Genitourinary Cancers

C H A P T E R

19 Genitourinary Cancers RENAL CELL CANCER The estimated incidence in the United States is 65,340 with an estimated 14,970 deaths in 2018. The right and left kidneys are located between the eleventh ribs and the third lumbar vertebrae in the retroperitoneal fatty tissue. The left kidney resides slightly higher than the right kidney in the posterior abdominal wall. The kidneys and renal pelvis lymphatics drain to the renal hilar, paraaortic (PA), and paracaval lymph nodes (LNs).

Workup Risk Factors • Smoking, analgesic abuse (containing phenacetin) • Hypertension • Von HippeleLindau disease Symptoms and Signs • Occasionally constitutional symptoms such as malaise, fever, night sweats, weight loss,“classic triad” of abdominal pain/flank pain, flank mass, and hematuria. • Paraneoplastic syndromes such as erythrocytosis and hypercalcemia. • Physical exam should note flank mass, any supraclavicular LN, organomegaly, and lower extremity edema. Investigations • CBC, with hepatic and renal function, urinalysis, and cytology. • Ureteroscopy. • Consider needle biopsy if indicated. • Chest X-ray, CT abdomen/pelvis (or MRI), bone scan (if elevated alkaline phosphatase or bone pain are present), brain MRI, if indicated.

Copyright © 2019 Elsevier Inc. All rights reserved.

Fundamentals of Radiation Oncology https://doi.org/10.1016/B978-0-12-814128-1.00019-2

429

430

19. GENITOURINARY CANCERS

TNM STAGING (RENAL CANCER) T1

Tumor 7 cm or less in greatest dimension, limited to the kidney

T2

Tumor more than 7 cm in greatest dimension, limited to the kidney

T3

Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota’s fascia

T4

Tumor invades beyond Gerota’s fascia (including contiguous extension into the ipsilateral adrenal gland)

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

M0

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

M1

Distant metastasis

Stage Grouping Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T1, 2

N1

M0

T3

N0, 1

M0

T4

Any N

M0

Any T

Any N

M1

Stage IV

M, (distant metastasis); N, (regional lymph nodes); TNM, T (tumor). Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.

Treatment • Stage I, II, III: Partial or radical nephrectomy is the standard treatment. Radical nephrectomy involves complete removal of Gerota’s fascia and its contents (kidney, adrenal gland). Patients with renal vein involvement may require aggressive surgical approach and may consider regional lymphadenectomy. • Stage I: Select patients can undergo active surveillance or ablative techniques. • T1a, select patients: Not surgical candidates or failed ablative techniques can consider SBRT [1, 2]. • Stage IV: Cytoreductive nephrectomy and metastectomy recommended for solitary metastasis. Post-op if margin positive or residual disease, then tyrosin kinase inhibitors may be indicated.

III. CLINICAL RADIATION ONCOLOGY

TNM STAGING (RENAL CANCER)

431

• Resected high risk clear cell RCC (Stage 3, positive regional nodal disease, or both) can consider adjuvant sunitab
1 year. • Consider SBRT to the primary and to the solitary metastasis (depending on the site) for up to three to five metastatic sites [1, 2]. • Medically unresectable: Consider tyrosine kinase inhibitors such as sunitinib, sorafenib, pazopanib, and temsirolimus. A novel TKI Cabozantinib has greater activity in the front line setting and, if available, is an appropriate first line agent. • Asymptomatic patients with low tumor burden and favorable risk stratification may be followed with active surveillance. • Intermediate and high risk group consider combined immunotherapy with nivolumab and ipillimumab. • Chemotherapy had limited success; however, interleukin 2 and interferon A have shown 10%e20% objective responses. • Postoperative radiation: It can be considered in high-risk patients with features such as large tumors (>¼7 cm), positive margins, invasion of Gerota’s fascia, positive LNs, renal vein and/or inferior vena cava involvement, and sarcomatoid features.

