Prostate cancer is a common malignant tumor of the male reproductive system. According to statistics, the new incidence of prostate cancer in the United States ranked first among male tumors in the United States in 2012 [1]. There has been a significant increase in incidence in China in recent years, rising from 6th in 2010 to 5th in 2012 among new cases of malignant tumors. External radiotherapy, as one of the radical treatments, plays an important role in the treatment of prostate cancer. Accurate outlining of the target area of prostate cancer is important to improve the efficacy of radiotherapy and reduce adverse effects. The scope of postoperative target area outlining is generally adopted by RTOG consensus [2], which is less controversial. However, there are still controversies on how to accurately outline the target area for radical radiotherapy, especially on some specific clinical details. The meeting invited many experts and professors from radiotherapy, urology, imaging and pathology to have a comprehensive and in-depth multidisciplinary discussion on these 2 diseases. The discussion on the details of radical radiotherapy target area for prostate cancer was particularly lively, and the results are summarized below.
I. GTV
The principle of GTV outline: For most tumors, GTV refers to the lesion visible to the naked eye, i.e., the lesion with a certain shape and volume that can be determined by clinical examination or imaging. However, because prostate cancer is often a multifocal lesion, imaging and other means cannot detect all cancer foci in the prostate, so the prostate and the envelope as a whole need to be considered as GTV. those with stage T3 or above need to classify clearly invaded parts as GTV, such as clearly invaded parts of seminal vesicles, invaded parts of bladder and rectum, etc. for local addition. Metastatic lymph nodes are defined as GTVnd. It is important to note that outlining the entire prostate and envelope as GTV presupposes that the boundaries of the prostate envelope can be distinguished on the images.
(1) Outlining on CT: At present, most domestic radiotherapy centers still outline the target area on CT images in actual clinical work, and it is often difficult to distinguish the prostate envelope from the extra-envelope fibrofatty tissue on CT images, plus partial volume effects, so outlining the GTV on CT often includes several millimeters of connective tissue around the envelope. It is recommended to outline the CTV of the prostate area directly when the envelope boundary is indistinguishable, and to outline the clearly invaded part (such as the clearly invaded part of the seminal vesicles, the invaded part of the bladder and rectum) as the GTV after local addition.
(2) Outlining on MRI: MRI has obvious advantages in distinguishing the prostatic envelope, especially on T2 images that can clearly show the prostatic envelope. In the literature, it was reported that the size of the prostate gland was 10%-30% smaller on MRI than on CT when comparing the size of the prostate gland outlined with the two images separately using CT-MRI fusion technique [3-6]. If outlined on MRI, it is recommended to directly outline the prostate, the envelope and the clearly invaded part as GTV.
II. CTV
Principles of CTV outlining: CTV includes primary tumor, subclinical lesions and lymph nodes to prevent irradiated areas. For the details of CTV drawing, several experts and professors discussed enthusiastically and reached the following initial drawing principles.
(1) CT: The prostate and peritoneum can be directly outlined as CTV without outlining the GTV, and the principles of outlining the seminal vesicles and pelvis are the same as those of outlining on MRI.
(2) MRI outline: low-risk CTV is the same as GTV, intermediate-risk CTV is GTV with 5-mm outgrowth + 25px seminal vesicle root ± pelvic lymph node drainage area, high-risk CTV is GTV with 5-mm outgrowth + 50px seminal vesicle root + pelvic lymph node drainage area, stage T3b (seminal vesicle invasion) CTV is GTV with 5-mm outgrowth + all seminal vesicle + pelvic lymph node drainage area.
