INTRODUCTION
Radical radiotherapy is routinely used for the curative treatment of localised prostate cancer. Dearnaley et al. recently reported that conformal radiotherapy (CFRT) techniques in the radical treatment of prostate cancer provided significant reduction in late rectal morbidity when compared with conventional open-field techniques.Reference Dearnaley, Khoo, Norman, Meyer, Nahum, Tait, Yarnold and Horwich1 Using prescribed doses of up to 64 Gy, rectal complications greater than or equal to grade 2 as measured on the Radiation Therapy Oncology Group (RTOG) scale were reduced from 15% to <5% (p = 0.01). Radiation doses received by the bladder and femur heads were found to be acceptable, and there were no serious complications resulting from these doses. This finding laid the foundation for the randomised Medical Research Council RT-01 trial of dose escalation for localised prostate cancer. This ongoing trial involves the use of CFRT for patients with prostate cancer; the patients are randomly assigned to two groups, one of which receives a dose of 64 Gy and the other an escalated dose of 74 Gy.
On the basis of dose–response data relating to radiotherapy for prostate cancer the Patterns of Care Study suggested that there is improvement in local control with a dose of >70 Gy in stage C tumours,Reference Hanks, Martz and Diamond2 but that this dose is accompanied by an increase in toxicity to normal tissues. However, 3D-CRT studies have shown that doses >70 Gy can be delivered to achieve better local control in prostate tumour with no associated increase in either acute or late toxicity.Reference Hanks, Hanlon, Schultheiss, Pinover, Movsas, Epstein and Hunt3
Although external beam radiotherapy is commonly used in the treatment of localised prostatic carcinoma, the optimal beam arrangement is still being debated. Traditionally, a four-field ‘box’ technique has been used, but more recently other approaches have been applied, including three-field (3F), four-field (4F), six-field (6F) and arcing fields. Each of these different treatment plans has its own advantages and disadvantages in terms of sparing of critical structures, delivery of treatment, and ease of verification. Pickett et al. concentrated on the 6F technique and found that anterior and posterior oblique beams angled at 35° from the lateral direction, combined with bilateral fields (i.e., gantry angles at 55°, 90°, 125°, 235°, 270° and 305°), provided the best combination of CTV coverage and maximum sparing of the femoral heads, rectum and bladder.Reference Pickett, Roach, Horine, Verhey and Phillips4 Several authors have reported results of comparative studies involving different numbers of fields for prostate radiotherapy. These studies include the one by Lennernäs et al.Reference Lennernäs, Rikner, Letocha and Nilsson5 who compared 4F, 5F and 6F techniques. They found that the use of more than four fields did not reduce the dose to the organs at risk, and that if increased sparing of these organs was necessary, it must be achieved through application of reduced tumour margins. This conclusion was supported by Neal et al., who found that, although the use of a larger number of fields reduced the dose to the femoral heads and bladder, the 4F technique was the most advantageous in terms of clinically relevant rectal sparing.Reference Neal, Oldham and Dearnaley6 Fiorino et al. concluded, after comparing 3F, 4F and 6F techniques, that no one technique was better than the others, because sparing of the rectum was always achieved at the expense of increased dose to the femoral heads.Reference Fiorino, Reni, Cattaneo, Bolognesi and Calandrino7
In this study, our aim was to compare the femur head doses resulting from co-planar beam arrangements relating to various 4F, 5F, 6F and 7F plans in a dose-escalated CFRT schedule for prostate cancer. The aim was to determine which of these plans (4F, 5F or 6F) provides the maximum sparing of femoral heads, while maintaining the radiation doses to the rectum and bladder within acceptable limits.
PATIENTS AND METHODS
Patient characteristics
A total of 22 patients with prostate adenocarcinoma were selected for this study. We used the data from computed tomography (CT) abdomen scans of 22 patients who were treated for prostate cancer in our institute in 2005–2006. All these patients were treated with 3D-CRT. They had undergone complete clinical evaluation and laboratory studies including complete blood count, renal and liver function tests and prostate-specific antigen estimation. CT scan of abdomen and pelvis, chest radiography and bone scan formed part of the staging procedure. The median Gleason score was 7 (range 6–9).
