Predictive Models of Toxicity in External Radiotherapy

Transcription

1 Predictive Models of Toxicity in External Radiotherapy Dosimetric Issues* Claudio Fiorino, PhD 1 ; Tiziana Rancati, PhD 2 ; and Riccardo Valdagni, MD 2 Dose-volume modeling of late and acute toxicity in radiotherapy for prostate cancer is a rapidly evolving field of investigation. The availability of individual, 3-dimensional dose distribution and dose-volume histograms (DVHs) permits the quantitative assessment of dose-volume relations for specific endpoints by investigating the correlation between individual dose-volume data and clinical outcomes. These studies often entail a huge effort in collecting data from large populations that have been followed properly for long time. The rectum is the most investigated organ, especially concerning late bleeding, and a good consensus regarding serial-like behavior for this endpoint comes from various investigations. Concerning the bladder, the existence of a clear dose effect when the organ is wholly or partially irradiated is well known. Concerning erectile dysfunctions, the wide use of hormone therapy and drugs against impotence suggests that large, prospectively scored populations will be necessary to definitively assess dose-volume relations. Bowel irradiation during prostate cancer radiotherapy occurs during pelvic lymph node irradiation, and severe acute toxicity has yet to be modeled clearly. Evidence of a correlation between the DVH of the intestinal cavity and bowel toxicity recently was reported, providing important information about optimal dose-volume constraints to be used during whole-pelvis irradiation with intensity-modulated radiotherapy. Cancer 2009;115(13 suppl): VC 2009 American Cancer Society. KEY WORDS: radiotherapy, radiation-induced effects, toxicity, dose-volume models. Dose-volume modeling of late and acute toxicity in the radiotherapy of prostate cancer is a rapidly evolving field of investigation. The prostate is in close proximity to organs at risk, such as the rectum and bladder, which should be spared as much as possible; conversely, evidence of a dose-effect relation in the probability of local control, at least in some subgroups of patients, suggests the advisability of escalation to very high doses. Intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) exploit new tools and methods for dose painting distributions strictly tailored around the planning target volumes (PTV) to reduce the fraction of organs at risk irradiated to moderate/high doses while escalating the dose and/or the dose per fraction. Corresponding author: Claudio Fiorino, PhD, Servizio di Fisica Sanitaria, H. S. Raffaele, Via Olgettina 60, Milano, Italy; Fax: (011) ; fiorino.claudio@hsr.it 1 Department of Medical Physics, San Raffaele Hospital, Milan, Italy; 2 Prostate Program, Scientific Directorate, National Cancer Institute, Milan, Italy Presented at the Inside Track Conference, Predictive Modeling in Prostate Cancer, organized by the European School of Oncology, Venice, Italy, April 17-19, *Predictive Modeling in Prostate Cancer, Supplement to Cancer Received: September 22, 2008; Revised: February 16, 2009; Accepted: March 2, 2009 Published online: June 19, 2009 VC 2009 American Cancer Society DOI: /cncr.24354, Cancer July 1,

2 In this context, accurate knowledge of the dose-volume relations concerning the side effects to the organs at risk is of paramount importance in terms of treatment optimization in minimizing the risk of complications (normal tissue complication probability [NTCP]) while maximizing the probability of local control (tumor control probability). The availability of individual, 3-dimensional, dosimetric information and dose-volume histograms (DVHs) permits the quantitative assessment of dose-volume relations for specific endpoints by investigating the correlations between dose-volume data and clinical data. The availability of biologic-based models 1-7 may help investigators in the further fitting of these data to NTCP models that attempt to condense the dose-volume information into a number that expresses the risk of a certain toxicity. Most NTCP models are phenomenologic and have the advantage of being characterized by few parameters (typically 3), the most important of which probably is the volume-effect parameter, which describes how an organ fits a serial or parallel architecture. In a serial organ, the complication probability depends on the (high) dose received in a small volume (ie, the maximum dose); inversely, in a parallel organ, the complication probability depends on the dose bath received by the whole organ (ie, the mean dose). 2,3,5,7 Another highly effective biologic parameter is the socalled equivalent uniform dose (EUD). 4 With this approach, the DVH is reduced to an effective homogeneous dose to the whole organ through a power-law relation: EUD ¼ X i m i D 1 n i! n (1) where D i is the dose received by the volume m i,andn is the volume parameter. For small values of n (n!0; serial organs),theeudtendstobethemaximumdose;whereas, for n ¼ 1 (parallel organs), the EUD is the mean dose. Depending on the organ and the endpoint investigated, dose-volume modeling studies entail a huge effort in collecting data from large populations in a consistent way with regard to the toxicity score. Moreover, the combination of dosimetric factors and clinical factors may jeopardize the correct dose-volume relation; and, consequently, larger populations may be required. Thus, it is not surprising that the dose-volume relations of most organs have not yet been fully assessed. In the discussion below, a critical review of the dose-volume effects of the main organs at risk involved FIGURE 1. This chart provides a summary of rectal dose-volume constraints that have been suggested in several recently published investigations: Keeping the percentage volume of the rectum (y-axis) that receives more than a certain dose (x-axis) and following the suggested values should guarantee the possibility of keeping late moderate/severe rectal bleeding well below 10% while irradiating prostate patients to doses between 70 grays (Gy) and 80 Gy (modified constraint was reported by Fiorino et al 22 for patients who underwent previous abdominal surgery [abd surg]). Ref indicates reference (numbers correspond to the list of References). in prostate radiotherapy is presented. We selected published reports of major relevance in terms of content and methodology in an attempt to condense the most important information into a short, usable text. Consequently, this review should not be considered fully comprehensive. Dose-Volume Modeling of Rectal Toxicity The rectum is the most investigated organ, especially concerning late rectal bleeding There is very good agreement among several investigations indicating a prevalently serial behavior for this endpoint, especially when considering severe (ie, Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer grade 3) bleeding. Several dose-volume constraints have been suggested and validated to keep the rate of moderate/severe late bleeding at an acceptable level (<5%-10%): A schematic plot of suggested dose-volume constraints is provided in Figure 1, which indicates that there is very strong agreement in suggesting several 3136 Cancer July 1, 2009

