in the recent literature. Fortunately, there is quite good consistency among the various studies dealing with this topic. A number of reasons may be cited to explain this success: the large data-sets available from several prospective trials; the relative simplicity/consistency along with the objective assessment of the end-point; the prevalently serial component of the mechanisms of the damage. There is a good agreement among several investigations on the prevalently serial-like behaviour of rectal bleeding, especially when considering severe bleeding [6–15]. Furthermore, it has been shown that the strict application of rectal dose–volume constraints in highdose inversely optimised intensity-modulated radiotherapy (IMRT) translates into a greatly reduced rate of bleeding [16–19]. A number of dose–volume constraints have been suggested and validated in order to maintain the rate of moderate/severe late bleeding at an acceptable level (<5–10%) [6–15,20–30]: a schematic plot of the major results is shown in Table 1. As can be seen, there is quite strong agreement in suggesting a number of constraints in both the ‘‘high” (65–78 Gy) and ‘‘interme-

diate” (40–60 Gy) dose regions when delivering prostate doses between 70 and 80 Gy. In particular, keeping the fraction of rectum receiving more than 70 Gy and more than 75 Gy (V70Gy and V75Gy) below 25% and 5%, respectively, has been demonstrated to be predictive of a very low incidence of late bleeding [7,8,10–12,15,22,23,31]. It is important to underline that at least some of the differences among the studies may depend on how the rectum is defined and contoured (cranial extension, as a solid organ or not, etc.), and this will be the subject of discussion in a specific section. In any case, the upper portion of Table 1 (focused on bleeding) summarizes rectal dose–volume constraints as suggested in large studies (>150 patients) using a consistent, anatomically based definition of rectum extension (i.e. from the anus to the point where it turns into the sigmoid [21,32,33]). Although the ‘‘high-dose” region is the prevalent one in predicting the risk of rectal bleeding, a dose bath of around 40–50 Gy to large portions of the rectum has been reported to increase the incidence of bleeding, even when treating patients at relatively low doses (<70 Gy) [4,6,7,26,27], as in non-conformal series; however,

Table 1 Summary of dose–volume constraint for rectal bleeding suggested in the largest (>150 patients) dose–volume effect studies including patients treated to P70 Gy for localized prostate cancer: in the upper part the results concerning rectal bleeding as end-point and applying a consistent definition of rectum extension (Ref. [33]) are shown; in the lower part, other studies using different scores for rectal toxicity (including bleeding) and different rectal extension definition are shown. Organ: Rectum; End-point: Late bleeding (only) and consistent definition of rectum length [33] Ref.

No. of pts

Doses

Suggested constraints

Jackson [6]

171

70.2 or 75.6 Gy

Fiorino [7]

229

70–76 Gy

Fiorino [8]

245

70–78 Gy

Vargas [10]

331

70.2–79.2 Gy

Peeters [11]

641

68 or 78 Gy

Fiorino [15]

506

70–78 Gy

Fellin [61]

718

70–80 Gy

RTOG Grade P 2: V40Gy < 60% V77Gy < 14% (for patients treated at 75.6 Gy) Modified RTOG Grade P 2: V50Gy < 60% V60Gy < 50% Modified RTOG Grade P 2: V50Gy < 60% V60Gy < 45% V70Gy < 25% CTC 2.0 Grade P 2: V70Gy < 25% Bleeding requiring lasers/transfusions: V65Gy < 30% SOMA/LENT Grade P 2: V50Gy < 55% V60Gy < 40% V70Gy < 25% V75Gy < 5% SOMA/LENT Grade P 2: V75Gy < 5%

Organ: Rectum; End-point: Late ‘‘Rectal toxicity” (including bleeding) Storey [22] 189 70 or 78 Gy GI RTOG Grade P 2: V70Gy < 25% Huang [23] 163 70 or 78 Gy GI RTOG Grade P 2: V60Gy < 40% V70Gy < 25% V75.6Gy < 15% V78Gy < 5% Michalski [64] 256 74 Gy GI RTOG Grade P 2: V65Gy < 50% Fonteyne [47] 241 74–80 Gy Rectal toxicity questionnaire-based scale Grade P 2: V40Gy < 84% V50Gy < 68% V60Gy < 59% V65Gy < 48% Karlsdottir [63] 247 70 Gy GI RTOG Grade P 2: V40Gy < 70% Kuban [62] 301 70 or 78 Gy GI RTOG Grade P 2: V70Gy < 25% a b

11 cm in length starting at 2 cm below the caudal limit of ischial tuberosities. Cranial border: ‘‘1.5 cm above the limit of the target”.

Comments

Including non-conformal patients; excluded pts with rectal volume > 100 cc V70 more predictive for Grade 3 bleeding

Chronic rectal toxicity, mostly bleeding V50 also correlated (no specific constraints suggested) V55–V65 correlated with V65 most predictive; independent impact of abdominal/pelvic surgery Prospectively scored patients; previous abdominal/pelvic surgery independently predictor of bleeding (suggested V70 < 15%); V75 best predictor of Grade 3 bleeding Prospectively scored patients; previous abdominal/pelvic surgery independently predictor of bleeding (suggested V70 < 15%) and best predictor of Grade 3 bleeding Different definitions of rectuma Different definitions of rectuma

All patients were treated with IMRT technique; different definitions of rectumb

A number of cut-offs predictive of toxicity; V40– V43 most predictive Different definitions of rectuma

C. Fiorino et al. / Radiotherapy and Oncology 93 (2009) 153–167

with the routine use of 3DCRT this situation has become increasingly uncommon. In any case, the application of constraints in the V40Gy–V50Gy region of the DVH may reasonably be recommended in order to reduce the risk not only of rectal bleeding but also of other aspects of rectal toxicity, as explained later. In addition to DVH, other clinical parameters may significantly impact the risk of rectal bleeding, as discussed in the next section; however, at present, the dose–volume histogram remains the most reliable tool in the prediction of risk of rectal bleeding. Moreover, several investigators have reported that the spatial distribution of the dose may be important as well [7,28,34–37]: Skwarchuck et al. [34] showed that the irradiation of the posterior rectal wall was predictive of bleeding; similar findings were reported in Fiorino et al. [7], Heemersbergen et al. [35] and Peteers et al. [36] suggesting a correlation between the shape of the dose map calculated on the rectal surface and risk of bleeding. In a very recent work, Munbdoh et al. [37] analysed dose–surface histograms and rectal dose maps of a relatively small sample of patients (10 patients with toxicity and 29 without toxicity) treated with high-dose IMRT, and found a correlation between the shape of the dose maps and rectal toxicity, the mean dose to the upper part of the rectum being on average higher in those patients experiencing toxicity (7/10 patients were bleeders). When considering ‘‘spatial effects”, it is still controversial as to whether local damage as assessed by endoscopy correlates with the local rectal dose [38,39]; on the other hand, it is also unknown whether and how pre-clinical endoscopic findings are correlated with the clinical occurrence of bleeding, especially due to the individual variability of the repair capacity of the rectal surface. An important issue concerning the dose–volume effect of rectal bleeding is the lack of knowledge about the irradiation of very small fractions of the rectal wall (i.e. <1 cc) at ultra-high doses (>90 Gy). A specific interest concerns the possibility to boost subvolumes of the prostate on the hypothesis that they contain the most resistant clonogens (the so-called dominant intra-prostatic lesions, DILs, [40,41]) that would require a total 2 Gy-equivalent dose (EQD2) as high as 100–120 Gy to be sterilized [42]. Some information may be derived from the brachytherapy experience [43]; however, in the case external beam radiotherapy and, particularly, image-guided radiotherapy (IGRT) is used to escalate the dose to ultra-high levels in such a focal treatment, great caution regarding maximum dose to the rectum is warranted. Late bleeding: impact of clinical variables Rectal bleeding is a relatively common symptom in the general population regardless of prior history of pelvic radiotherapy and is most commonly caused by haemorrhoids and anal injuries of little importance. According to a questionnaire survey in the UK, the lifetime prevalence of rectal bleeding in the community is about 24% [44]. In the US, using a cross-sectional survey by mail and a previously validated self-report symptom questionnaire, rectal bleeding was reported by 235/1643 subjects (age and gender adjusted prevalence, 15.5 per 100; 95% confidence interval 13.6–17.4). The prev-