Radiotherapy treatment planning and dose calculation algorithms
For the 3D-CRT procedure the patients were immobilised (pelvis and leg) in a thermoplastic mask system or a vacuum lock fixation device in the supine position. All the patients underwent treatment planning intravenous contrast enhanced CT scans with 5 mm axial contiguous cuts which extended from midpoint of sacroiliac joint to below the lesser trochanter of the femur. The scans were imported through an electronic network. Clinical target volume (CTV) and organs at risk (rectum, bladder and femur heads) were contoured. The CTV included the prostate and seminal vesicles. The lower pelvic nodal areas were included in the CTV for purposes of planning, after which they were contoured only if pre-treatment CT/magnetic resonance imaging scans revealed involvement of the pelvic nodal area. The planned target volume (PTV) was contoured on the basis of the CTV, allowing a margin of 0.5 cm. The dose planned to the prostate was 70–76 Gy, and to the seminal vesicles 50.4–60 Gy; the lower pelvic nodal region received a prophylactic dose of 45 Gy. All treatment planning was normalised to the ICRU reference point.
The prescribed dose was normalised to 100% at the isocentre, and 95% isodose surface covered the PTV.
The doses received by the bladder, rectum and femoral heads were measured for statistical analysis.
Target volumes
For all the patients, the delineation of target(s) and critical structures was done by a single physician with extensive experience in the treatment of prostate cancer. The CTV for each of the patients included 2 cm of seminal vesicles of the peri-prostatic rectum and a 5 mm expansion of the gross tumour volume (prostate only) in all directions, except posteriorly. The prostate planning target volume (PTVprostate) was generated by expanding the prostate CTV by a uniform 5 mm in all directions. The nodal CTV included a 1 cm expansion of pelvic lymph nodes in all directions excluding the anterior portion of 1 cm of skin, prostate PTV, bladder, rectum, small bowel, and femoral heads. The nodal PTV volume (PTVnodes) was arrived at by expanding the nodal CTV by 5 mm in all directions excluding prostate PTV and anterior skin 1 cm.
Critical structures
The critical structures included the rectum, bladder, small bowel and femurs. The nodal CTV included a 1 cm expansion of pelvic lymph nodes in all directions prostate PTV, bladder, rectum, small bowel and femoral heads. In addition, the unspecified tissue was also contoured and included in the optimisation.
Statistical analysis
Normal tissue doses for bladder, rectum, femur heads were calculated.
The data were analyzed using the software from Statistical Package for Social Sciences (SPSS 12.0).
The various 4F, 5F, 6F and 7F plans were compared using mean dose–volume statistics. A two-tail Student’s t-test was used to verify the significance of differences in the mean results of the treatment plans, after correlation of quantile–quantile plots had shown the data to be normally distributed.
RESULTS
The mean statistical values relating to the 4F, 5F, 6F and 7F plans are shown in Table 1. Each of the optimised plans (4F, 5F, 6F and 7F) improved on its respective reference plan in terms of V50 (Figures 1–4).
Figure 1. Four-field conformal planning techniques.
Figure 2. Five-field conformal planning techniques.
Figure 3. Six-field conformal planning techniques.
Figure 4. Seven-field conformal planning techniques.
Table 1. Mean statistics for each of the 4F, 5F, 6F and 7F plans
We calculated the radiation doses received by the femur under each of the treatment conditions: For the left femur, these were: 4F, V50 1030 cGy (minimum 58, maximum 1390); 5F, V50 2425 cGy (minimum 540, maximum 3631); 6F, V50 1769 cGy (minimum 1234, maximum 3912); and 7F, V50 3230 cGy (minimum 2150, maximum 4137). For the right femur, the doses were: 4F, V50 1040 cGy (minimum 88, maximum 1350); 5F, V50 2325 cGy (minimum 483, maximum 3074); 6F V50 1780 cGy (minimum 1352, maximum 3968); and 7F, V50 3275 cGy (minimum 2250, maximum 4050). The 4F plan irradiated a smaller volume of femoral head than the other three reference plans did.