2. Analysis of the extent of subclinical lesions
(1) The scope of irradiation of prostate envelope: the scope of subclinical foci of prostate envelope is different for different stages and risks. lieberfarb et al [7] statistically analyzed the pathological results of 2099 cases of prostate cancer after radical surgery and found that there were few envelope invasion in low-risk patients and the probability of envelope invasion increased in medium- and high-risk patients. teh et al [8] statistically analyzed the pathological results of 712 cases after radical surgery and showed that more than 97% of Based on these 2 studies, the EORTC guidelines recommend a CTV consistent with the GTV in low-risk patients and a CTV of 5 mm outgrowth of the GTV in medium- and high-risk patients [9]. This recommendation was adopted by several European radiotherapy centers. However, it is important to note that all cases in both studies mentioned above did not receive endocrine therapy. This is because the prostate volume will be reduced after endocrine therapy and the extent of the corresponding surrounding subclinical foci may also be reduced to some extent.
Unlike in Europe, most radiotherapy centers in the United States believe that unless tumor invasion can be clearly seen beyond the prostate, CTV in the prostate area is generally recommended in line with GTV, regardless of stage and risk level. In the two ongoing phase III randomized controlled clinical studies, RTOG 0815 and RTOG 0924, for example, the study protocol clearly states that the CTV in the prostate area is consistent with the GTV. As the dose of radiotherapy gets higher, there is a substantial increase in the dose decremented down around the GTV, and here perhaps the prophylactic dose has been reached.
(2) The scope of irradiation of seminal vesicles: there is no uniform standard, but irradiation of seminal vesicles will bring adverse effects in rectum and bladder accordingly. Based on the pathological findings of subclinical foci of the seminal vesicles, it is believed that the seminal vesicles are rarely invaded in low-risk patients, so there is no need to irradiate the seminal vesicles; in intermediate- and high-risk patients, the probability of seminal vesicle invasion increases, so it is recommended to irradiate a range of 25 px vertically upward from the root of the seminal vesicles. 25 px range is evidenced from the study of Kestin et al [10], who counted seminal vesicle invasion in 344 specimens after radical prostate cancer surgery. The results showed that only 1% of low-risk patients had seminal vesicle invasion, while 27% of intermediate and high-risk had seminal vesicle invasion; the median invasion length was 25px for all invaded seminal vesicles counted; only 1% of all specimens had seminal vesicle invasion length >50px. Based on this study, several RTOG study protocols specify that intermediate-risk patients should be irradiated to a range of 25px vertically upward from the root of the seminal vesicles, specifying that this 25px is drawn from the CT level where both seminal vesicles and prostate are present, including the 25px axial range at this level and the seminal vesicles within the 25px upward range at each level. Most radiotherapy centers currently believe that CTV generally needs to include the entire seminal vesicle for stage T3b patients with clear foci of seminal vesicle invasion visible on imaging. However, for the very few patients with particularly long seminal vesicle glands, it is recommended that the target area be treated individually according to the specific situation, and also refer to the pathological findings of the seminal vesicles by Kestin et al [10], where CTV should include at least 50 px of the seminal vesicles above the imaging-visible foci of seminal vesicle invasion. When the entire seminal vesicle is irradiated, it needs to be retracted to the GTV after 50-60 Gy.
In the guidelines published by EORTC, it is recommended that the seminal vesicles are not routinely irradiated in low-risk patients, 25 px at the root of the seminal vesicles in intermediate-risk patients, and 50 px at the root of the seminal vesicles in high-risk patients, also based on the study by Kestin et al [10]. However, it should be noted that all patients in the study by Kestin et al [10] did not receive endocrine therapy, but most intermediate and high-risk patients now undergo a period of neoadjuvant endocrine therapy prior to radiotherapy. Therefore, there are some opinions that CTV can exclude the seminal vesicles in intermediate- and high-risk patients who have received neoadjuvant endocrine therapy, because the seminal vesicles are significantly reduced after treatment, but there is no clear evidence-based medical evidence for this opinion.
Therefore, when outlining the CTV in the prostate area, it is important to know the probability and extent of possible invasion of the envelope and seminal vesicles on the one hand, and to consider the accuracy of outlining the CTV on localized CT on the other hand, and to consider the possible rectal and bladder reactions.