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alence of rectal bleeding was significantly higher in younger persons (18.9%, 20–40 years vs 11.3%, >40 years; p < 0.001) [45]. Interestingly, the probability of rectal bleeding is also correlated to the frequency of stool inspection, with patients who always examine their stool and toilet paper more likely to report it compared with those who never examine either (23% vs 4%) [46]. Therefore, it is not surprising that factors other than those strictly correlated with dose/volume parameters of the rectum have been found to be associated with rectal bleeding in patients treated with radiotherapy for prostate cancer. Table 2 summarizes the major findings from selected studies. Abdominal/pelvic surgery has been found to be associated with a higher risk of rectal bleeding. Although the exact mechanism is unclear, it has been speculated that previous surgery may act through a limitation in blood supply or by ‘fixing’ the bowel. However, it is intriguing that this was a consistent finding in the only two studies that took into consideration abdominal surgery as a covariate [11,15]. It is noteworthy that few other studies found a negative impact of surgery in smaller groups of patients [47,48]. Androgen deprivation (AD) has also been found to be correlated with late rectal bleeding [49,50], though inconsistently [10,51,52]. It has been hypothesized [53] and shown [54,55] that androgen deprivation may expose a higher volume of the rectum to radiation if the planning is performed prior to start of AD. Alternatively, it has been speculated that AD may interfere with the reparative process of the rectum after radiotherapy injury [54]. Finally, the intensity of acute reactions has also been found to be correlated with the development of late toxicity in several series [10,52,56], raising the possibility of the so-called ‘consequential late damage’ for the rectal mucosa [52]. However, in one series, the effect of acute toxicity disappeared after including rectal dose/volume parameters, suggesting that acute toxicity may only be a (rough) surrogate of the dose/volume received by the rectum. Moreover, in general, patients who develop acute reactions may simply be more prone to develop or to complain of late reactions as well; while an association between acute and late toxicity is shown, a causative relationship between the two remains unproven. From a practical standpoint, the only factor that is taken into consideration for dose prescription is diabetes. Patients with diabetes are traditionally regarded as being at higher risk of developing late complications [34,57]; in the pre-IMRT era, they were sometimes prescribed to a lower than intended dose to the prostate in an attempt to reduce the risk of complications [15]. The work-up of patients who develop rectal bleeding after radiotherapy is somewhat controversial. In the general population, symptoms accompanying rectal bleeding which should warrant closer evaluation include abdominal pain and change in bowel habits. In patients treated with radiotherapy, rectoscopy is usually included in the initial evaluation of rectal bleeding. Based on the data obtained from 26 patients, for symptomatic individuals, Moore et al. recommend endoscopic evaluation by sigmoidoscopy or colonoscopy until the source of bleeding is found [58]. Another important criterion is timing, with most radiotherapy related rectal events described within 3 years after treatment end.

Table 2 Summary of main studies investigating the impact of clinical variables on rectal bleeding. Organ: Rectum; End-point: Late rectal toxicity (bleeding) Ref.

No. of pts

Covariate

Stratification

HR

P value

End-point

Herold [57] Skwarchuk [34] Feinberg [50] Sanguineti [49] Peeters [11] Fiorino [15]

944 743 1204 182 641 506

Diabetes Diabetes Androgen Deprivation Androgen deprivation Abdominal Surgery Abdominal Surgery

Yes vs No Yes vs No >6 months vs < 6 months Yes vs No Yes vs no Yes vs no

– 1.8 1.3 2.2 2.7 4.4

<0.01 0.04 <0.01 0.02 <0.01 0.06

Modified Fox Chase Grade 2 GI Modified MSKCC Grade P 2 Modified Fox Chase Grade P 2 RTOG grade 82 Bleeding requiring laser or transfusion Bleeding requiring laser or transfusion or > twice a week

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Late rectal incontinence: dose–volume relationships Mainly due to the impact on quality of life, there has been increasing attention to the relatively rare occurrence of late incontinence [11,15,35,59,60,61]: in the two largest recent studies dealing with rectal incontinence [11,15,61] the actuarial/cumulative 3–3.5 year incidence of incontinence requiring pads was around 7–9%, while a chronic use of pads at 2–3 years, more likely to be caused by radiotherapy, is around 3% with an incidence of severe incontinence (more than 2 pads/week) below 1% [15,61]. In addition to the low incidence of moderately/severely incontinent patients, a strong correlation with DVH patterns was recently reported in two large prospective trials [11,15]. Based on the analysis of more than 500 prospectively scored patients, Fiorino et al. [15] suggested that V40Gy be kept <65–70% in order to reduce the risk of persistent late incontinence (defined as ‘‘use of pads”) to under 1.5%. Similar results were previously reported by Peeters et al. [11] who described a ‘‘parallel” behaviour of the rectum when considering late fecal incontinence, according to a large volume effect (as happens, for instance, for lungs or liver). Both investigations are quite consistent with the fact that a dose bath of around 40–50 Gy received by a large portion (>80–90%) of the rectum is predictive of late incontinence. Potential mechanisms involved in the generation of incontinence could be the reduced ability of absorption of the rectal mucosa, which may be reasonably expected to show a large volume effect. On the other hand, some effect due to neurovascular damage impairing the musculature around the rectum cannot be excluded, nor can a combination of the two mechanisms. We should also not exclude ‘‘spatial” effects differentiating between the upper and lower portion of the rectum: few authors have reported a higher risk of fecal incontinence/leakage for wider irradiation of the anal/ sphincter region [35,59,60]. Most of these studies refer to the pre3DCRT era, when large fractions of the anal region and/or sphincter were often irradiated; currently, using 3DCRT/IMRT, these portions of the rectum are efficiently spared. A possibly important role of the previous abdominal/pelvic surgery was reported by Fiorino et al. [15] and Peeters et al. [11] with quite large odd ratios (ORs) between patients with and without previous abdominal surgery (i.e. an OR of around 4 was reported in [15]). In a recent update of an Italian trial on more than 700 patients with a 3-year follow-up, these results were mainly confirmed, along with an independent predictive role for acute incontinence, suggesting that incontinence may be regarded as a prevalently ‘‘consequential” damage [61].

Late rectal toxicity: other GI symptoms Many groups have investigated rectal dose–volume relationships, taking some comprehensive GI score as an end-point. As most late events concerned bleeding, it is difficult to separate non-bleeding from bleeding effects; due to the prevalence of bleeding as the major late effect, most investigations report a dose–volume correlation consistent with the results coming from the studies focusing only on bleeding: as an example, a number of dose–volume constraints in the range V40Gy–V78Gy were found to be correlated with an increased risk of late P Grade 2 RTOG rectal toxicity, and are summarized in Table 1 [22,23,47,62–64]. The differences among studies are examples of how the best correlation is strongly influenced by the delivery technique and the prescribed dose, as the high-dose regions of the DVH are correlated with the intermediate dose region, as shown and discussed in a number of papers [7,65]. Recently van der Laan reported a slight difference also in the predictive value

