Fig. 11.1
(a, b) 4-field 3D-conformal pelvic plan with electron boost (20MeV) for a patient with penile cancer and involved inguinal node. Elective nodal PTV highlighted in pink, nodal boost PTV is highlighted in red. Prescription is 45 Gy to elective nodal PTV and 14.4 Gy to the nodal boost PTV. The 95% isodose (green) shows deficient coverage at a depth
Four-Field Box and 3D Conformal Therapy
An alternative technique uses a 4-field or a 3D conformal plan. Here, opposing right and left lateral fields are added to create a box-like photon distribution. The shape of the pelvis and location of the inguino-femoral lymph node region lends itself well to this technique, as 4-field distributions offer a more homogenous distribution compared to AP-PA techniques. See Fig. 11.2a, b for illustrative dosimetry seen in 4-field 3D conformal distributions. Please note the improved coverage of the nodal planning target volume (PTV) boost.
Fig. 11.2
(a, b) 4-field 3D-conformal plan for penile cancer with involved inguinal node. Elective nodal PTV shown in pink and boost volume PTV shown in red. Prescription is 45 Gy/25 fractions with a 14.4 Gy/8 nodal boost. Although the 100% isodose cuts through the middle of the boost target volume, it is now adequately covered by the 95% isodose. The disadvantage of this plan is that the entire pelvic contents receive 45 Gy
Although the 100% prescription isodose cuts through the middle of the boost target volume, it is now adequately covered by the 95% isodose. Note that entire pelvic contents receiving 45 Gy.
Historical bony landmarks (superiorly at the L4–L5 interspace, inferiorly at the greater trochanter, laterally 1.5–2 cm beyond the pelvic brim, anteriorly at the pubic symphysis, and posteriorly at the S2–3 interspace) [51] have been replaced with 3D planning adapted to target volumes delineated using CT-based planning systems. While effective in covering the areas at risk, 4-field distributions still expose central pelvic organs to unnecessary radiation. In order to improve the therapeutic window by reducing toxicity, advanced techniques using IMRT have been developed.
Intensity-Modulated Radiotherapy (IMRT)
IMRT allows more conformal treatment through modulation of radiation beam intensity, providing increased degrees of freedom in spatial and temporal dimensions [52]. Using predefined organ and target volume constraints, an inverse-planning process creates a highly conformal treatment plan, reducing the dose to important organs at risk, such as the bowel, bladder, and rectum, without compromising the coverage of target volumes [46].
For IMRT (and 3D-CRT) clinical target definitions are used to guide the treatment planning process. Gross tumor volume (GTV) is defined clinically or radiographically and delineates residual gross disease. The clinical target volume (CTV) defines the nodal regions according to their accompanying vessels, the internal and external iliac, as well as common femoral vessels, with a 0.7–1 cm expansion (cropped for anatomical boundaries), to allow for microscopic disease. The anteromedial margin may need to be larger to encompass all lymph nodes, especially if using highly conformal techniques. The planning target volume (PTV) includes a 1 cm isotropic expansion on the CTV such that volumes extend superiorly to the L5–S1 interspace [45]. The additional margin is to accommodate treatment setup variation and beam penumbra. Please see Fig. 11.3a, b for illustrative dosimetry of a volumetric arc therapy (VMAT) plan. Note the highly conformal distribution and organ-at-risk sparing properties. Given these advantages, these techniques have become preferred at our center.
Fig. 11.3
(a, b) VMAT pelvic and nodal boost plan for penile cancer with involved inguinal node. Elective nodal PTV shown in pink and nodal boost PTV shown in red. Prescription is 45 Gy/25 to elective nodal PTV and 14.4 Gy/8 to the nodal boost PTV. The 100% isodose (yellow) now covers the boost volume perfectly. The bladder dose is reduced (<45 Gy)
Dosimetric comparisons between plans generated with IMRT or 3D-CRT show a significant decrease in mean dose to the rectum, bladder, and small bowel by 41%, 26%, and 27%, respectively [45]. While there are some concerns about highly conformal treatments missing the intended target volumes by nature of tight margins, early clinical outcomes in management of vulvar cancers with IMRT appear favorable to historical comparisons [44]. If done well, highly conformal treatments like IMRT allow the safe delivery of higher doses of radiotherapy, without compromising tumor control.
