Concurrent chemoradiation is the established standard of care for locally advanced carcinoma of the anal canal. Attempts to decrease the important side-effects of this treatment by modifying the chemotherapy regimen with the suppression of Mitomycin-C (MMC) have resulted in increased loco-regional recurrence and higher colostomy rates [5, 7]. Furthermore, a recent Intergroup trial led by the RTOG to evaluate the possible replacement of MMC by induction and concomitant cisplatin (CDDP) has shown disappointing preliminary results, with a non-statistically significant higher colostomy rate in the CDDP arm, which was however better tolerated in terms of hematologic toxicity . While longer follow-up is needed, at present MMC still plays a major role in the management of carcinoma of the anal canal.
As well, decreasing the radiation dose or using split-course techniques is no longer recommended. Instead, several groups have focused their attention on modifying the radiation delivery technique using a 3D-CRT "diamond technique" [23, 24] or through IMRT [21, 25, 26]. While IMRT has successfully reduced small bowel, perineal and genitalia doses, hematologic toxicity remains a clinical concern. This is in part because a large proportion of the body bone marrow reserve is located within the lumbar spine and pelvic bones . Moreover, apart form the ovaries, the bone marrow is the most radiosensitive pelvic tissue , and concurrent chemotherapy likely lowers this threshold dose and is in itself myelotoxic.
The issue of chemotherapy-induced bone marrow suppression worsened by pelvic irradiation has been studied in patients with gynecologic malignancies. Brixey et al.  showed that intensity-modulated whole pelvic radiotherapy (IM-WPRT) decreased the number of women experiencing Grade 2 or greater white blood cell count (WBC) toxicity as compared with conventional WPRT in 36 patients receiving chemotherapy. This resulted in chemotherapy being held back less often for hematologic toxicity. Of note, these benefits in hematologic toxicity were initially seen without explicitly using a bone marrow sparing (BMS) radiation technique. Subsequently, the same group used BMS IM-WPRT and significantly reduced the volume of bone marrow receiving > 18 Gy compared with both IM-WPRT and 4 field box techniques .
In the current trial, we compared four radiation delivery techniques with the intent of determining the optimal regimen that achieves maximal target volume coverage and provides adequate gastrointestinal and dermatologic sparing without compromising the bone marrow. We have shown that using BMS IM-WPRT throughout the entire treatment (arms C and D) is feasible and reduces threshold radiation doses to the small bowel, bladder, genitalia and femoral heads as compared to conventional AP/PA plans with 3D conformal boost. The mean values that we obtained for these critical structures with a prescription dose of a 59.4-Gy treatment are comparable to those obtained by Milano et al.  in their IMRT treatment arm with a dose of 45 Gy. This was achieved in our study with both N0–N1 tumors with an upper field border at the level of S2–S3 and in N2–N3/T4 tumors with an upper field border at the level of L5-S1 that allowed proper coverage of the mesorectal and presacral nodes.
Furthermore, BMS WP-IMRT provided comparable mean and threshold doses to the iliac crests in N0–N1 tumors, but statistically reduced mean and threshold doses to this structure in N2-3 and/or T4 tumors. The mean V10 and V20 for our N2-3/T4 tumor patient subgroup were 53 and 33%, respectively, compared to the 73% and 59% obtained by Milano et al. . Whether these lower doses to iliac bone marrow will result in less acute hematologic toxicity remains to be seen in further clinical studies.
The dose given to femoral heads in our trial deserves more discussion. Although the volume of femoral heads receiving ≥ 45 Gy was reduced with all plans incorporating IMRT compared to the conventional 3D plan, it was higher than expected. In comparison, Hsu et al.  treated five patients with T2 N0-1 tumors with definitive chemo-radiation using IMRT plans. For each patient, AP/PA plans with supplemental inguinal electrons boosts, 4-field box, 7-field IMRT, and 7-field IMRT integrated boost plans were generated. The volume of bowel and bladder receiving threshold doses were similar to ours, but the V45 of the femoral heads is 0% in both of their IMRT arms, which is much less than what we obtained. This may be explained by several factors including different definitions of target volumes, more stringent dose constraints used in their study (i.e. femoral head V45 < 1%) and the smaller tumor sizes of their patients which were all staged T2 N0-1. Furthermore, the mean V20 for the iliac crests was 77% for both their IMRT arms as compared with 28% and 33% in our N0-1 and N2-3/T4 groups, respectively. Interestingly, Milano et al.  noted higher than expected hematologic toxicity with an iliac crest V20 of 59% and V10 of 73%. It is possible that sparing of the femoral heads and/or other organs comes at the cost of increasing dose to the iliac crests. The results of our study reinforce the idea that specific dose constraints for all OAR must be considered during the IMRT optimization process in anal cancer, namely with regards to the iliac crests.
Another study which focused on femoral head dose was published by Chen et al. . They compared 7 coplanar fields IMRT with conventional plans for the coverage of pelvic and inguinal/femoral nodes in two patients with anal cancer. The whole pelvic dose was 36 Gy in 20 fractions. The mean dose to the femoral head was 58.3% and 59.5% of the prescription dose for their 2 patients using conformal avoidance IMRT. Similarly, the mean dose to the femoral head with the IMRT plans in our study ranged from 52.2% to 56.5% of the prescribed dose. This confirms that the whole pelvis may be treated to 45 Gy with an additional 14.4 Gy boost to the tumor while keeping the mean dose to the femoral heads at a relatively constant percentage of the prescription dose.
A third IMRT study using a single-phase dose painting technique has been described by the Boston Medical Center and Massachusetts General Hospital. Six patients were treated (in text, RTOG 0529 protocol draft, p.11) and dose-painting IMRT provided better normal tissue sparing than 3D CT-based conformal therapy plans. No patient required a treatment break of more than one week and all patients completed therapy as initially planned. Comparisons with our dosimetric study are limited since they did not use the same threshold OAR doses. However, the mean V30 and V40 values for the bladder were similar to ours, whereas our mean V30 values for the genitalia were similar or lower than the mean V35 that they obtained. However, they achieved lower V30 and V40 values for the small bowel and much lower V45 for the femoral heads. Differences may be due to the lower total dose, which ranged from 42 to 45 Gy to elective nodes and from 50.4 to 54 Gy to gross tumor. The RTOG is currently accruing patients for a phase II trial of dose-painted IMRT.
There was no significant difference between the 2-phase (arm C) and single-phase IMRT plans (arm D). Both of these arms seem superior, at least for genitalia sparing, to arm B although there was no statistical analysis comparing these treatment arms. As for the greater volume of iliac crest receiving doses above 45 Gy observed in the DVH of arm D (Fig. 3), this difference is not clinically significant since it is probable that theses segments of marrow are not functional after having received 45 Gy. Also, the doses shown in the DVH are physical doses. If we consider the radiobiological equivalent dose calculated in daily 1.8 Gy fractions for the SIB arm (arm D), the DVH will be shifted to the left and 49.5 Gy in 1.5 Gy fractions would be approximately equivalent to 45 Gy in 1.8 Gy fractions.