of the best cut-off for moderate/severe late rectal toxicity when scoring the toxicity with different systems [31]. On the other hand, several investigations have focused on specific aspects of late rectal syndrome other than bleeding and incontinence, mainly through the prospective collection of self-reported questionnaires. Mild diarrhoea was found to be correlated with V40Gy in a group of 241 patients treated with IMRT while V70Gy was correlated with increased urgency [47]. High stool frequency was investigated in several reports [11,15,35]: Peeters et al. [11] found V40Gy and mean rectal dose to be most predictive of stool frequency, while no clear correlation was found in another large prospective trial [15]. Rectal acute toxicity: dose–volume relationships Moderate/severe acute lower-GI side effects, although typically transient in nature, may occur in approximately 25% of patients, and there is mounting evidence that acute damage may play a significant role in late toxicity [66,67]. Furthermore, acute toxicity can be severe enough to actually result in the interruption of the planned treatment, with potentially detrimental effects. A limited number of studies have reported quantitative estimates of the relationship between dose–volume rectal parameters and acute rectal toxicity [64,68–72] and fewer still have reported on each specific symptom: a summary of the published results is given in Table 3. In general, the difficult task of distinguishing rectal from bowel acute toxicity, especially when pelvic nodes are irradiated, is generally accomplished by considering diarrhoea and cramps as ‘‘bowel effects” (upper GI) while proctitits, tenesmus and lower bowel pain as referred to the rectum. The findings reported in the table confirm the existence of a dose–volume effect for acute toxicity, with some evidence for the choice of mean rectal dose and DVH constraints on the high-dose region (65–70 Gy) as predictive parameters for acute side effects. Peeters et al. [70] considered dose–volume data referring to the first 6 weeks of treatment and found that both intermediate and high-dose regions of the DVH were correlated with GI toxicity. Relative and absolute rectum lengths irradiated to doses greater than 5, 15 and 30 Gy were also found to be correlated with acute side effects. The mean rectal dose was also weakly predictive of acute toxicity. In another very large study including more than 1000 prospectively scored patients, Vavassori et al. [71] investigated the impact of the mean rectal dose and of numerous clinical factors as predictors of various aspects of acute rectal toxicity; different end-points were scored by questionnaire and grouped in synthetic scores (increased frequency, diarrhoea, tenesmus, bleeding, continence and pain). Focusing only on severe symptoms, mean dose was found to be highly correlated with tenesmus and bleeding. In the same study, as well as in several other recent prospective trials, the correlation between acute toxicity and a number of clinical and dosimetric parameters was investigated [70,71,52]. Androgen deprivation was found to be a protective factor for acute GI toxicity [70,71,52]. The androgen deprivation effect may be due to prostate volume reduction, which leads to smaller irradiated volumes and less exposed rectal wall [54]. Patients with diabetes mellitus and those with haemorrhoids were found to have a higher risk of acute side effects [71]: diabetes was strongly associated with acute severe diarrhoea, while the presence of haemorrhoids was predictive of overall RTOG GI toxicity, acute rectal bleeding and tenesmus. The use of anticoagulants/antiaggregants and hypertension medication may delay or reduce the damage induced by radiation, especially when we consider the role of haemostasis and vascular permeability [71]. This may explain the protective role of anticoag-

C. Fiorino et al. / Radiotherapy and Oncology 93 (2009) 153–167

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Table 3 Summary of dose–volume constraint for acute rectal toxicity. Organ: Rectum; End-point: Acute rectal toxicity Ref.

No. of pts

Dose range

Suggested constraints

Comments

Nuyttens [68]

64

72–80 Gy 2 Gy/fr

Karlsdottir [69]

132

70 Gy 2 Gy/fr

V75Gy < 11 cc Mean dose < 38 Gy V40Gy, V70Gy

Peeters [70]

336

68–78 Gy 2 Gy/fr

Michalsky [64]

225

78 Gy 2 Gy/fr

Mean dose V30Gy, V35Gy, V60Gy, V65Gy absolute V50Gy, V60Gy, V65Gy %rectum length > 5 Gy, >30 Gy absolute rectum length > 5 Gy, >15 Gy, >30 Gy V65Gy < 20%

PG2 modified RTOG toxicity; acute toxicity during treatment retrospectively assessed; solid rectum including filling PG2 modified RTOG toxicity; acute toxicity during treatment; solid rectum including filling PG2 modified RTOG toxicity; acute toxicity during treatment prospectively assessed; rectal wall; DVH of the first 6 weeks of treatment

Vavassori [71]

1132

70–81.6 Gy 1.8–2 Gy/fr

Mean dose

Cheng [72]

146

63–80 Gy 1.8–2 Gy/fr

Mean dose Minimal dose to 10%, 20%, 50% of rectum

Arcangeli [81]

102

56 Gy 3.5 Gy/fr

V53Gy < 8%

PG1 modified RTOG toxicity; acute toxicity within 120 days after onset of RT prospectively assessed; solid rectum including filling PG2 modified RTOG toxicity; acute toxicity within one month after RT completion prospectively assessed; solid rectum including filling PG2 RTOG toxicity; including patients who underwent prostatectomy; acute toxicity within 90 days after RT completion prospectively assessed; solid rectum including filling PG2 RTOG toxicity; acute toxicity within two months after RT completion prospectively assessed; solid rectum including filling

ulants/antiaggregants for the development of RTOG Grade P 2 toxicity and the correlation between hypertension and less diarrhoea. Based on the prospectively collected data analysed in the Vavassori et al. paper [71], Valdagni et al. [73] have recently presented nomograms estimating the risk of acute lower-GI side effects after conformal irradiation for prostate cancer. This user-friendly tool includes dosimetric as well as clinical variables in radiotoxicity prediction and could help radiation oncologists to predict EBRTrelated morbidity; as an example, Fig. 1 presents the nomogram for the prediction of G2–G3 RTOG/EORTC lower-GI toxicity.

Rectal toxicity and altered fractionation The use of hypofractionation in prostate cancer radiotherapy has rapidly increased in the recent years in a number of clinical studies. This trend is due to the assumption that the a/b ratio for prostate cancer is lower than that for most other tumors [74], although this has not yet been demonstrated [75–78]. In most cases dose–volume constraints for late rectal toxicity can be derived from the constraints used in standard fractionation taking the non-conventional dose fractionation into account through the linear quadratic model. When considering acute morbidity, overall treatment time has to be taken into account; for this purpose application of the modified BED formula proposed by Fowler et al. [79] should be preferable. Two studies have reported on the correlation between acute GI toxicity and DVH parameters in altered fractionation schedules [80,81]. Both studies observe that acute toxicity reached maximum incidence 3–4 weeks from the initiation of radiotherapy. Pollack et al. [80] compared 76 Gy in 38 fractions to 70.2 Gy in 26 fractions and found a significant correlation between acute GI toxicity and rectal V65Gy/V50Gy (for the two arms, respectively, and using a/ b = 1.5 Gy for the rectum); multivariate logistic regression analysis indicated that the higher the percentage of rectum exposed to 65 Gy/50 Gy, the greater the risk of grade P 2 acute rectal reactions, with a relative risk of 1.109 (V65Gy/V50Gy continuous variables, V65Gy/V50Gy < 17% was used as tissue planning limit for rectum). Arcangeli et al. [81] investigated predictors of acute toxicity in a group of 102 patients treated with 56 Gy in 16 fractions over 4 weeks. V53Gy was highly predictive of acute GI morbidity, with the highest incidence when V53Gy > 8%.

Fig. 1. Pre-treatment nomogram for moderate/severe RTOG/EORTC lower gastrointestinal (LGI) acute toxicity [73]. To use the nomogram, locate the patient’s mean rectal dose in Gy on the ‘mean rectal dose’ axis. Draw a line straight upwards to the ‘pre-points’ axis to determine how many points towards LGI acute toxicity the patient receives for his mean rectal dose. Repeat this process for the ‘Use of anticoagulants’ (0 = no and 1 = yes), ‘Diabetes’, ‘haemorrhoids’, ‘irradiation of pelvic nodes’ and ‘hormonal therapy’ axes, each time drawing straight upward to the ‘prepoints’ axis. Sum the pre-points achieved for each predictor and locate this sum on the ‘total points’ axis. Draw a line straight downwards to find the patient’s probability of developing moderate/severe lower LGI acute toxicity. For example, for a patient with mean rectal dose of 50 Gy (17 pre-points), with haemorrhoids (4.5 pre-points) and who undergoes androgen deprivation (0 pre-points) (no diabetes – 0 pre-points, no anticoagulants – 5 pre-points, and no irradiation of pelvic nodes – 0 pre-points), this nomogram predicts 30–32% acute LGI toxicity probability (26.5 total points). (Reproduced from Valdagni R et al., Int J Radiat Oncol Biol Phys 2008;71:1065–73.)