Radiation Therapy Technique 3D Technique Simulation: Supine, arms-up, immobilization with Vac-Lok bag or knee/ankle fix, wire scar, CT planning scan fuse with pre-op imaging. Borders: Superior, top of T12; inferior, bottom of L4; contralateral transverse processes; ipsilateral renal bed with clips. If possible, scar should be included in the target. IMRT Technique Patient set up as 3D-CRT, fuse MRI with planning CT. 6-MV photons, seven to nine fixed-beam IMRT or two-arc VMAT. Volumes GTV ¼ none in post-op (or primary gross tumor) CTV1 ¼ post-op nephrectomy bed, surgical clips, scar (or GTV) þ at risk LNs þ 0.5e1.5 cm (respecting anatomical borders) CTV2 ¼ post-op nephrectomy bed, surgical clips, scar (or GTV) þ 0.5e1.5 cm (respecting anatomical borders) PTV ¼ CTV þ 0.5 cm At risk LN: PA nodes Doses PTV1 ¼ 180 cGy/fx to 45 Gy PTV2 ¼ 180 cGy/fx to 50.4e59.4 Gy (positive margins or gross residual disease) SBRT/SRS Doses Intact disease, SBRT: Single fraction 14e26 Gy (median dose 25 Gy); Multiple fractions 24e70 Gy (median dose 40 Gy) delivered in 2e10 fractions.

III. CLINICAL RADIATION ONCOLOGY

432

19. GENITOURINARY CANCERS

Extracranial metastases, SBRT: 16e60 Gy delivered in 1e10 fractions. Dose and fractionation is greatly dependent on size, location, and proximity to other organs at risk. Intracranial metastases, SRS: tumor size <2 cm is 24 Gy, <2e3 cm is 18 Gy, >3e4 cm is 15 Gy. Constraints Consider organs at risk in the treatment area, and make sure to follow standard constraints; liver, bowel, contralateral kidney, spinal cord, and stomach. Contralateral kidney: maximum dose <20 Gy. If both kidneys are irradiated, one must not receive more than 15 Gy. Liver: V36 < 30% Spinal cord: maximum dose <45 Gy Small bowel: V45 < 195 cc SBRT: Dose constraints vary because of fractionation and treatment site.

Outcome Five-year overall survival rates for stage I is 80%; stage II is 74%; stage III is 50%e55%; stage IV is 10%e30%.

Complications • Fatigue, nausea, vomiting, increased bowel frequency, and loose stool • Damage to the kidney and small bowel

Follow-Up • Every 3 months for the first year, every 6 months for the second year, then every 12 months thereafter • Imaging with chest X-ray and abdominal CT as indicated

BLADDER CANCER The estimated incidence in the United States is 81,190 with 17,240 estimated deaths in 2018. The anterosuperior portion of the bladder (apex) lies behind the symphysis pubis and peritoneum. The base is the posteroinferior part, which lies adjacent to the vagina or rectum. The portion adjacent to the prostate or urethra (in females) is the neck of the bladder. The triangle formed by the ureteral and urethral orifices is the trigone and the base of the bladder. Lymphatic drainage is from the bladder to the external and internal iliac and presacral nodes.

Workup Risk Factors • Aniline dye, tobacco, chronic bladder infection, and bladder stones • Schistosoma hematobium (squamous cell cancer) Symptoms and Signs • Microscopic or gross hematuria, increase urination frequency, bladder irritability, and dysuria • Bimanual exam and examination under anesthesia (EUA) III. CLINICAL RADIATION ONCOLOGY

TNM STAGING (BLADDER CANCER)

433

Investigations • CBC, chemistry with renal function, urine cytology • Evaluation of entire genitourinary (GU) tract with IVP • Cystoscopy with biopsy, EUA, transurethral resection of bladder tumor (TURBT), biopsy of prostatic urethra, and mapping biopsies if diffuse in situ disease • Chest X-ray, CT of the abdomen and pelvis, bone scan if symptomatic or for increase in alkaline phosphatase

TNM STAGING (BLADDER CANCER) Ta

Noninvasive papillary tumor

Tis

Urothelial carcinoma in situ: flat tumor

T1

Tumor invades subepithelial connective tissue

T2

Tumor invades muscularis propria

T2a

Tumor invades superficial muscularis propria (inner half)

T2b

Tumor invades deep muscularis propria (outer half)

T3

Tumor invades perivesical tissue

pT3a

Microscopically

pT3b

Macroscopically (extravesical mass)

T4

Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall

T4a

Tumor invades prostatic stroma, uterus, vagina

T4b

Tumor invades pelvic wall, abdominal wall

N0

No regional lymph node metastasis

N1

Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac or sacral lymph node)

N2

Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac or sacral lymph node)