Treatment Strategies and Applications of Radiotherapy
Radiation plays a variety of roles for the management of vulvar, anal, and penile squamous cell carcinomas and malignant melanoma of the skin that have spread to the groin lymph nodes. Definitive radiotherapy, either alone or combined with concurrent chemotherapy, can be an effective strategy for treating malignancies involving the inguinal nodes. Additionally, it may be used in a neoadjuvant manner to improve resectability, and finally, radiation may be used in an adjuvant setting, to help mitigate the risk of micrometastatic disease and decrease locoregional relapses. We will review the various treatment strategies in each of the discussed sites and the evidence supporting their use.
Vulvar Carcinoma
Vulvar Cancer: Definitive or Neoadjuvant Radiation Therapy
Vulvar cancer is treated primarily with surgical resection due to the significant morbidity and toxicity of radiation, which can be magnified with the use of radiosensitizing chemotherapy. However, patients with locally advanced lesions or unresectable lymph nodes may be converted to surgical candidates with neoadjuvant RT or chemo-RT. Furthermore, vulvar cancer afflicts older women who may never be surgical candidates because of age or comorbidities. Definitive chemo-RT may be used in these situations. Multiple studies have supported the role of chemo-RT as an alternative to surgery for the nonsurgical candidate or to help facilitate surgical resection [44, 53, 54].
While most of the evidence comes from phase II trials, the principles are supported by the multinational guidelines published by the NCCN [9]. In the GOG trial 101, 96 women with unresectable vulvar cancer were treated with split-course radiation to 47.6 Gy (two courses of 23.8 Gy) combined with cisplatin and 5-FU chemotherapy. This was followed by resection of the residual tumor and bilateral ILND. For the subset of women with N2 or N3 lymphadenopathy (n = 41), 95% became resectable, and of these, 41% achieved a complete pathological response [54].
The subsequent GOG trial 205 study eliminated the split course and adopted daily fractionated RT to 57.6 Gy (in 1.8 Gy daily) combined with weekly cisplatin [53]. Surgical resection was planned for residual disease, and clinical response was confirmed by biopsy. Interim results report that 64% of the 58 patients (n = 37) had a complete clinical response, of which 78% (n = 29) were confirmed histologically. The study continues in a second stage of accrual.
The pelvis and standard areas at risk require RT to a dose of 45–50.4 Gy in standard 1.8 Gy fractions. Gross primary disease and positive lymph nodes (or scenarios where significant extracapsular extension is present) require higher doses ranging from 59.4 to 64.8 Gy, depending on the extent of disease and whether concurrent chemotherapy is used. Concurrent weekly cisplatin at 40 mg/m2, as per the approach for SCC cervix, has become the standard of care.
Vulvar Cancer: Adjuvant Radiation Therapy
The main indications for adjuvant radiation therapy in vulvar cancer are the presence of multiple involved inguinal nodes or any extracapsular extension. As discussed above, in GOG 37, 114 patients were randomly assigned to adjuvant pelvic and groin radiation (45–50 Gy, n = 59) or PLND (n = 55) after radical vulvectomy and ILND. At a median follow-up of 74 months, adjuvant RT reduced the incidence of inguinal recurrence from 24 to 5% and was associated with an improvement in the 6-year overall survival from 41 to 51%. This study has paved the way for modern practice in adjuvant inguinal and pelvic radiation for vulvar cancer [12].
The current recommendation is to treat the pelvis to 45–50.4 Gy in 1.8 Gy per fraction using either 3D-CRT or IMRT. Extracapsular extension or gross lymphadenopathy requires a higher dose, graduated according to the bulk of disease to maximize locoregional control. Consistent with recent guidelines, adjuvant radiotherapy to the inguinal and pelvic lymph node region is omitted for patients who are node negative based on lymphadenectomy or SLNB, even in the presence of high-risk features (LVI, deep invasion, or close/positive margins) [9].
Anal Canal Cancers
Definitive Chemoradiotherapy
As discussed previously, surgical series in the 1980s established the role of abdominoperineal resection for the definitive management of early and advanced anal SCC. While limited wide local excision can still be considered for early T1N0 cancers [21], surgical resection for locally advanced primary cancers requires abdominoperineal resection and permanent colostomy. Primary chemoradiotherapy was established in the 1980s and 1990s as definitive management in order to avoid the morbidity associated with permanent colostomy [55, 56]. Local control and complete response (CR) were reported from 71 to 93%. Abdominoperineal resection is now typically reserved for patients who fail primary chemo-RT.