Recently, Stigari et al. [82] fitted acute toxicity data following hypofractionated RT for prostate cancer to a modified NTCP model which was based on the Lyman–Kutcher–Burman (LKB) model and which included overall treatment time [83,84]. The LKB model uses the probit formula in order to describe the dose–response relationship for normal tissues. The standard format uses three parameters as descriptors: TD50(e), i.e. the dose that causes 50%

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probability of injury when a fraction e of the organ volume is uniformly irradiated; the slope of the response curve at TD50, the steepest part of the curve, which is named m; and n, a parameter describing the importance of the volume effect for the considered organ (higher values correspond to more resistant organ or parallel architecture). Stigari et al. considered three treatment schemes: 80 Gy in 40 fractions within 8 weeks (Group A), 62 Gy in 20 fractions within 5 weeks, 4 days/week (Group B) and 56 Gy delivered in 16 fractions (4/week) of 3.5 Gy (Group C). In this study the best fitted m and n values were 0.17 and 0.08, respectively, and the TD50 parameters were 79, 62.5 and 53 Gy for Groups A, B and C, respectively.

including a significant fraction of patients treated with 2D techniques, suggesting that when large fractions of the rectum are irradiated at intermediate doses (i.e. 40–60 Gy), the rectum may behave in a more parallel way. It is important to note that patients are no longer treated with such ‘‘older” techniques. The dose–response relationship for fecal incontinence was analysed in two published studies: a small study considering the dose distribution delivered in the anal sphincter [86] using the relative seriality model [87], and a large prospective study [11] which analysed the dose distribution in the anal canal wall and fitted the Lyman–Kutcher–Burman (LKB) model. The best fitted parameters for the relative seriality model showed that fecal leakage is characterized by a medium relative seriality s = 0.35, which has to be coupled to D50 = 70.2 Gy and c = 1.22 [86]. The prospective study found a large volume effect in the anal wall (high n-value), and demonstrated [11] that the mean dose to the anal wall (n = 1) may be used for treatment plan optimisation coupled to D50 = 105 Gy and m = 0.43. In the same paper, a modified NTCP model where predisposing clinical features can be taken into account was applied. The authors fitted the LKB model with four parameters: n, m, D50 for patients without clinical risk factor (D50N) and D50 for patients with clinical risk factors (D50Y). For rectal bleeding and fecal incontinence, the patient’s history of abdominal surgery was considered as a risk factor. The fitting procedure leads to the following parameters: D50N = 85 Gy, D50Y = 78 Gy, n = 0.11, m = 0.14 for bleeding (the organ at risk is the rectal wall), D50N = 157 Gy, D50Y = 74 Gy, n = 1, m = 0.45 for incontinence (the organ at risk is the anal canal wall). As mentioned previously, these results are highly consistent with the findings of another large prospective trial [15,61].

Late toxicity: NTCP models The first parameters describing rectal complications (severe proctitis/necrosis/fistula/stenosis, D50 = 80 Gy, n = 0.12, m = 0.15, Lyman model [1]) suggested that the rectum is a prevalently serial organ. In NTCP modelling organs at risk can be classified as serial, parallel and serial–parallel. Serial organs can lose their complete functionality if even a small volume of the organ receives a dose above the tolerance limit. In contrast, parallel organs are damaged only if a larger volume is included in the irradiation region. In many cases these two models are combined in a serial–parallel organ configuration. It is worth remembering that the first Emani–Kutcher–Burman parametrization was derived from the clinical experience of the 2D planning era, without any individually assessed dose–volume information: NTCP predictions based on this estimate constituted a good tool for plan comparison for more than a decade; however, more reliable parameterizations, fitting radiobiological models to individual clinical and dosimetric data, have subsequently been published [9,11–13,85]. Concerning NTCP fit based on DVH reduction to effective homogeneous dose given to total volume (EUD), recent investigations on large populations have produced highly consistent results, with n-values between 0.06 and 0.13 for moderate/severe bleeding [11–13,85], thus indicating the importance of the high-dose range (detailed values are reported in Table 4). These results suggest that EUD-based optimisation may be reliably performed when considering the rectum as a main organ at risk (as for prostate cancer). It is also interesting to underline that in the case of moderate bleeding, a greater n-value was reported (n = 0.24, [9]) in one study

Impact of geometrical uncertainties on dose–volume modelling of rectal toxicity In general, the DVH of an organ at risk calculated using only one CT study (planning CT) is affected by a number of ‘‘geometrical” uncertainties. The ‘‘true” DVH of an organ is always different from the planned one, due to a number of factors such as set-up error, inter- and intra-fraction organ motion and organ deformation; contouring uncertainty is also a significant source of error. The impact of geometrical uncertainties on rectal DVHs and dose–volume parameters has been investigated in many studies, due mainly to the significant body of consistent data on the correlation between

Table 4 Summary of NTCP modelling studies of rectal toxicity for rectal bleeding and fecal incontinence. Organ: Rectum; End-point: Late rectal bleeding (NTCP) Ref.

Rancati [9] Rancati [9] Peeters [11] Soehn [12] Tucker [13] Rancati [14]

No. of pts

Dose range 1.8–2 Gy/fr

LKB model parameters (68% confidence intervals) n

D50 (Gy)

m

547

64–79.2 Gy

81.9 ( 5.1; +9.3)

547

64–79 Gy

0.24 ( 0.09; +0.19) 0.06 (±0.01)

0.19 ( 0.04; +0.06) 0.06 (±0.005)

468

68–78 Gy

80.7 ( 6.0; +9.0)

319

70.2–79.2 Gy

1023

68.4–79.2 Gy

1119

64–81.6 Gy

0.13 ( 0.09; +0.12) 0.08 ( 0.02; +0.04) 0.08 ( 0.04; +0.18) 0.085 (±0.047)

78.6 (±3.7)

78.4 (±2.1) 78 (±6.0) 97.7 (±1.8)

0.14 ( 0.03; +0.05) 0.11 (±0.03) 0.14 ( 0.04; +0.12) 0.27 (±0.13)

Organ: Rectum; End-point: Late fecal incontinence (NTCP) Dose range Model parameters (68% confidence intervals) c = 1.22 (±0.73) Mavroidis 65 70.2 Gy s = 0.35 D50 = 70.2 Gy (±11.2 Gy) [86] (±0.32) m = 0.43 Peeters 468 68–78 Gy n = 1 (fixed) D50 = 105 Gy ( 15.0; +33) ( 0.05; +0.06) [11]

Comments

G2–G3 late rectal bleeding; solid rectum including filling; including 90 non-conformal patients G3 late rectal bleeding; solid rectum including filling; including non-conformal patients G3 late rectal bleeding; rectal wall G2–G3 late rectal bleeding; rectal wall defined starting from solid rectum contours + 3–4 mm thickness G2–G3 late rectal bleeding; solid rectum including filling G2–G3 late rectal bleeding; solid rectum including filling; including 90 non-conformal patients

Severe late fecal incontinence (more than twice/week);relative seriality model; solid anal sphincter G3 late rectal incontinence; LKB model; anal wall

C. Fiorino et al. / Radiotherapy and Oncology 93 (2009) 153–167

DVH and rectal toxicity together with some peculiarity of the rectum itself, especially its mobility due to variable rectal content. A significant point regards the definition of rectal volume and the calculation of the dose distribution within it. The use of the dose–volume histogram of the rectal wall (dose–wall histogram, DWH) has been reported in some investigations [6,11,21,28,34], although its use is relatively uncommon due to the intrinsic difficulty in assessing the thickness of the rectal wall on CT images and in dose calculation, due to the thin thickness of the rectal wall (typically 2–10 mm [88–92]). The DWH should ideally offer an accurate representation of the dose received by the rectal mucosa cells and by the vascular structures likely to be involved in the formation of radiation-induced damage. Some authors have suggested the drawing of the external surface and the artificial creation of a rectal wall with a constant thickness; however, this approach is formally incorrect and could result in the calculation of a dose–volume histogram very different from the true DWH [88,89]. In routine clinical practice the DVH of the rectum including filling has some advantages: it is easy to calculate and inter-/ intra-observer variability in drawing the external surface of the rectum is expected to be lower than that for the rectal wall. However, some investigators have stressed the possibility that the DVH may be quite different from the DWH [88,90] and more sensitive to the effects of organ motion [92,93]. As an alternative to both DVH and DWH, the concept of the dose– surface histogram (DSH) has been introduced [94]. Furthermore, the concept of normalized dose–surface histogram (NDSH) has been suggested as a potentially robust ‘‘surrogate” of the DWH [89]. In the original NDSH concept, the surface of the rectum is binned in the place of the volume and the number of points for calculation is assumed to be the same on each axial slice. A similar concept was also recently introduced for the rectum including filling and was named normalized DVH (NDVH, [95]). It is noteworthy that the relative differences between DWH, DVH, DSH, NDSH, NDVH are expected to depend on a number of variables such as the degree of filling and the lumen variation, the irradiation technique, and the quantity of rectum irradiated to high dose. A very good correlation between DVH and DWH was found in the case of empty rectum, while a poorer correlation is expected in the ‘‘full rectum” situation where the DSH could be more reliable in estimating the DWH [95,96]. On the other hand, the practice of emptying the rectum in order to reduce the risk of missing the target [97,98] dramatically reduces rectal motion [99–101] and consequently improves the correlation between DVH and DWH [99]; thus, the current practice of using the DVH should be considered sufficiently robust for the application of dose–volume constraints, especially when rectal emptying protocols are applied. This robust statement was also confirmed in an investigation of the impact of rectal motion on the best-fit parameters of NTCP modelling of rectal bleeding when patients are instructed to empty their rectum before planning CT scan and therapy [102]. On the other hand, in the case of intentionally distended rectum, as when using balloons/immobilizers in the rectum, DSH/NDSH could be preferred [95,96]. As stated previously, intra- and inter-observer variations in contouring the external surface of the rectum on CT were found to be acceptable, once a clear definition of the cranial and caudal limits of the rectum is set [32,33,103]. It is important to underline that the DVH constraints (bleeding) reported in Table 1 come from the studies where the rectum was contoured consistently. Rectal toxicity: introducing genetic parameters in the prediction of risk In clinical radiotherapy, planning optimisation is performed taking only the ‘‘average sensitivity” of the population into account.

