Purpose: Post-operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to review treatment recommendations among Radiation Oncologists (ROs) in the management of CSCC with PNI. Materials & Methods: In March 2011, we contacted all ROs and trainees in the US through email addresses listed in the 2009 ASTRO directory. Our web-based survey presented clinical vignettes in volving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical PNI (cPNI). For each vignette, ROs were asked to indicate if PORT was appropriate and to further specify the dose and volume to treat. Results: Three hundred fifty two responses were completed and analyzed. The majority of ROs (72%) had over 10 years of post residency experience. 64% of the sampled ROs had a special interest in treating head and neck cancers, and 64% treated 4 or more cases per year. Approximately 95% recommended PORT for cPNI whereas 59% recommended PORT for mPNI. Post residency experience (10+ yrs vs. <10 yrs) was associated with a greater propensity to recommend PORT for mPNI (48% vs. 30%, p = 0.005) and for mPNI of deep subcutaneous non-named nerve involvement (80% vs. 60%, p = 0.001). ROs treating 8 or more cases per year (vs. <7) were more likely to recommend PORT for mPNI in immunocompromised patients (74% vs. 57%, p = 0.01). Conclusions: Our study demonstrates significant variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority recommended PORT. In cases of mPNI, there was no consensus for recommending PORT, although experienced practitioners had a lower threshold for offering treatment. These results indicate the need for prospective clinical studies to clarify the role of PORT in CSCC patients with mPNI.
An estimated 700,000 new cases of cutaneous squamous cell carcinoma (CSCC) are diagnosed each year in the US, and the incidence is rising [
Perineural invasion (PNI) is defined as the presence of malignant cells within the perineural space of nerves [
PNI may be classified into two broad categories: microscopic PNI (mPNI) or more extensive clinical PNI (cPNI) [
Approximately 60% - 70% of all cases of PNI have mPNI [
The uncertainties and controversies in the literature are reflected in a 2010 survey of Mohs surgeons that demonstrated a great variability in the management of CSCC with PNI, including indications for radiotherapy referral [
This study was approved by our Institutional Review Board in 2010 (IRB #7211).
According to the American College of Radiology’s 2003 Survey of Radiologists and Radiation Oncologists, 97% of post-training, professionally active radiation oncologists are members of ASTRO [
We defined a standardized patient as a healthy 50 year old asymptomatic male who is status post Mohs surgical resection of a 1.0 cm well differentiated CSSC of the infra orbital medial cheek region that is confined to the dermis. Negative margins were obtained after two stages of excisions. There were no clinical symptoms suggestive of cPNI, nor radiographic evidence of PNI on an MRI. There was no clinical or radiographic evidence of lymph node involvement. Adjuvant chemotherapy was not an available option (
In the first clinical vignette, the standardized patient presents with incidentally detected mPNI and ROs were asked if they would recommend PORT (
Six subsequent vignettes followed each introducing one additional poor prognostic factor (
The standardized patient: 50 yr. old asymptomatic male, status post Mohs surgical resection with negative margins of a 1.0 cm well differentiated CSSC of the medial cheek that is confined to the dermis. You receive the following additional informationa: | % ROs recommending PORT | 95% CI |
---|---|---|
1. Pathology: Tumor is 1.0 cm with mPNI. | 43 | 0.37 - 0.48 |
2. As in #1, but patient had a renal transplant and is on immunosuppressive medications. | 61 | 0.56 - 0.67 |
3. sPNI: As in #1, but extends deep along a non-named subcutaneous nerve and required a third Mohs stage for clearance. Post-op MRI: clear. | 74 | 0.69 - 0.79 |
4. cPNI: As in #1, but pre-op exam revealed numbness along V2 distribution. Post-op MRI: clear. | 87 | 0.82 - 0.90 |
5. nPNI: Tumor is 1.0 cm with PNI involving the infraorbital nerve. Required excision through infraorbital foramen. Patient is asymptomatic. Post-op MRI: clear. | 96 | 0.93 - 0.98 |
6. cPNI: As in #5, AND Pre-op exam showed numbness along V2. Post-op MRI: clear. | 98 | 0.95 - 0.99 |
7. cPNI: As in #6, AND Post-op MRI shows thickening/enhancement of infraorbital nerve (V2) up to the foramen rotundum. | 99 | 0.97 - 0.99 |
Abbreviations: mPNI is microscopic PNI. nPNI is PNI of a named nerve. cPNI is symptomatic PNI or radiologically detectable tumor. NB: nPNI is also considered as cPNI; a. Questions 1 - 3 consider a patient with mPNI, and Questions 4 - 7 consider a patient with cPNI.
All statistical analyses were performed using SPSS version 16. We used standard descriptive statistics and frequency tabulation. Associations between willingness to recommend PORT for each vignette were assessed by cross-tabulation and 95% confidence intervals calculated using the Wald method. Responses were stratified according to years of post residency experience (<10 yrs vs. 10+ yrs), special interest in treating head and neck cancers and number of cases treated per year (0 - 7 cases vs. 8+ cases). Associations between sub-categorical variables were assessed via cross-tabulation and Fisher’s exact test to generate two tailed p values and differences were considered statistically significant when the p value was <0.05.