When paired samples t-test was carried out, we found considerably lower femur doses for 4F techniques (p = 0.05). We concluded that, during radiotherapy for prostate carcinoma, the dose received by rectum is the overriding factor to consider, in view of potential for late toxicity in this organ. When lateral fields were used (90–270°) with a view to protecting the rectum, the doses received by the femur heads were observed to increase.
Especially in older patients, the critical doses of 52 Gy for TD5/5, 65Gy for TD 50/5 were observed to be not reached late toxicity for 4F, 5F, 6F and 7F.
DISCUSSION
Prostate cancer is the most frequently diagnosed non-skin cancer in the male population in Western countries.Reference Parker, Tong, Bolden and Wingo8 The prostate cancer clinical guidelines panel of the American Urological Association recommended radiation therapy as an important option in the management of localised prostate cancer.Reference Middleton, Thompson, Austenfeld, Cooner, Correa, Gibbons, Miller, Oesterling, Resnick and Smalley9 A comparison of outcomes of external beam therapy versus radical prostatectomy for 382 patients with low-risk prostate carcinoma treated at a single institution revealed similar 7-year rates of biochemical control and cause-specific survival.Reference Martinez, Gonzalez, Chung, Kestin, Balasubramaniam, Diokno, Ziaja, Brabbins and Vicini10
The 3D-CRT technique overcomes the limitation of conventional open-field radiotherapy, in that it avoids toxicity to normal tissues. In 3D-CRT, the prescribed radiation doses conform to the outline of planned target volume in its entire 3D configuration. Therefore the risk of under-dosing the target is reduced. Effective exclusion of normal tissues permits dose escalation to the target to high levels.
The standard 3D conformal beam arrangement consists of six co-planar fields, comprising two lateral, two anterior and two posterior oblique beams.Reference Leibel, Kutcher, Zelefsky, Burman, Mohan, Ling and Fuks11 Several other beam arrangements have been proposed for 3D-CRT, with the most common being the conformal four-field.Reference Lee, Hanks, Hanlon, Schultheiss and Hunt12–Reference Ten Haken, Perez-Tamayo, Tesser, McShan, Fraass and Lichter15
Dose–volume histograms (DVHs) were generated for the PTV, femoral heads, and rectal and bladder walls (Figures 5–8). Wherever the bowel was located near the prostate and seminal vesicles, a dose calculation for the bowel was also done. In the Memorial Sloan-Kettering Cancer Center 6F plan, the two lateral beams typically delivered approximately half of the total dose to the isocentre with the four oblique beams contributing the rest. The beam weights of the anterior and posterior oblique beams were adjusted to obtain a uniform dose within the PTV and to place the hot spots away from the rectum. The plan was normalised so that the prescription isodose (100%) covered the PTV with a hot spot of 6–9% within the PTV. Although the portion of the rectal wall enclosed within the PTV was expected to receive the prescription dose, or slightly higher, the rectal wall volume that received 75.6 Gy or more did not exceed 30%. For these 3D-CRT plans, the other dose limits relating to normal tissue included limiting the maximum dose to the femurs to ≤68 Gy (90%), the maximum dose to the large bowel to ≤60 Gy (79%), and the maximum dose to the small bowel to ≤50 Gy (66%).
Figure 5. Four-field conformal planning dose–volume histograms.
Figure 6. Five-field conformal planning dose–volume histograms.
Figure 7. Six-field conformal planning dose–volume histograms.
Figure 8. Seven-field conformal planning dose–volume histograms.