159

Some exceptions to this statement regard the very limited group of individuals affected by genetic disorders such as ataxiatelangiectasia, Fanconi anemia and Nijmegen breakage syndrome, who are exquisitely sensitive to radiation but are easily identified by their clinical symptoms. Inter-patient variability in expressing radiation-induced toxicity of normal tissues is widely recognized and evident in the clinic, suggesting that such a phenomenon may be, at least in part, genetically determined. Few studies in the literature have attempted to identify individually assessed biological predictors of acute/late toxicity in prostate cancer irradiation and examine the potential correlation between rectal injury, dosimetric variables, clinical factors and the individual gene profile in the single patient [104–110]. Very recently, data regarding the evidence of a genetic predisposition for late rectal bleeding have become available: Burri et al. [109] and Damaraju et al. [108] reported on an association between susceptibility to the development of late adverse effects after RT for prostate cancer and single nucleotide polymorphisms in SOD2, XRCC1 and XRCC3 [109] and XRCC3, LIG4, MLH1, CYP2D6 and ERCC2 [108]. Based on the data of AIROPROS 0101 trial [7], Valdagni et al. [110] recently reported that reduced expression of AKR1B1, BAZB1, LSM7, NUDT1, PSMB4, SEC22L1 and UBB was significantly associated with enhanced sensitivity to late toxicity (high probability of late rectal bleeding despite attention to the satisfaction of DVH constraints); at the same time, DDX17, DRAP1, RAD23 and SRF were identified as predictors of resistance to radio-induced late rectal bleeding (no bleeding despite the fact that DVH constraints were widely violated). It is worth noting that all correlations were found in single studies; validation studies are not yet available. It is important to note that, in order to highlight its potency, any research on genetic susceptibility should be coupled to dose–volume information (and possibly to clinical information), given the well-established role of dosimetric variables in rectal injury prediction. These early results are introducing a new era in the prediction and evaluation of radio-induced toxicity, with the ultimate aim of developing genetically adjusted dose–volume modelling of rectal toxicity. The characterization of the independent contribution of a patient’s individual genetic make-up to the development of late radiation toxicity could lead to the clinical application of predictive tests to better tailor treatments to the individual.

Bladder Dose–volume effects Clinical experience suggests the evidence of a dose effect for whole bladder irradiation; Emami et al. [111] estimated a tolerance dose of 65 Gy in order to maintain severe urinary toxicity below 5% and of 80 Gy to keep bladder injury probability below 50%. In their review, Marks et al. [112] found that the majority of the bladder can be irradiated to approximately 30–50 Gy, and that global injury is infrequent if the maximum bladder dose is <60–65 Gy. If small volumes of the bladder receive 60–65 Gy, a fairly low rate of serious complication is possible. When the whole bladder dose approaches 50–60 Gy, the risk of global bladder dysfunction begins to increase, and in this case severe urinary toxicity may be seen even when the maximum bladder dose is low. Furthermore, the clinical data presented earlier suggest that fraction sizes >2.0 Gy are associated with an increased risk of complications [112]. In most cases of irradiation of pelvic malignancies (such as prostate, rectum and gynecological cancer) the bladder is only partly irradiated at the prescribed dose.

160

Dose volume effects in the pelvis

Severe toxicities have been reported to occur prevalently in high-dose treatments (>70 Gy) and then mainly concern prostate cancer irradiation; in this case, the cranial portion of the bladder is generally spared while bladder neck and urethra are irradiated to a dose similar to the prescribed dose. A prevalently serial behaviour was recently reported for late mild-to-severe toxicity [113], while a mixed serial–parallel behaviour was found for chronic urinary moderate/severe toxicity [114]: both studies indicate that a small fraction of bladder (few cc) receiving more than 78–80 Gy is highly predictive of late genitourinary toxicity. The lack of knowledge about dose–volume modelling of bladder toxicity probably reflects, at least in part, the difficulty in carefully assessing the amount of bladder wall receiving a certain dose, deriving from the wide variations in bladder shape during treatment due to highly variable filling. In any case, the recently reported large increase of moderate/severe late GU toxicity when escalating to ‘‘high” doses [17,18, 63,115–118] is a further confirmation that at least one of the primary mechanisms of urinary function impairment depends on the irradiation of a ‘‘small” volume (i.e. the caudal portion of bladder unavoidably included in the PTV) to a ‘‘high” dose, again suggesting a prevalently serial-like behaviour; as a consequence, when escalating the prostate dose to >75 Gy with IMRT and adequate application of rectum constraints, GU toxicity seems to become the main limiting factor. The possibility that specific regions of the bladder could be more sensitive than others has also recently been suggested by Heemsbergen, who analysed the dose surface maps of 522 patients of a Dutch trial [119]: in this study the impact of ‘‘high-dose” spots was confirmed; moreover, it was demonstrated that the dose received in the trigone is associated with an increased risk of late urinary obstruction (best predictive cut-off value: 47 Gy) indirectly suggesting that the inclusion of the seminal vesicles could be a predictive factor of GU toxicity when delivering high doses. This point should also be addressed in future investigations.

Impact of clinical variables Few studies exist in the literature clarifying the role of clinical variables affecting the risk of developing symptoms of the GU syndrome. Pre-treatment GU complaints, prior transurethral resection of prostate (TURP), prior transurethral resection of bladder tumor (TURBT) and the presence of acute GU toxicity are now suggested as factors probably involved in conditioning urinary morbidity. Nonetheless, published results are still controversial, as can be easily deduced from four recently reported large analyses: Liu et al. [120] (isocentric dose range: 50 Gy ? 72 Gy, twodimensional + three-dimensional techniques) found that late Grade 3 GU toxicity was significantly correlated to coexisting GU disease, prior TURP or TURBT and presence of acute GU toxicity; Peeters et al. (Dutch multicenter randomized trial) [52] found prior TURP, androgen deprivation therapy and pre-treatment GU symptoms (but no dose influence) all statistically related to late RTOG/EORTC urinary toxicity; while Zelefsky et al. (MSKCC group 3DCRT + IMRT patients) [17] found radiation dose (<81 Gy vs >81 Gy) and acute toxicity (Grades 0–1 vs 2–4) to be the only variables significantly conditioning late GU morbidity; Cahlon et al. (MSKCC group IMRT patients) [115] found GU medications prior to IMRT and development of grade P 2 acute GU toxicity to be significantly correlated to the presence of grade P 2 late morbidity. Such difficulties are probably related both to the maintaining of similar bladder filling within the same study, and to different prescriptions for bladder filling among various studies.

It is evident that to clarify this issue, new trials focused on clinical as well as dosimetric factors affecting the GU syndrome should be specifically designed.