3. Prophylactic irradiation of the pelvic lymph node drainage area: This is also a controversial topic. A review of randomized controlled studies of pelvic prophylactic irradiation for prostate cancer shows both studies supporting pelvic prophylactic irradiation such as RTOG9413 [11] and opposing voices such as GETUG01 [12]. There is also the RTOG0924 randomized controlled study, currently in the enrollment phase, examining the prognostic impact of adding or not adding pelvic prophylaxis in intermediate and high-risk patients, which was designed to enroll 2580 cases and has now enrolled 478 cases, and we expect the results.
It is now generally accepted that pelvic prophylaxis is not required in low-risk patients, and is determined on a case-by-case basis in intermediate-risk patients. In high-risk cases, irradiation of the pelvic lymph node drainage area combined with endocrine therapy may reduce the biochemical recurrence rate. If the risk of lymph node metastasis is >15% (empirical formula for pelvic lymph node metastasis: LN+=2/3 PSA+(Gleason Score-6)×10), prophylactic irradiation of the pelvic lymphatic drainage area is recommended.
The scope of pelvic irradiation included part of the common iliac, external iliac, internal iliac and presacral lymph node drainage areas, and closed lymph node drainage areas. Referring to the RTOG consensus guidelines [13], the specific scope is: (i) starting from the level of L5~S1 above, i.e., the distal end of the common iliac vessels and the proximal end of the presacral lymph node area; (ii) 7 mm of external expansion of the internal and external iliac vessels, avoiding the bowel, bladder, femoral head, etc.; (iii) the posterior border of the presacral lymph nodes (S1~S3) is anterior to the sacrum and the anterior border is 25 px anterior to the sacrum, avoiding the bowel, bladder, femoral head, etc.; (iv) the external iliac lymph node area terminates at the superior border of the femoral head (bony marker of the inguinal ligament); ⑤ the closed lymph nodes terminate at the superior border of the pubic symphysis.
PTV
The PTV of prostate cancer should take into account the filling status of the rectum and bladder, the physiological movement of the organ, respiratory movement, and positional error. As the position of the prostate changes with the filling status of the bladder and rectum, it is generally recommended that the PTV of the prostate and seminal vesicles should be expanded by 5-10 mm on the basis of CTV, including 10 mm in the up and down direction and 5 mm in the left and right, anterior and posterior directions, but the rectal direction should be reduced appropriately, especially in the case of high-dose irradiation to protect the rectum. The PTV in the pelvic lymphatic drainage area can be expanded by 5~10mm on the basis of CTV, including 10mm in the up and down direction and 5mm in the left, right, and anterior and posterior directions. If IGRT is available every day, the PTV can be reduced appropriately. Of course, the range of PTV outgrowth is closely related to the positional error of each radiotherapy center and the bladder and rectal management of patients before radiotherapy. Therefore, each radiotherapy center should not only know the mastery level of radiotherapy technology in their own unit, but also know the accuracy of positional and rectal bladder preparation in their own unit, and have their own data to achieve precise radiotherapy and individualized treatment.
IV. OAR limits
RTOG consensus [13] stipulates that rectal V50≤50%, V70≤20%, bladder V55≤50%, V70≤30%, femoral D50<50gy, small intestine dmax<52gy. The radiotherapy center of the Medical College of Wisconsin in the United States adopts high-dose radiotherapy, so the dose limit for rectum is more strict, generally requiring rectal v70≤10%, V65≤25%, and V45≤50%. Our limitations are rectal V50≤40%, V60≤30%, V66≤20%, V70≤10%, bladder V50≤30%, V60≤20%, V70≤10%, pubic symphysis V70≤15%, femoral V50≤5%, Dmax<52gy, and small bowel v50≤5%, Dmax<52gy.< span="">
V. Outlook
At present, the target area outline of radical external radiotherapy for prostate cancer is still a hot spot of concern for radiation oncologists at home and abroad, and many problems remain to be solved. With the increase of the number of prostate cancer patients in China and the advancement of radiotherapy equipment and technology, it is believed that more and more experience of target area outlining and treatment of prostate cancer in China will be available.