Subsequently, two major European trials have demonstrated the superiority of combined modality treatment (chemo-RT) compared to RT alone. The UK Coordinating Committee on Cancer Research (UKCCCR) ACT 1 trial randomized 585 patients of any stage to RT alone (45 Gy to the pelvis with a 15–35 Gy boost to the primary) or to chemo-RT with 5-FU and mitomycin-C. Both complete response (39% vs. 30%, p = 0.08) and locoregional control (53.7% vs. 29.5%) were improved (HR 0.46, p < 0.001) [57, 58]. A similar local control benefit was seen in the EORTC trial where 110 patients were randomized between radiotherapy alone (total dose of 60–65 Gy) and radiotherapy combined with infusional 5-FU and bolus mitomycin-C [25]. At 5 years, locoregional control was improved favoring the combined modality treatment arm (68% vs. 50%, p = 0.02).
Recently the results of a phase II trial, Radiation Therapy Oncology Group (RTOG) 05-29, have further defined the treatment of anorectal cancers. Using concurrent 5-FU and a dose-painting IMRT technique, the primary tumor and inguinal and pelvic lymph node regions are treated to differential dose levels depending on their associated risk. Elective nodal regions are treated to 42–45 Gy in 28–30 fractions (for T2 N0 and T3-T4 N0 patients, respectively), while involved metastatic nodes are boosted to 50.4–54 Gy in 30 fractions depending on their size (<3 cm or >3 cm, respectively) [59]. The NCCN guidelines recommend and support the use of multi-field treatment techniques and recommend using PET-CT for identifying pathologically involved lymph nodes [60].
Penile Cancer
The role of radiation in the management of penile cancer varies depending on the stage, indications for treatment, and patient-specific factors. For localized presentations, organ preservation should be considered and discussed with patients. In this capacity, patients may undergo radiation therapy (external or brachytherapy) to the primary tumor and, for high-risk primaries, undergo surgical staging of the inguinal groin nodes [34].
Penile Cancer: Definitive/Preoperative Management
Given the low incidence of penile cancer in western societies, large multicenter randomized controlled trials are currently lacking. InPACT (International Penile Advanced Cancer Trial (NCT 02305654)) will randomize node-positive patients to standard ILND or neoadjuvant chemotherapy or chemo-RT. Fundamental in this trial design was the extrapolation of treatment strategies from published literature on other SCCs with HPV etiology, particularly vulvar cancer.
Downstaging penile cancer with neoadjuvant chemotherapy using triple regimens consisting of paclitaxel, ifosfamide, and cisplatin yields response rates reaching 50% in patients with locally advanced presentations [61]. However, only 10% achieve a complete pathological response, and in another phase II series, only 38.5% of patients demonstrated an objective response with docetaxel, cisplatin, and 5-FU chemotherapy [62]. Lessons learned from gynecological malignancies and head and neck cancers suggest that SCC responds well to combined modality strategies with chemo-RT and should be further explored for squamous histology cancers of the penis.
For patients who are surgically fit but have unresectable disease at diagnosis, neoadjuvant chemo-RT strategies for downstaging have been described [63, 64]. In practice, select patients with locally advanced unresectable disease are considered for neoadjuvant chemo-RT strategies. In one of the largest series for chemo-RT for penile cancer, 26 patients were treated with cisplatin-based chemotherapy combined with a median radiation dose 49 Gy (range 18–70 Gy) [65]. Progression-free survival was only 6 months in the absence of surgical intervention. The small sample size, low radiation dose, and heterogeneity of the patient population make conclusions difficult in this study. However, the small number of patients per institution suggests that chemoradiation strategies remain underutilized and that further studies, such as InPACT, looking at the use of chemo-RT strategies in a systematic fashion, are warranted.
Melanoma
Malignant melanoma is primarily treated surgically. While some small institutional series advocate definitive radiation, this should only be considered in the context of medically inoperable patients [66, 67]. For the vast majority of situations, radiation therapy will be used in an adjuvant setting.