Bowel Acute bowel toxicity: dose–volume relationships It is common knowledge for any radiation oncologist that for a number of malignancies (gynecological, rectum and prostate) the irradiation of large volumes of the bowel to doses around 45– 50 Gy (1.8–2 Gy/fr) during whole pelvis irradiation (WPRT) with two- to four-field techniques is associated with moderate/severe acute GI toxicity (primarily diarrhoea) in a significant fraction of patients, and furthermore that the probability and the severity of these effects increase with the field width [121,122] and the dose per fraction. Despite this evidence, clear quantitative dose–volume relationships for bowel are still lacking. Only recently have a few attempts to quantify the dose–volume effect of bowel been reported (summarized in Table 5), mostly concerning patients treated with conventional techniques. Baglan et al. [123] reported a correlation between the DVH of bowel loops and Grade 3 acute bowel toxicity in 40 patients treated with four-field technique and concomitant chemotherapy for rectal cancer, with V15Gy as the best predictor. A significant correlation between the DVH of the bowel and acute Grade 2 toxicity was also found by Roeske et al. [124], who analysed 50 patients treated with WPRT IMRT for gynecological malignancies. The fraction of bowel receiving more than 45 Gy was found to be correlated with risk of bowel toxicity (V45Gy < 150 cc was the suggested cut-off). Sanguineti et al. [125] found V15Gy to be the best predictor of acute bowel toxicity in a group of 149 patients treated with IMRT for prostate cancer with and without pelvic node irradiation; however, given the heterogeneous group of patients and the correlation between the various dose–volume parameters (i.e. V15Gy vs V40Gy–V45Gy), the authors do not exclude the possibility that V15Gy may simply be a ‘‘geometric” surrogate without any biological significance, and suggest further investigations on larger and more homogeneous populations. Several other studies have reported dose–volume relationships for bowel in patients treated for gynecological [126] or rectal cancer [127,128] with four-field techniques; although they refer to different treatment modalities (for instance with/without concomitant chemotherapy), different scoring systems and different definitions of ‘‘bowel”, they agreed in suggesting the DVH of the bowel to be a predictor of acute toxicity, with the highest correlation for V10Gy–V20Gy. In particular, Huang et al. [126], in a cohort of 80 gynecological patients, reported the low dose (V40%) as more predictive of acute bowel toxicity for patients without a history of abdominal surgery, while the high dose (V100%) resulted more predictive for patients with previous abdominal surgery. In a recent paper, 175 patients irradiated with WPRT for prostate cancer were analysed [129]; the authors suggested that the predictive value of the low dose region (V15Gy) found in populations irradiated mainly using the four-field box-technique, was probably due to geometrical factors; in fact, pooling IMRT and 3DCRT (box-technique) patients, it was clearly shown that P Grade 2 RTOG acute bowel toxicity was highly correlated with the fraction of the intestinal cavity receiving 40–50 Gy. Based on these findings, a number of constraints were suggested in the 30–50 Gy range when contouring the whole intestinal cavity or the intestinal cavity outside PTV (not only the loops). This finding is in agreement with the clinical experience and the paper by Roeske et al. [124].

C. Fiorino et al. / Radiotherapy and Oncology 93 (2009) 153–167

161

Table 5 Summary of suggested dose–volume constraints for acute bowel toxicity during pelvic nodes irradiation. Organ: Bowel; End-point: Moderate/severe acute toxicity

a b

Ref.

No. of pts

Dosesa

Suggested constraints

Definition of bowel/Comments

Baglan [122]

40

45 Gy

Loops/four-fields technique; rectal patients; concomitant chemotherapy V5Gy–V40Gy correlated with toxicity

Roeske [123] Tho [126]

40

45 Gy

41

45 Gy

Huang [125]

80

39.6– 45 Gy

Robertson [127]

91

45 Gy

Sanguineti [124] Fiorino [128]

149

0/ 54 Gyb 50.4– 54 Gy

Grade 3 CTC 3.0: V15Gy < 150 cc (V40Gy < 125 cc) P Grade 2 RTOG: V45Gy < 150–200 cc P Grade 2 CTC 3.0: V15Gy < 100 cc (risk < 20%) P Grade 2 diarrhoea CTC 3.0: V16–18Gy and V40–45Gy independently predictive for pts without/with previous surgery, respectively Grade 3 diarrhoea CTC 3.0: V15Gy < 120 cc V25Gy < 105 cc V40Gy < 71 cc P Grade 2 CTC 2.0: V15Gy < 1186 cc P Grade 2 RTOG: Intestinal cavity outside PTV/Whole cavity V50Gy < 35 cc/100 cc V45Gy < 100 cc/250 cc V40Gy < 150 cc/350 cc V30Gy < 300 cc/500 cc

175

Loops/IMRT; gynecological patients Loops/four-fields technique; rectal patients; concomitant chemotherapy V5Gy–V45Gy correlated with toxicity Loops/four-fields technique; gynecological patients

Loops/four-fields technique; rectal patients; concomitant chemotherapy; V5Gy–V40Gy correlated with toxicity

Intestinal cavity/IMRT; prostate patients; pooled patients with/without pelvis irradiation Intestinal cavity/four-fields technique and IMRT; prostate patients; V20Gy–V50Gy correlated with toxicity; V15Gy best predictor for nonIMRT patients

To the pelvis, 1.8–2 Gy/fr. Pooling patients with/without pelvic nodes irradiation.

The message is very important for IMRT planning optimisation: if constraints to limit V15Gy are applied without considering V30Gy–V50Gy, a relatively high incidence of acute bowel toxicity may be expected. Dose–volume relationships may be greatly modified by other clinical parameters, primarily chemotherapy. Acute diarrhoea may be simply caused by chemotherapy alone [130], surgery alone [130], or proctitis from RT [125,132]. In particular, it has been shown that previous abdominal/pelvic surgery increases the risk of diarrhoea in patients with rectal cancer [131]. A weakly significant impact of previous abdominal/pelvic surgery was also reported for a large cohort of prostate patients [129]. ‘‘Bowel” definition and implications for IMRT planning The bowel is a mobile structure [133,134]. Two studies have consistently found that only about 20% of the bowel always occupies the same position during the course of a treatment [135,136]. Such mobility contributes to a blurring of the evidence for a dose/volume relationship with toxicity [137,138]. The expansion required to cover all possible locations of intestine in 90% of patients during treatment has been estimated to be up to 3 cm around the bowel as defined in the planning scan [135]. However, if one focuses only upon the volume containing the bowel for at least 50% of the treatment period, isotropic margins of 1 cm would allow coverage of 90% of the volume in 90% of the patients. Expansion beyond 1 cm would not significantly increase either percentage significantly. Most studies have considered the bowel as a whole without differentiating between the small and large bowel: differentiating between the two is best when the planning CT includes the overall abdominal cavity; moreover, there is no currently available method to track individual parts of the bowel during treatment. Sanguineti et al. [136] have compared the following three different methods to define the bowel and their implications in planning whole pelvic IMRT for prostate cancer: each bowel segment (‘BS’); ‘BS + 1’ (BS uniformly expanded by 1 cm); intestinal cavity (‘IC’) or the ‘container’ of the bowel loops up to the pelvic/abdom-

inal walls. Three rival plans, each considering a different bowel definition, otherwise identical, were generated for each patient. All definitions provided a very similar average bowel DVH at planning. During treatment BS allowed an average of 20 cc more of the bowel to receive at least 45 Gy than BS + 1 and IC (p = 0.008 and 0.029, respectively); on the contrary, bowel V45Gy between IC and BS + 1 was not significantly different (p = 0.65). Similarly, a large impact of bowel loop motion on bowel EUD during treatment was also reported in another recent study [139]. A definition taking internal organ motion into account is warranted to maximize bowel protection during treatment; contouring IC is very robust and should be favoured over BS + 1 when using IMRT to spare the bowel [136]. Another modified definition of IC has recently been reported and consists in drawing the IC outside the PTV, with a 5–7 mm margin [129]; in the same paper, dose–volume constraints for intestinal cavity defined in both ways (i.e. IC and IC outside PTV) have been suggested, as discussed in the previous section. Sexual function Erectile dysfunction: dose–volume relationships Due to the growing proportion of potent patients before radiotherapy of prostate cancer and the widespread availability of antiimpotence drugs, the exclusion of structures potentially involved in penile erection (bulb of the penis, neurovascular bundles, crura, corpora cavernosa) from the irradiated volume is a very sensitive and controversial topic. Recently, some studies have reported a correlation between the dose received by penile structures (mostly the penile bulb) and sexual function alterations (mostly impotence) [140–145]. In particular, a median dose to the penile bulb greater than 52 Gy was found to be highly correlated with an increased risk of erectile dysfunction (ED) [145]. Other authors have reported results consistent with this finding: Wernicke et al. [144] suggested keeping V50Gy < 20% and V40Gy < 40% to drastically reduce impotence. Mangar et al. [143] reported a median bulb dose of 59.2 and