The dose tolerance limits of the rectum and bladder have been the main limiting factors for dose escalation in radiotherapy for prostate cancer. After the introduction of 3D-CRT, the early results reveal no significant increase in gastrointestinal and genitourinary toxicity with increased doses of radiation to the prostate. In 96 patients treated with 3D-CRT to a level of 75.6 Gy or 81 Gy, the occurrence of acute grade II morbidity was 17% for the rectum and 36% for the urinary bladder.Reference Hanks, Hanlon, Schultheiss, Pinover, Movsas, Epstein and Hunt3 All the other patients had either no morbidity at all, or grade I morbidity. No acute grade III side effects were observed. Late rectal morbidity was nil or grade I in 85% of the patients. Grade II morbidity occurred in 15% of the patients. The acute and late effects of high-dose 3D-CRT were studied in the RTOG 9406 prostate cancer trial.Reference Michalski, Winter, Purdy, Perez, Ryu, Parliament, Valicenti, Roach, Sandler, Markoe and Cox16 In 262 patients with T1T2 prostate cancer who were treated at dose levels of 74 Gy, the tolerance has been found to be better than would be expected on the basis of historical data.
The safety-related constraints regarding dose to the femoral head during radiotherapy for prostate cancer are not yet well established.Reference Bedford, Khoo, Oldham, Dearnaley and Webb17–Reference Beckendorf, Guérif, Le Prisé, Cosset, Lefloch, Chauvet, Salem, Chapet, Bourdin, Bachaud, Maingon, Lagrange, Malissard, Simon, Pommier, Hay, Dubray, Luporsi and Bey19 For example, Bedford et al. recommend that no more than 10% of the femoral head should receive a dose higher than 52 Gy. Such a conservative upper limit for the tolerable dose was suggested in view of the presumed low α/β ratio for the femoral head.Reference Bedford, Khoo, Oldham, Dearnaley and Webb17 Emami et al. suggest that a dose of 52 Gy to the whole femoral head produces a complication probability of 5% at 5 years, i.e., TD5/5 = 52 Gy (tolerance dose, TD).Reference Emami, Lyman, Brown, Coia, Goitein, Munzenrider, Shank, Solin and Wesson20 Clinical experience suggests that a higher dose (≥70 Gy) to a small part of the femoral head may be tolerated.Reference Fiorino, Reni, Cattaneo, Bolognesi and Calandrino21 Fiorino et al. demonstrated, after comparing five techniques (3F, 4F and 6F), that the sparing of the rectum may be achieved at the expense of an increased dose to the femoral heads.Reference Fiorino, Reni, Cattaneo, Bolognesi and Calandrino21 They suggest that, in taking dosing decisions, priority should be given to assessing the doses that will be received by the dose-limiting organs such as the rectum and bladder; the dose to the femoral head is of less relative importance.Reference Chuba, Sharma, Yudelev, Duclos, Shamsa, Giacalone, Orton, Maughan and Forman22 In their study, the 3F and 6F techniques spared the femoral heads to a greater extent than the 4F technique did. Both our study and the study by Tobler et al., the 6F technique offered better sparing of femoral heads as compared with dynamic conformal arc therapy.Reference Tobler, Watson and Leavitt23 The increase in the femoral dose was small (10.1%) with the 6F technique, and slightly more (10.9%) with optimised arc therapy. Importantly, in all the situations the femoral head DVH constraints were fulfilled.
A study carried out in France in 306 patients treated with CFRT and randomised to either a 70 Gy or an 80 Gy dose, reported similar rectal, bladder and femoral head toxicity in both groups.Reference Beckendorf, Guérif, Le Prisé, Cosset, Lefloch, Chauvet, Salem, Chapet, Bourdin, Bachaud, Maingon, Lagrange, Malissard, Simon, Pommier, Hay, Dubray, Luporsi and Bey19 A morbidity evaluation report of a 3D-CRT dose-escalation trial at Fox Chase Cancer Centre in 232 patients (median dose of 71.58 Gy and median follow-up of 60 months)Reference Hanks, Hanlon, Schultheiss, Pinover, Movsas, Epstein and Hunt3 showed 5-year grade III and IV gastrointestinal toxicity to be <1%, and there was no toxicity in the femur heads.