N3

Lymph node metastasis to the common iliac lymph nodes

M0

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

M1a

Distant metastasis limited to lymph nodes beyond the common iliac

M1b

Nonelymph node distant metastases

III. CLINICAL RADIATION ONCOLOGY

434

19. GENITOURINARY CANCERS

Stage Grouping Stage 0a

Ta

N0

M0

Stage 0is

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2a, 2b

N0

M0

Stage IIIA

T3a, 3b,4a

N0

M0

T1, 2, 3, 4a

N1

M0

Stage IIIB

T1, 2, 3, 4a

N2, 3

M0

Stage IVA

T4b

N0

M0

Stage IVA

Any T

Any N

M1a

Stage IVB

Any T

Any N

M1b

M, (distant metastasis); N, (regional lymph nodes); TNM, T (tumor). Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.

Treatment Superficial Disease (Ta, Tis, T1) • Low-grade TadTURBT only. • High-grade Ta/Tis, T1dTURBT followed by intravesical BCG (Bacillus Calmettee Guerin vaccine). BCG is given, 50 mg intravesical every week
6 cycles. Consider a single dose of intravesicular mitomycin C within 24 h of TURBT, before BCG is given. • Radical cystectomy is considered in patients who have no response to one to two courses of BCG, tumors >5 cm in size, involvement of the ureters, bladder neck, and multiple recurrences. • ChemoRT therapy can be considered for patients who are medically inoperable or refuse cystectomy for the abovementioned indications. Invasive Disease, N0 • Pre-op chemotherapy followed by partial or radical cystoprostatectomy or anterior exenteration in women. • Pre-op chemotherapy is with gemcitabine 1000 mg/m2 days 1, 8, 15 and cisplatin 70 mg/m2 on day 2 [3, 4]. • Post-op pT3eT4 tumor or node positive can also be considered for chemotherapy provided they have not received any pre-op chemotherapy [5]. • Post-op RT benefit is unclear; however, it can be considered for gross residual disease, positive margins, pathological nodal involvement, pT3-T4, LVI, and high-grade disease.

III. CLINICAL RADIATION ONCOLOGY

TNM STAGING (BLADDER CANCER)

435

• Bladder preservation management: maximum TURBT followed by concurrent chemoRT [6, 7]. Chemotherapy CDDP 100 mg/m2 every 3 weeks
2 cycles. The patients then have UA cytology and a biopsy done after 4e6 weeks of treatment. The patient with pathologic complete response (pCR) continues with chemoRT, while the patient with pathologic partial response/no response (pPR/NR) undergoes cystectomy. • Patients refusing surgery or medically unable to have a cystectomy should undergo maximum TURBT followed by concurrent chemoRT. Chemotherapy CDDP 15 mg/m2 and 5-FU 400 mg/m2
3 cycles (preferred) or CDDP 100 mg/m2 every 3 weeks
2 cycles. • In elderly, medically unfit patients, bladder preservation therapy can be expedited with hypofractionated chemoRT. After maximum TURBT, followed by concurrent chemoRT. Chemotherapy is weekly gemcitabine 100 mg/m2 or CDDP 40 mg/m2. In elderly, medically unfit patients, bladder preservation therapy can be expedited with hypofractionated chemoRT. After maximum TURBT, followed by concurrent chemoRT. Chemotherapy is weekly gemcitabine 100 mg/m2 or CDDP 40 mg/m2. Invasive Disease, Nþ, and Metastatic • Chemotherapy or concurrent chemoRT. Combination chemotherapy with gemcitabine and cisplatin (GC) is preferred over M-VAC (methotrexate, vinblastine, adriamycin, cisplatin). • Multiple PD-1 and PD-L1 monoclonal antibodies such as pembrolizumab, nivolumab, durvalumab can be considered for metastatic urothelial cancer progressing on chemotherapy.