162

Dose volume effects in the pelvis

45.5 Gy for impotent and potent men, respectively, in a cohort of 51 patients included in a randomized trial. However, other investigators found no clear dose–volume effect [146–148]; a more complete review can be found in [4]. The wide use of hormonal therapy and of anti-impotence drugs suggests that large prospectively questionnaire-based scored populations would be necessary to reliably assess dose–volume relationships taking into account pre-treatment erectile status and impact of both hormonal therapy and anti-impotence drugs; this point will be discussed in the next section. In any case, based on the available literature data, sparing the bulb, even partially, without compromising the coverage of the PTV, may be suggested: in particular, the use of MRI to better define the prostate apex in potent patients with prostate cancer may safely spare the bulb of the penis without missing the prostate in most patients [149–152]. This issue is further complicated by a lack of evidence based knowledge on the anatomical regions involved in the expression of erectile dysfunction. If several clues lead to the penile bulb as the true target for radio-induced ED, other anatomical regions which seem to play a major role in achieving an erection have also been considered, such as the neurovascular bundles, the crura and the corpora cavernosa [153]. A very interesting point comes from recent data on genes predicting ED. Peters et al. [107] found that the possession of certain TGFb1 genotypes is associated with the development of ED. Therefore, the identification of patients harbouring these genotypes may represent a means to identify men who could have a poor quality of life after radiotherapy of pelvic malignancies, especially prostate cancer. Confounding factors in erectile dysfunction dose–volume modelling studies Potency after treatment for pelvic cancers is a relevant topic with implications on patient quality of life [146], especially for prostate cancer patients, due to the proximity of the target to the penile structures. Moreover, since the choice of the local treatment modality often depends on its toxicity profile, potency is regarded as one of the most prevalent aspects driving this decision. From a clinical standpoint, ED defined by NIH as the consistent inability to attain and maintain a penile erection sufficient to permit satisfactory sexual intercourse, implies the presence of a ‘willing partner’ and the man’s interest in sex. The latter two factors, along with psychological aspects, contribute to define the broader status of sexual activity, rather than ED. Potency depends on the anatomic integrity and the proper function of several structures. There is no single organ responsible for ED as detailed in an excellent review by van der Wielen et al. [4]. Radiation-induced ED is believed to be primarily arteriogenic with a minority of patients experiencing structural damage to the erectile tissue [153]. Moreover, of the structures potentially involved in ED, the neurovascular bundles (NVB) cannot be seen on a (planning) CT; furthermore, the proximal part of the corpora cavernosa or crura that house the erectile tissue are often in a dose gradient region in a typical prostate beam treatment, and subject to daily dose variations. Several studies have considered as OAR for potency the penile bulb that is the most proximal part of the corpus spongiosum; in other studies, however, its role in ED has been questioned since it is not an erectile body itself [154]. In addition to dosimetric factors, several other confounding factors can hamper the proper evaluation of potency after treatment. It is imperative that the patient is potent before treatment [155]. Aging, of course, can be responsible for the (physiologic) loss of potency in a proportion of patients. The typical mean age of patients treated for prostate cancer with external beam radiation is in the late 60s/early 70s, and older than the typical patient undergoing surgery.

Moreover, at this age, up to 5% of patients would develop ED every year, regardless of cancer and its treatment [156]. Vascular co-morbidities (smoking, hypertension, hypercholesterolemia, etc.), and psychological issues (anxiety, depression, anger, fear, etc.) are the most important factors correlated to ED in the elderly [157]. The timing of RT-related ED would also imply that longer the post-treatment interval is when evaluating potency, the more confounded (by aging) it will be. Some authors believe that most radiotherapy related effects on potency are manifested within 2 years [4], although in one recent meta-analysis, no significant difference was found in ED rates between 1 and 2 years after treatment [158]. Potency should be prospectively evaluated with the help of a validated questionnaire filled in by the patient [159]: as pointed out by Incrocci et al., this is rarely the case [146]. In particular, it is well known that physician based assessment tends to underestimate/underreport findings that negatively impact the quality of life [160].

Dose to the gonads and sexual dysfunction Testosterone deprivation affects potency as well. Historically it was thought that androgen acted on sexual interest or libido [161]. More recently a role has been accorded to testosterone in the synchronizing of the erectile process as a function of desire. While erections can still be possible in (temporary) hypogonadal conditions [162], long term treatments with luteinizing hormone–releasing hormone (LH–RH) agonists (here androgen deprivation, AD) have a negative impact on the structure of penile tissues and erectile nerves. More recently, it has been found that testosterone improves cavernous vasodilatation and response to sildenafil [163]. Below normal testosterone levels are quite common even in the absence of drug manipulation. In one study on postoperative radiotherapy for prostate cancer, 30% of patients had testosterone levels below the normal range prior to treatment [164]. In another study, 17% of treated patients who had never received androgen deprivation developed subnormal levels of testosterone at 3 years after treatment [165]. While virtually all patients reach castrate levels of testosterone during treatment with LH–RH agonists, most regain some testosterone after treatment cessation. Normal levels are achieved in 70– 90% of patients in a mean period ranging from 7 to 27.3 months, depending on patient ‘reserve’ (age, baseline testosterone value and concomitant RT) and treatment ‘aggressiveness’ (duration of androgen deprivation, 3 vs 1 month administration) [164–177]. The dose–volume relationships between testicle dose and testosterone reduction is an open and very topical issue: Daniell et al. [171] found a lower level of testosterone level in patients with prostate cancer treated with RT compared to surgery alone. In their analysis of testosterone reduction after RT, Zagars and Pollack [172] expressed doubt that the low dose received by gonads could be correlated to this effect (range 1.84–2.42 Gy). Similar levels of dose to the testicles were recently reported by Bohemer et al. (196 cGy ± 145 cGy), who underlined the significant impact of port film check in increasing the testicle dose [173]. In any case, doses as low as 0.8 Gy have been reported to cause transient azoospermia after radiotherapy for prostate and rectum cancer, while dose above 2 Gy may cause irreversible azoospermia [172–175]. The issue of a potential increase of the dose to the gonads (well outside the irradiation fields) due to the use of IMRT and IGRT is still open. The significant increase of the head scatter dose to gonads due to the increase of beam-on time with IMRT should be better investigated. Moreover, it is important to note that if special care is not devoted to taking testicles into account, the use of non-coplanar beams may increase the dose to testicles well above the levels normally delivered with conventional coplanar 3DCRT or IMRT.

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At the present time, no reliable dose constraints for testicles are available, due in part to the difficulty in measuring/estimating the dose outside the fields in a clinical setting. However, it is always important to avoid any unnecessary irradiation of the testicles, making every effort to reduce the dose to the testicles for both young patients interested in preserving their reproductive function and potent older patients. Herrmann [174] has attempted to summarize the effects of radiation therapy on female and male gonadal function. In women the mean tolerance dose for sterilization is between 5 and 10 Gy. In men, total gonadal doses of 1 Gy with single doses of 0.03–0.05 Gy can result in a temporary azoospermia with subsequent recovery in most cases. If total gonadal doses exceed 1.5 Gy a substantial increase in irreversible azoospermia must be expected [176,177]. Recently a review was published on the impact of radiotherapy on fertility, pregnancy and neonatal outcomes in female cancer patients [178]: ovarian impairment is related to the biological dose as well as to age at treatment. A recent mathematical model employed by Wallace et al. [179] suggested that the dose required to destroy 50% of the immature oocytes (LD50) is less than 2 Gy. The effective sterilizing dose (ESD), or dose of fractionated radiotherapy at which ovarian failure occurs immediately after treatment in 97.5% of patients, was found to decrease with increasing age at treatment. The estimated ESD at birth was 20.3 Gy; at 10 years, 18.4 Gy; at 20 years, 16.5 Gy; and at 30 years, 14.3 Gy [179]. The Wallace model can be used to estimate the age at which premature ovarian failure occurs for individual patients from birth to 50 years at any given dose of radiotherapy. It should be noted that novel radiation techniques, including IMRT and proton radiotherapy, would allow the sparing of the ovaries from significant radiation, thus reducing the negative effects on fertility. In all treatment situations an additional effect of the combination of chemotherapy with radiation on gonadal function has been shown; however, the severity of damage by radio-chemotherapy is highly dependent on the drugs used [174].