Three thousand six hundred eighty eight physicians were contacted to participate in our survey, of which 368 of the emails were undeliverable for various reasons and 636 opened the survey. One hundred ten responded requesting not to participate in this or any other surveys in the future due to a lack of time. One hundred eighty four responded indicating they preferred not to participate in this survey due to a lack of experience in treating CSCC with PNI. Finally, 352 completed responses were eligible for analysis. Characteristics of the respondents are listed in
Variable | Total % of respondents (n = 352) |
---|---|
Years post-residency | |
1 - 3 | 8 (29) |
3 - 5 | 5 (16) |
5 - 10 | 11 (40) |
10+ | 70 (245) |
Currently in residency | 6 (21) |
Practice location | |
Academic | 32 (102) |
Private | 57 (183) |
Both | 11 (34) |
Special interest in treating H & N cancer? | |
Yes | 64 (207) |
No | 36 (115) |
Number of CSCC with PNI cases treated in past year | |
0 - 3 | 36 (117) |
4 - 7 | 38 (123) |
8 - 10 | 16 (51) |
11 or more | 10 (34) |
Recommendations of the ROs to offer PORT for each clinical vignette are listed in
The majority of ROs (95%) recommended PORT for patients with cPNI (including nPNI). However, opinion was divided among respondents for cases of mPNI. 59% of ROs indicated they would offer PORT to patients presenting with mPNI. With each additional poor prognostic factor such as immunosuppression, there was a greater willingness to offer PORT. The majority of ROs (74%) also recommended PORT for cases of PNI involving a subcutaneous nerve (sPNI, 95% CI, 69% - 79%).
ROs with over ten years’ of experience were more willing to offer PORT for mPNI than the less experienced ROs (48% vs. 30% p = 0.005). The majority of ROs with over ten years’ of experience (80%) also indicated they would offer PORT for cases of sPNI, compared to 60% by those with less than 10 years’ experience (p = 0.001).
ROs treating a greater case volume (8+ cases per year) are more likely to offer PORT for an immunocompromised patient with mPNI (74% vs. 57%, p = 0.011).
Special interest in treating head and neck cancers was associated with a borderline significance to offer PORT for sPNI (78% vs. 67% p = 0.053).
Cutaneous squamous cell carcinoma is a common cancer, and its incidence is increasing [
Our study demonstrated a wide variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority of ROs recommended PORT. In contrast, for cases of mPNI there was no clear consensus on PORT. To our knowledge, this is the first study that examines the treatment recommendations among ROs in the management of CSCC with PNI.
These results are strikingly similar to a study by Jambusaria-Pahalajani et al. who evaluated the patterns of practice among fellowship trained Mohs surgeons through a survey [
The uncertainty surrounding the management of CSCC with mPNI is not surprising. Published data do not establish who may or may not benefit from PORT after a microscopically clear resection of CSCC with incidentally detected mPNI [
Furthermore, in an investigator-blinded retrospective cohort study of 48 patients, Ross et al. reported that 32% with CSCC with “larger nerve” involvement (≥0.1 mm) died of their disease and 50% had a local recurrence [
Additionally, while it is generally believed that radiotherapy is an effective treatment, PORT may be inconvenient for some patients, as it requires multiple daily visits to a Radiotherapy center for five to six weeks, and may be associated with toxicity. Garcia-Serra et al. reported that 10% of patients treated with PORT had treatment-related toxicity, including soft tissue necrosis, bone exposure, and osteoradionecrosis [
Currently available management guidelines [
Some caution is required in interpreting the results of any voluntary survey. Selection bias and sampling errors are inherent issues as respondents usually represent a “self- selected” group and their views may not reflect those of the wider community of clinicians thus, limiting their generalizability. For example, the majority (70%) of ROs that responded to our survey had greater than 10 years of experience and 64% had a self- identified special interest in treating head and neck cancers.
The overall response rate to this survey was approximately 10%. However, the completion rate, which represents the ratio of opened and completed surveys, was 55% which is within the reference range for an e-mail-based survey [
In this survey, we examined the impact of prognostic factors that are common in clinical practice. Iatrogenic immunosuppression in organ transplant recipients is a major risk factor for morbidity and mortality in CSCC [
Further research is needed to clearly define, and determine the treatment related implications, of mPNI of varying extents. For example, a controlled prospective study where PORT is omitted for patients with mPNI but is substratified according to the known prognostic factors is necessary to fully elucidate the role of PORT in this population of patients.
The results of this study demonstrate wide variability without a clear consensus in the management of CSSC with mPNI among U.S. based ROs. A good first step in situations where there is uncertainty in practice is to conduct a survey to attempt to understand the views of practitioners. In this survey, experienced practitioners in general had a lower threshold to offer treatment. In cases of cPNI, there was a clear consensus with an overwhelming majority of ROs recommending PORT. On the other hand, treatment recommendations from ROs were split in cases of mPNI. More data from carefully designed prospective studies are necessary to establish a clear standard of care for CSCC with mPNI.
Parvathaneni, U., Shetti, M., Berg, D., Takagishi, S., Laramore, G.E., Schmults, C.D., Jambusaria-Pahlajani, A., Hess, S.D., Heyboer III, M. and Liao, J.J. (2016) Treatment Recommendations among Radiation Oncologists in the Treatment of Cutaneous Squamous Cell Carcinoma with Perineural Invasion. Journal of Cancer Therapy, 7, 824-835. http://dx.doi.org/10.4236/jct.2016.711082