Radiation Therapy Technique 3D Technique Patient is supine, arms above chest, CT simulated for four-field box. CT scan is done twice, once with empty bladder for initial whole bladder treatment then with full bladder for the boost treatment. Borders are superior S2/S3, inferior bottom of obturator foramen, lateral 2 cm on bony pelvis, anterior 2 cm anterior to bladder wall, posterior 2 cm posterior to bladder wall/tumor. Treat to 39.6 Gy (45 Gy for patients refused/medically unfit) then cone down with 2-cm margin around the tumor to final dose of 64.8 Gy. Patient always voids before each treatment. IMRT Technique Patient supine, CT simulate as 3D technique. Bladder mapping from biopsies and placement of fiducial markers to define tumor bed. Initial treatment is with empty bladder and boost treatment is with full bladder. 6-MV photons, with seven to nine IMRT beams or two-arc VMATS for treatment. Daily CBCT is recommended. Fig. 19.1. Volumes GTV ¼ gross disease defined by cystoscope and/or CT/MRI imaging CTVtumor ¼ GTV þ tumor bed (defined by bladder mapping) CTVbladder ¼ entire bladder CTVother ¼ elective LN þ radical cystectomy structures

III. CLINICAL RADIATION ONCOLOGY

436

19. GENITOURINARY CANCERS

(A)

(B) PTV

LN CTV LN GTV

Bladder

(C)

(D)

FIGURE 19.1 Coronal CT (A) and sagittal CT (B) of bladder cancer treated with definitive chemoRT with PTV1 (outer red line) delivering 45 Gy. Sagittal (C) and coronal CT (D) of the boost field PTV2 (red) delivering 64.8 Gy to the whole bladder and an involved lymph node. Superior border at L4/L5 and inferior border below the prostate at the genitourinary diaphragm. PTV1 includes the prostate, seminal vesicles, bladder, internal and external iliac nodes, and common iliac nodes (due to involved node). PTV2 includes the gross tumor, whole bladder, and involved node with margin. PTVtumor ¼ CTVtumor þ 2 cm PTVbladder ¼ CTVbladder þ2 cm PTVother ¼ CTVother þ 0.5 cm PTV1 ¼ PTVtumor þ PTVbladder þ PTVother PTV2 ¼ PTVtumor þ PTVbladder PTV3 ¼ PTVtumor Elective Lymph Nodes/Radical Cystectomy Structures Internal, obturator, and external iliac LNs up to S2/S3 structures included in radical prostatectomy: prostate/urethra/SVs in men; uterus/Fallopian tube/upper vagina in women. Doses PTV1 ¼ 180 cGy/fx to 45 Gy PTV2 ¼ 180 cGy/fx to 54 Gy PTV3 ¼ 180 cGy/fx to 64.8e66.6 Gy Hypofractionated RT ¼ 250 cGy/fx to 50 Gy

III. CLINICAL RADIATION ONCOLOGY

PROSTATE CANCER

437

Constraints Small bowel: V45 < 195 cc Femoral heads: V45 < 25%, V50 < 5% Urethra: maximum dose<70 Gy

Outcome • Overall survival for Ta is 95%; HG T1 is 50%; T2, T3 is 50%; LN þ 20%. • Bladder conservation is 40%, and overall survival is 50%.

Complications • Urinary frequency with burning sensation, hematuria, bladder damage with shrinkage, loss of capacity, urethral stricture (<5%), and recurrent bladder infection; change in bowel habit, diarrhea, cramps, rectal inflammation, soreness, rectal bleeding, bowel or rectal damage requiring surgical correction (5%e15%), bone damage with softening or fracture. • Impotence with loss of erection.

Follow-Up • Every 3 months for the first year, every 6 months for the second year, then every 12 months thereafter • Cystoscopy and urine cytology every 3 months for 2 years, then every 12 months • CT scan of the abdomen and pelvis every 12 months and as indicated

PROSTATE CANCER The estimated incidence in the United States is 164,690 with 29,430 estimated deaths in 2018. The prostate gland is located deep in the pelvis and is surrounded anteriorly by the dorsal vein complex, posteriorly by the rectum, and superiorly by the bladder. The subcapsular lymphatic system drains to a periprostatic lymphatic network, which drains into the internal iliac, obturator, external iliac, and less frequently presacral LNs. Nonregional (distant) nodes ¼ aortic, common iliac, inguinal, and superficial femoral. Pelvic LN involvement can be predicted by the following equations and nomograms: Percent LN risk ¼ 2/3 PSA þ (GS-6)
10 (Roach formula) Percent LN risk ¼ (GS-5)
(PSA/3 þ 1.5
T) (Yale formula) Where GS is gleason score, T ¼ 0, 1, two for cT1c, cT2a, and cT2b/c. Percent LN risk ¼ Memorial Sloan-Kettering nomogram: http://www.mskcc.org/ mskcc/html/10088.cfm.