Femoral heads and pelvic bones A possible, but uncommon, late side effect of radiotherapy to the pelvic area is damage to the pelvic bones: fine, hair-line cracks known as pelvic insufficiency fractures may occur. Sacral insufficiency fractures, fractures of the pubic rami and femoral neck may complicate pelvic radiation therapy. Less common effects of pelvic irradiation include acetabular protrusion and avascular necrosis of the femoral head. Femoral head dose constraints are not well established. The early work of Emami et al. [111] indicated a tolerance dose of 52 Gy to the whole organ in order to keep the probability of complication below 5%. Bedford et al. [180] recommended V52Gy < 10%; this was suggested on the basis of a low a/b ratio for femoral heads. On the other hand, clinical practice suggests that small volumes of femoral heads may tolerate high doses (>55– 60 Gy). Clearly, more studies are needed on this topic, although the extremely low incidence of this complication, even in very high dose pelvic radiotherapy (as for prostate cancer), suggests that the routinely followed approaches in limiting femoral head dose based on the few reported studies are probably effective; it is also important to underline that in most cases of high-dose (>50 Gy) radiotherapy, most fractions of femoral heads are irradiated at a dose per fraction significantly lower than the conventional 1.8–2 Gy, leading to EQD2 significantly lower than the physical dose. It is worthwhile to remember that several reports on cases of radio-induced pelvic bone fracture have been published: Herman et al. reported a 3-year actuarial incidence of sacral insufficiency

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fractures of 3.1% among rectal cancer patients [181]. Baxter et al. [182,183] evaluated the effect of irradiation on the incidence of pelvic fractures over time (on a total of 6428 women aged 65 years and older diagnosed with pelvic malignancies) and found that women who underwent radiation therapy were more likely to have a pelvic fracture (cumulative 5-year fracture rate, 14.0% vs 7.5% in women with anal cancer, 8.2% vs 5.9% in women with cervical cancer, and 11.2% vs 8.7% in women with rectal cancer). No dose–response relationship for this end-point is available; nonetheless, the reduction of volumes and dose to pelvic bone could be helpful in minimizing the risk of fracture, especially in elderly patients and in patients receiving LH–RH therapy. It must be emphasized that androgen deprivation therapy is a risk factor for the occurrence of osteoporosis and bone fracture [184].

Hematological toxicity Pelvic bones contribute significantly to the production of blood components: around 50% of the bone marrow of an adult man is distributed in the pelvic region [185]. The irradiation of the pelvic nodes with large fields is known to have an impact on the white blood cell count as well as other hematological parameters such as hemoglobin and platelet count, especially in combined chemoradiation treatments (as for gynecological and anal cancer); field dimension, dose and age have been found to be correlated with the regeneration of pelvic bone marrow since the 1970s, suggesting a clear dose–volume relationship for pelvic bone marrow [186,187]. More attention has been devoted in the recent years to the quantification of dose–volume relationships of the pelvic bone for hematological toxicity, due to the introduction of IMRT as a tool to spare bone marrow in the treatment of pelvic malignancies, especially for gynecological and anal cancer [188–191]. IMRT has been found to be effective in reducing the irradiated volume of pelvic bones, compared to conventional four-field technique, with a consequent reduction of hematological toxicity [188]. Several groups have attempted to assess a dose–volume relationship between the amount of pelvic bone irradiated at different dose levels and hematological toxicity: Mell et al. found the fraction of pelvic bone receiving more than 10–15 Gy to be the best predictor of hematological toxicity in two cohorts of patients irradiated for cervical [185] and anal [192] cancer. In particular, a V10Gy > 90% was found to be highly predictive of a greatly increased risk of leukopenia, neutropenia and anemia in a group of patients treated with IMRT for cervical cancer with concomitant chemotherapy [185]; this result is consistent with a high sensitivity of bone marrow at these low doses, and with a strong regeneration capacity if even 10% of the pelvic bone marrow is spared (i.e. receiving less than 10 Gy). Similar findings (i.e. V10Gy–V20Gy as best predictors) were reported for a cohort of patients treated with IMRT and concomitant chemotherapy for anal cancer [192]. In both cases, the DVH of lumbosacral bones was more correlated to toxicity than the DVH of the remaining pelvic bones. More recently, another study confirmed these findings in a group of patients treated with IMRT and concomitant cisplatin for cervical cancer and suggested constraints for V10Gy (<95%), V20Gy (<80%) and V30Gy (<64%) with best predictive value for V20Gy [193]. No clear dose–volume relationships have yet been reported for prostatic patients, although anemia has been clearly reported in series both with and without the use of hormonal therapy [194,195]; as pre/during/post radiotherapy anemia in combination or not with hormonal treatment has seldom been found to be correlated with poorer local tumor control in prostate patients [196,197], it could be difficult to differentiate between the direct hematological effect due to pelvic bone marrow irradiation and

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other potential correlations between tumor hypoxia and the ratio between pre- and post-treatment hemoglobin levels. Final remarks: predictive tools for radiation toxicity? The prediction of radio-induced toxicity is a very complex task: late radiation injury is related to both dosimetric factors and clinical risk factors, as well as, at least in part, the patient’s genetic make-up. Interestingly, very limited attention has been devoted to the development of clinical instruments for predicting EBRT side effects; nevertheless, a reliable prediction of potential toxicities could help clinicians in optimising treatment planning, and patients in choosing responsibly among the various treatment strategies proposed by clinicians. Predictive tools refer to probability formulas, look-up and propensity scoring tables, risk-class stratification models, classification and regression tree analysis, nomograms, and artificial neural networks. In this scenario, the use of nomograms as predictive instruments appears to be particularly attractive as they weigh the combined effects of multiple independent factors found to be correlated to a specific clinical end-point: the evaluation of clinical/dosimetric parameters of the single patient provides a tailored probability of the specific outcome. In the field of the prediction of normal tissue side effect due to the irradiation of the pelvic region, Valdagni et al. presented a set of nomograms predicting moderate/severe acute lower-GI toxicity using a combination of dosimetric and clinical variables [73] (as an example, the nomogram for moderate/severe RTOG/EORTC lowerGI acute toxicity is shown in Fig. 1). With respect to the prediction of late GI toxicity, preliminary data on AIROPROS 0102 trial [15,61,71] with a minimum follow-up of 36 months were used to develop a nomogram predicting G2–G3 late rectal bleeding [198,199]. We are currently working on the construction of a final set of nomograms predicting various symptoms of the late rectal syndrome, based on the data of 718 patients accrued in the AIROPROS 0102 trial. Acknowledgements Fondazione Mozino is gratefully acknowledged for its support to the Prostate Program of the Istituto Nazionale Tumori. We would like to express our gratitude to T. Magnani for her kind assistance. References [1] Burman C, Kutcher GJ, Emami B, et al. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys 1991;21:123–35. [2] Jackson A. Partial irradiation of the rectum. Semin Radiat Oncol 2001;11:215–23. [3] O’Brien PC. Radiation injury of the rectum. Radiother Oncol 2001;60:1–14. [4] Van der Wielen GJ, Mulhall JP, Incrocci L. Erectile dysfunction after radiotherapy for prostate cancer and radiation dose to penile structures: a critical review. Radiother Oncol 2007;84:107–13. [5] Incrocci L. Sexual function after external-beam radiotherapy for prostate cancer: what do we know? Crit Rev Oncol Hematol 2006;57:165–73. [6] Jackson A, Skwarchuk M, Zelefsky M, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer (II): volume effects and dose– volume histograms. Int J Radiat Oncol Biol Phys 2001;49:685–98. [7] Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions. Radiother Oncol 2002;64:1–12. [8] Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose–volume constraints in high-dose conformal radiotherapy for localized prostate cancer. J Radiat Oncol Biol Phys 2003;57:953–62. [9] Rancati T, Fiorino C, Gagliardi G, et al. Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101). Radiother Oncol 2004;73:21–32.

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