3 ERT Toxicity Models: Dosimetric Issues/Fiorino et al constraints both in the high-dose region (65-78 grays [Gy]) and in the intermediate-dose region when delivering prostate doses between 70 Gy and 80 Gy. In particular, it has been demonstrated that keeping the volume of the rectum that receives >70 Gy (V70) below 25% and keeping the volume that receives >75 Gy (V75) below a few percentage points are predictive of a very low incidence of late bleeding. 8,10-12,14,17,19-21 The application of these constraints combined with highly sophisticated delivery techniques (IMRT and IGRT) is contributing to a significant reduction in the risk of late bleeding while substantially increasing the delivered dose compared with the recent past. The reliability of DVH constraints in predicting the risk of late rectal toxicity is highly influenced by the management of rectal filling: A full rectum at the planning scan is less likely to represent the dose actually delivered to the rectum, 23 and the practice of emptying the rectum also reduces the differences in calculating the DVH of the whole rectum (including filling) and of the wall. 24 Conversely, it is also very important to remember that most studies that have assessed DVH constraints for late rectal bleeding have used a very similar anatomic-based definition of the cranial-caudal extension of the rectum. For this reason, contouring the rectum from the anus to the point where the rectum turns into the sigmoid may permit the safe application of these constraints; it also has been demonstrated that this definition is sufficiently robust from the point of view of contouring uncertainty. 25 Concerning NTCP/EUD-based fit, recent investigations of large populations have produced very similar results, with n values between 0.06 and 0.12 for moderate/severe bleeding, 16,19,20 suggesting that EUD-based optimization may be performed reliably for prostate radiotherapy. It also should be emphasized that, in the case of moderate bleeding, a greater value for the value parameter n was reported (n ¼ 0.24) 16 in a study that included patients who received 2-dimensional techniques, suggesting that, when large fractions of the rectum are irradiated at intermediate doses (ie, Gy), the rectum may behave in a more parallel way. It is important to note that patients no longer are treated with such old techniques. Several recent studies have produced evidence of dose-volume relations for other endpoints, such as late rectal incontinence 19,22 and acute rectal toxicity, in which more parallel behavior was reported. In particular, it was demonstrated recently that a DVH constraint on the fraction of rectum receiving >40 Gy (V40, <65%) reduced the risk of late incontinence by a factor of approximately Although late incontinence is quite a rare effect, the application of this constraint has the potential to reduce the risk to below 2%. Potential mechanisms involved in the generation of incontinence could be the reduced absorption capacity of the rectal mucosa, which reasonably may be expected to have a large volume effect; however, neither an effect caused by neurovascular damage impairing the musculature surrounding the rectum nor a combination of the 2 factors can be excluded. Grade 2 and 3 acute toxicity was highly correlated to the mean dose, suggesting that the reduction of the dose bath to the whole rectum may have an impact on the risk of acute toxicity Dose-Volume Modeling of Genitourinary Toxicity Concerning the bladder, the existence of a clear dose effect when the whole organ is irradiated (ie, for cystitis) 7 is well known. In the case of prostate irradiation, the cranial portion of the bladder generally is spared, whereas the bladder neck and urethra are irradiated near the prescribed dose. A serial behavior recently was reported for late mild-tosevere toxicity, 29 whereas a serial-parallel behavior was reported for chronic moderate/severe urinary toxicity 30 : both studies indicated that the fraction of bladder receiving >78 Gy to 80 Gy was most predictive of late genitourinary toxicity. The lack of knowledge regarding dosevolume modeling of bladder toxicity probably reflects the difficulty in carefully assessing the amount of bladder wall that receives a certain dose because of the large variations in bladder shape during treatment related to variable filling. Dose-Volume Modeling of Erectile Dysfunction Recent studies have identified a correlation between the dose received by penile structures (primarily the penile bulb) and alterations in sexual function (primarily impotence) In particular, a median dose to the penile bulb >52 Gy was correlated highly with an increased risk of Cancer July 1,