Adjuvant Radiation Therapy
The cornerstone trial by the Trans Tasman Radiation Oncology Group (TROG) defined high-risk melanoma (as applicable to the groin metastases) as ≥3 inguinal nodes, extranodal extension, or lymph node size ≥4 cm. The planned treatment volume included the dissected lymph node field and lymphadenectomy scar [40]. In this study, adjuvant RT improved locoregional control but did not affect overall survival or relapse-free survival. At 3 years, the cumulative incidence of lymph node relapse was 19% in the radiation group versus 31%. Extranodal spread was the only independent risk factor for infield relapse [HR 1.77; p = 0.001]. Patients were treated with 48 Gy in 20 fractions, which is now considered the standard dose and fractionation for adjuvant treatment.
While the TROG study has had the most impact on adjuvant radiotherapy, it is supported by other retrospective studies. Corry et al. reviewed 113 patients with regional node involvement. Forty-two patients had complete surgical resection of macroscopic disease and were treated with adjuvant radiotherapy to a median dose of 50 Gy. For these patients, ten were alive and failure-free (26%), while eight failed with nodal relapse (including three with in-transit metastases). Furthermore, in patients experiencing failure, more than half (52%) had distant relapse as their first site. The authors recommended adjuvant postoperative RT for proven nodal metastases at high risk of regional recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease) [68].
Historically, melanoma has been considered radio resistant, and although hypofractionation is an accepted means of overcoming radioresistance, randomized studies have not confirmed an advantage to this approach for melanoma. In RTOG 83-05, 137 patients with measureable lesions were randomized to 32 Gy in four fractions or 50 Gy in 20 fractions, with no difference in the clinical response rate (23–24%, respectively) [69]. Nonetheless, a fraction size of 2.5 Gy or greater has been adopted as the standard of care.
Treatment Toxicity
The acute and late toxicities of radiation therapy to the groin and pelvis are ultimately related to the ability to spare organs at risk. The choice of treatment technique plays a major role, even in the face of unfavorable patient anatomy and tumor location. The National Cancer Institute has standardized reporting of adverse events in the Common Terminology Criteria for Adverse Events (CTCAE), currently in its fourth version, and is a commonly accepted means of grading treatment toxicity on a scale of 1–5. Grade 1 toxicities (mild) are asymptomatic and based on clinical observations that do not require intervention. Grade 2 (moderate) toxicity necessitates local or noninvasive interventions. Grade 3 (severe) toxicity is medically significant and requires hospitalization, while Grade 4 toxicity is life-threatening and Grade 5 toxicity is fatal [70, 71]. The typical structures that contribute to the risk of acute and late effects of inguinal/pelvic radiotherapy include the small bowel, rectum, bladder, urethra, vagina, skin, femoral heads, and bone marrow. Constraints have been developed within many protocols but vary depending on the definitions used and techniques chosen. Given the heterogeneity and dependence on technique, organ-at-risk tolerance should be individualized for the situation.
Lower-Extremity Lymphedema
Lymphedema of the lower extremity is a common complication that increases with multimodality treatment including surgical resection, chemotherapy, and radiation therapy. Surgical resection disrupts lymphatic pathways, while radiation induces fibrosis of smaller lymphatic channels, resulting in chronic swelling of the lower limb. This can be quite debilitating, reflected in changes in quality-of-life domain scores [71]. It is important to counsel patients on this risk and refer early for symptom management.
The Bladder and Urethra
Acutely, radiation therapy will cause denudation of the bladder mucosa, resulting in symptoms of urinary frequency, urgency, dysuria, but very rarely hematuria. Long-term complications are related to microvascular damage and the ensuing fibrotic changes that happen over months to years following treatment. These late changes are attributed to collagen deposition in the bladder wall [72, 73]. Late hematuria should be assessed by cystoscopy and treated with laser photocoagulation. More global dysfunction can include decreased contractility of the muscular wall or fibrosis causing decreased bladder capacity [73]. Obstructive symptoms include hesitancy, decreased stream, and increased urinary frequency secondary to incomplete emptying. To reduce the risk of toxicity, published constraints limit the dose to the bladder such that <50% of the bladder receives 35 Gy, <35% receives 40 Gy, and <5% receives 50 Gy [74]. Dose tolerance for the urethra is harder to define. Generally, the dose tolerance for a 5% risk of severe toxicity is accepted to be between 65 and 74 Gy but may be difficult to achieve when the primary site of malignancy is the penis or vulva [75]. High doses to the cauda equina may cause neurovascular damage to the afferent and efferent pathways leading to the bladder [76], but as the dose tolerance of peripheral nerves exceeds 60 Gy, this is not a common complication.
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