The present study documents the results of one of the largest multi-institutional studies of SRT for the treatment with curative intent of primary NMSC of the skin. Of 1632 patients with NMSC treated, complete eradication of the tumor was achieved in all but 20 patients, representing a 98.8% rate of control of the malignancy at the patient level. It should be noted that the control rate by patient indeed underestimates the actual control rate as many patients have more than one lesion that was treated, making the denominator lower in calculations. In fact, the 20 patients with failures had a total of 66 lesions that were treated synchronously or metachronously. A more accurate measure of efficacy of this modality is control rate by lesion. Of 2917 NMSC lesions treated, local tumor control was achieved in 2897 lesions, representing a 99.3% rate of control. Because 58.0% of the NMSC lesions treated with IGSRT were located on the anatomically and cosmetically sensitive region of the head and neck, the tissue-sparing property of IGSRT is notable.
These results, while observed with approximately 55% of patients having follow-up for 12 months or more, appear at this time to be at least consistent with the results of standard surgical and nonsurgical modalities used to treat NMSC. Specifically, the finding of a complete lesion response rate of 99.3% on early follow-up for IGSRT compares favorably with that of a study of SRT by Hernández-Machin et al., reporting that SRT treatment of 710 patients led to 5-year cure rates of 94.4% for BCC and 92.7% for SCC, respectively. The authors concluded that SRT was effective for BCC and SCC and could be a suitable first option in many cases . The response rate observed in our study cohort also seems consistent with and, with further follow-up, has the potential to exceed that reported in a study of 1149 patients by Cognetta et al., who found that SRT-treated patients had mean cumulative recurrence rates for BCC of 2.0% and 4.2%, and for SCC of 1.8% and 5.8%, at 2 and 5 years, respectively . The findings of this analysis are in concordance with the previous conclusions presented by Yu et al., with this analysis of the IGSRT data subset using separate statistical software (SAS) by an outside third-party data analysis company (Summit Analytical). A limitation of the results presented here is the shorter period of follow-up (mean follow-up of 69.8 ± 54.62 weeks) compared to these earlier evaluations of SRT. Continued follow-up with these patients to 2 and 5 years is expected to yield additional observations relevant to the use of IGSRT.
In total, 1.2% (n = 20) of our patients, representing 0.7% (n = 20) of NMSC lesions, failed to achieve local tumor control with IGSRT. An evaluation of demographic and lesion characteristics for these patients was performed to examine any potential commonalities, including histopathology, lesion size and location, and patient demographics. This evaluation did not identify any significant predictor for patient non-responsiveness to IGSRT at this time. We observed that the non-response rate for SCCIS was 0.3% (n = 2) versus that for BCC (n = 13, 0.9%) versus SCC (n = 5, 0.6%). There was no significant difference in control rates between histologies (p > 0.05) by Fisher’s exact tests. We feel that an explanation of this non-significant difference between differing histologies may, in part, be due to the uniformly excellent control rate achieved in all subgroups with this IGSRT treatment. This suggests that IGSRT is effective in all subsets of NMSC on early follow-up. If this trend continues, a potential advantage of IGSRT in treatment of SCC over other older SRT techniques and MMS may become apparent with longer follow-up. In addition, 41 patients died during the course of the study. These deaths were determined not to be related to their NMSC treatment and had no impact on local control in this study. Indeed, NMSC are generally considered nonfatal, highly curable with rare metastases, and low recurrence with limited impact on mortality and morbidity [27, 28].
Recent studies of the effectiveness of MMS observed 5-year local control rates of 99% and 92–99% for primary BCC and SCC, respectively; the corresponding rates for recurrent BCC and SCC treated with MMS are 90–93% and 90%, respectively . Comparison of the results of this study with those achievable using surgical therapies, such as MMS, may be limited. MMS is indicated for higher-risk NMSC lesions, and situations based on expert opinion, smaller lesions and/or lower risk lesions with cosmetic or functional significance as well [2, 29].
In this study, IGSRT was administered to a range of tumor types and sizes, not only high-risk lesions. It is notable, however, that the median tumor diameter in this study was 1.0 cm, with an upper diameter of 5.5 cm. This indicates that most of the NMSC lesions treated in this study were clinically significant tumors that would have required substantial excisions to achieve surgical eradication—not minute, easily curable lesions. While the results of this retrospective review of IGSRT patients demonstrate a consistent local tumor control rate in a limited follow-up period, retrospective comparisons of matched cohorts or prospective trials with IGSRT given in this manner with further follow-up for additional years would be helpful to evaluate any differences observed in IGSRT and MMS outcomes in the treatment of NMSC. A prospective randomized trial comparing IGSRT vs MMS would provide an ideal comparison; however, ethically and practically, it may prove difficult to conduct a study randomizing patients to a surgical vs non-surgical modality. In this study cohort, patients were given the option of surgical versus non-surgical IGSRT options and they chose the non-surgical method for various reasons that were not documented or extracted. Presumably, many patients may have opted for IGSRT to avoid the pain, scarring, and risk of infection or bleeding that may be associated with surgery.
Absolute and relative contraindications of IGSRT include invasion of underlying bone or muscle, thickness (greater than 6 mm) that cannot be debulked, previous irradiation of the same site, ataxia telangiectasia, active connective tissue disease, active or uncontrolled lupus or rheumatologic conditions, concomitant administration of radiation sensitizing chemotherapy (i.e., doxorubicin), T4 or node positive status, amongst others.
The high rate of local tumor control suggests that the use of daily pre-treatment lesion ultrasound imaging and daily evaluation of tumor depth can improve delivery of the optimal radiation dose and energy over a fractionated treatment scheme. In this study, adjustments to the energy were typically performed after the 5th, 10th, or 15th treatments on the basis of review of the ultrasound depth by the practitioner. In certain circumstances, a significant change in tumor depth can be detected from one fraction to another, depending on tumor progression or external factors (i.e., bleeding, injury, excoriation, scab formation, etc.) which can prompt the radiation therapist to alert the provider to change the energy in order to cover the entirety of the new tumor configuration accordingly. Thus, pre-treatment ultrasound is reasonable and recommended for this purpose, in addition to daily verification/localization of the tumor. Indeed, 29% of the lesions treated utilized multiple energies, potentially due in part to the change in imaging characteristics (depth) encountered. Limitations of the ultrasound include that it cannot detect tumor deeper than 6 mm (though tumors invading beyond this depth are contraindicated for treatment with IGSRT). Additionally, ultrasound imaging is difficult to attain if the surface is irregular or actively bleeding, which does not allow adequate contact of the probe with the skin. Further study is warranted to evaluate the impact of pre-treatment ultrasound imaging on SRT efficacy, but an improvement in SRT efficacy with image guidance would be consistent with general principles and published results in radiation treatments at other sites of cancer that utilize image guidance and planning [30,31,32].
IGSRT was generally well tolerated and safe. Typical side effects of radiation to the skin, such as erythema, hyperpigmentation, dryness, edema, etc., consistent with historical SRT treatments were seen. RTOG toxicity grades were recorded for 2177 (74.6%) of lesions treated.Footnote 3 Among 2177 lesions, grade 3 and grade 4 toxicities were documented in only 16 (0.5%) and 4 (0.1%) lesions, respectively. This overall low level of toxicity is in accordance with prior literature indicating that radiation therapy for NMSC is generally well tolerated, with acute reactions being site-specific and self-limited .