4 erectile dysfunction. 36 Other authors have reported results consistent with the findings reported by Roach et al when considering the penile bulb as the target structure: Wernicke et al 35 suggested keeping V50 <20% and V40 <40% to drastically reduce impotence. Mangar et al 34 reported a median penile bulb dose of 59.2 Gy and 45.5 Gy for impotent and potent men, respectively, in a cohort of 51 patients who were included in a randomized trial. However, other investigators have observed no clear dose-volume effect. 37 The wide use of hormone therapy and drugs against impotence suggests that studies on large prospectively scored populations, preferably using magnetic resonance imaging to define the apex of the prostate (with consequently efficient sparing of the penile structures), 38 may be necessary for a definitive assessment of dose-volume relations. Nonetheless, based on the available literature data, sparing the penile bulb without compromising the coverage of the PTV in the most caudal portion seems to be justified: in particular, the use of magnetic resonance imaging to define the prostate apex better in potent patients may permit a safe sparing of the penile bulb without missing the prostate in most patients. Dose-Volume Modeling of Bowel Toxicity Bowel irradiation during radiotherapy for prostate cancer is extremely important in whole-pelvis irradiation. The practice of irradiating lymph nodes in patients who have intermediate/high-risk disease is increasing along with the use of IMRT techniques, mainly to spare the bowel, because it is recognized that there is a clear volume effect in the bowel with regard to acute/late upper gastrointestinal side effects; conversely, the dose-volume effect concerning the bowel during pelvic irradiation has not been modeled clearly. Recent investigations using IMRT have indicated that there is a dramatic reduction with in moderate/severe bowel toxicity with IMRT compared with conventional treatment. 42 Recent attempts to quantify the dose-volume effect concerning the bowel mostly have concerned patients who received conventional 4-field techniques that reveal a correlation between the DVH of bowel loops and grade 2/ 3 acute bowel toxicity, mainly in patients who were treated for rectal/gynecologic cancer, demonstrating that the low-dose region (around 15 Gy) is the best predictor, a finding that is not likely to have any biologic significance. The advent of IMRT for the treatment of pelvic lymph nodes will facilitate a better understanding of the dose-volume relations for the bowel: In an early report, a significant correlation between DVH of the bowel and acute grade 2 toxicity was observed by Roeske et al 47 in an analysis of 50 patients who received whole-pelvis IMRT for gynecologic malignancies. Those authors observed that the high-dose region was the best predictor of toxicity, suggesting that the fraction of bowel receiving >45 Gy (100% of the prescribed dose) may be used to assess the risk of bowel toxicity. Based on those findings, keeping V45 <150 ml should guarantee the possibility of keeping acute toxicity below a few percentage points. An investigation recently conducted at the San Raffaele Institute demonstrated a clear correlation between the DVH of the intestinal cavity (including the bowel) and acute upper gastrointestinal toxicity in a population of 175 patients who received or did not receive IMRT for prostate cancer at the same institute, 48 substantially corroborating the findings of Roeske et al. In conclusion, for this critical review, we tried to condense the most relevant information concerning the dose-volume relation of most of the organs at risk involved in planning optimization of prostate radiotherapy. Main points may be summarized as follows: 1) There is a clear need to increase our knowledge in the modeling of late and acute toxicity, especially because of the rapidly increasing use of inverse-planned IMRT, in which a careful assessment of dose-volume or biologic-based cost functions has to be set. 2) The rectum is the most investigated organ: The largest studies on dose-volume modeling of rectal toxicity produced very consistent results, suggesting that the rectum is a prevalently serial organ when bleeding is considered as the endpoint, whereas the rectum seems to be a prevalently parallel organ when fecal incontinence is considered as the endpoint. 3) Quantitative data on bladder, bowel, and erectile structures are coming rapidly; however, for these organs, further investigation on large groups of patients will be necessary to reliably assess quantitative models of dose-volume effects. Conflict of Interest Disclosures Sponsored by ASTRA Zeneca and the European School of Oncology Cancer July 1, 2009

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