In this study, the 4F (45°, 135°, 225°, 315°) plan consistently provided acceptable levels of femoral head doses. It provided better sparing of the femur heads in comparison with the 5F (0, 45°, 90, 270, 315), 6F (45, 90°, 135, 315°, 270°, 225°) and 7F (0°, 45°, 90°, 135°, 315°, 270°, 225°) beam arrangements that are currently used at our institution, with equivalent and acceptable bladder and rectal doses.
Emami had suggested that a dose of 52 Gy to the entire femoral head may result in a 5% probability of necrosis at 5 years (TD5/5 = 52 Gy). This 52 Gy level corresponds to 70% of 74 Gy. In practice, the dose to the whole femoral head seldom exceeds this 52 Gy threshold. The volume of the bladder that received 90% (V90) of the prescribed radiation dose was measured.Reference Emami, Lyman, Brown, Coia, Goitein, Munzenrider, Shank, Solin and Wesson20
A major dose-escalation report relating to radiotherapy for prostate cancer is the one from MD Anderson Cancer Centre. Pollack and Zagars studied 938 men with prostate cancer who received radiotherapy treatment at three dose levels, <67 Gy, 67–77 Gy and >77 Gy. 3D-CRT was employed for doses of 74–78 Gy. The actuarial freedom from failure at 3 years was 61%, 74% and 96%, respectively, for these three dose levels.Reference Pollack and Zagars24 The dose tolerance levels of the rectum, bladder and femur have been the main limiting factors for radiation dose escalation in prostate cancer. After the introduction of 3D-CRT, the early results have revealed no significant increase in gastrointestinal and genitourinary toxicity with increasing radiation doses to the prostate. In 96 patients treated with 3D-CRT to the level of 75.6 Gy or 81 Gy, the acute grade II morbidity was 17% for rectum and 36% for the urinary bladder.Reference Zelefsky, Fuks, Wolfe, Kutcher, Burman, Ling, Venkatraman and Leibel25 All the other patients had either no morbidity or grade I morbidity. No acute grade III side effects were observed. In 85% of the patients, late morbidity of the rectum was nil or grade I. Grade II morbidity occurred in 15% of the patients. The acute and late effects of high-dose 3D-CRT were studied in the RTOG 9406 prostate cancer trial.Reference Michalski, Winter, Purdy, Perez, Ryu, Parliament, Valicenti, Roach, Sandler, Markoe and Cox16 In 262 patients with T1T2 prostate cancer who were treated at dose levels of 74 Gy, the tolerance has been found to be better than would be expected on the basis of historical data. A study carried out in France in 306 patients treated with CFRT and randomised to either a 70 Gy or an 80 Gy dose, reported similar rectal, bladder and femoral head toxicity in both groups.Reference Beckendorf, Guérif, Le Prisé, Cosset, Lefloch, Chauvet, Salem, Chapet, Bourdin, Bachaud, Maingon, Lagrange, Malissard, Simon, Pommier, Hay, Dubray, Luporsi and Bey19 A morbidity evaluation report of a 3D-CRT dose-escalation trial at Fox Chase Cancer Centre in 232 patients (median dose of 71.58 Gy and median follow-up of 60 months)Reference Hanks, Hanlon, Schultheiss, Pinover, Movsas, Epstein and Hunt3 showed 5-year grade III and IV gastrointestinal toxicity to be <1%, and there was no toxicity in the femur heads.
In this study we compared the outcomes from 4F, 5F, 6F and 7F techniques as regards dose to the femoral heads. The distribution of the mean total dose, the probability of complications to the normal tissues, and the volume of the femoral head receiving radiation indicated that lower parameters were achieved in the case of the 4F technique using beam orientations of 45°, 135°, 225° and 315°. When the lateral fields (90–270°) were used in an effort to protect the rectum, the doses received by the femur heads were observed to increase.
This study has shown that the 4F technique with 18 MV photon energy applied provides the best level of protection for the femoral head. There are no significant differences among the plans evaluated in the study as regards dose distribution in the target (PTV). None of these techniques presented the problem of unacceptable levels of radiation dose leading to morbidity of the femoral heads. The 4F technique with beam orientations as described yielded the best sparing effect for the femoral heads.