Workup Risk Factors • Advanced age • Family history • RacedAfrican-American

III. CLINICAL RADIATION ONCOLOGY

438

19. GENITOURINARY CANCERS

Symptoms and Signs • Many patients are asymptomatic, hesitancy, frequency, nocturia, weak urinary stream, urinary tract infection, impotence (secondary to invasion to neuromuscular bundle). • DRE: palpate for gland dimension, consistency, sensitivity, mobility presence/size of nodules, involvement of any lateral rectal sulci. • Bone pain (secondary to bony metastasis). Investigations • CBC, CMP, LFTs, testosterone (baseline) • Prostate-specific antigen (PSA): • Screening discuss at the age of 45 • African-American patients offer screening at the age of 40 • High-risk patients with positive family history offer annual screening at the age of 45e50 • Biomarkers such as 4K (estimates probability of high-risk prostate cancer) or PCA3 >35 (may be indicative of prostate cancer) are not recommended as firstline screening tests. • TRUS-guided biopsy (12 cores) • CT or MRI of the pelvis for T3/4 or T1/2 with LN nomogram risk of >10% • Bone scan for T1 with PSA over 20, T2 with PSA >10, T3/4, gleason score >8, for symptoms or if elevated alkaline phosphatase • Calculation of life expectancy: https://www.ssa.gov/OACT/STATS/table4c6.htm

International Society of Urological Pathology Grade Groupsa ISUP Grade Group

Gleason Score

1

<¼6

2

3þ4¼7

3

4þ3¼7

4

8

5

9 or 10

a Epstein JI, et al. The 2014 international society of urological pathology (ISUP) consensus conference on gleason grading of prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol February 2016;40(2):244e52.

TNM Staging (Prostate Cancer) T1

Clinically inapparent tumor not palpable

T1a

Tumor incidental histologic finding in 5% or less of tissue resected

T1b

Tumor incidental histologic finding in more than 5% of tissue resected

T1c

Tumor identified by needle biopsy (because of elevated PSA)a

III. CLINICAL RADIATION ONCOLOGY

439

PROSTATE CANCER

T2

Tumor confined within prostate

T2a

Tumor involves one-half of one side or less

T2b

Tumor involves more than one-half of one side but not both sides

T2c

Tumor involves both sides

T3

Tumor extends through the prostate capsuleb

T3a

Extracapsular extension (unilateral or bilateral)

T3b

Tumor invades seminal vesicle(s)

T4

Tumor is fixed or invades adjacent structures other than seminal vesicles: such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall

Note: There is no pathological T1 classification. a

Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c. Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2 not as T3.

b

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph node(s)

M0

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

M1

Distant metastasis

Stage Grouping T1aec

N0

M0

PSA < 10

GG1

T2a, T2

N0

M0

PSA < 10

GG1

T1aec, T2a, T2

N0

M0

PSA > 10 < 20

GG1

T2bec

N0

M0

PSA < 20

GG1

Stage IIB

T1, 2

N0

M0

PSA < 20

GG2

Stage IIC

T1, 2

N0

M0

PSA < 20

GG3

T1, 2

N0

M0

PSA <20

GG4

Stage IIIA

T1, 2

N0

M0

PSA > 20

GG1-4

Stage IIIB

T3, 4

N0

M0

Any PSA

GG1-4

Stage IIIC

Any T

N0

M0

Any PSA

GG5

Stage IVA

Any T

N1

M0

Any PSA

Any

Stage IVB

Any T

N0

M1

Any PSA

Any

Stage I

Stage IIA

M, (distant metastasis); N, (regional lymph nodes); TNM, T (tumor). Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.

III. CLINICAL RADIATION ONCOLOGY

440

19. GENITOURINARY CANCERS

Treatment Very Low-Risk (T1c and gl < 6/GG1 and PSA <10 and < 3 cores with <50% cancer in each core and PSA density <0.15 ng/ml/g) • Life expectancy <10 years: observation • Life expectancy 10e20 years: active surveillance with DRE and PSA every 6e12 months; repeat biopsy at 12 months • Life expectancy >20 years: • Active surveillance [8, 9, 10] • Radical prostatectomy, which involves complete removal of prostate and surrounding capsule, SVs, ampulla, the vas deference, with the option of the bilateral pelvic LN dissection [8, 9, 10]. • External beam radiation therapy (no nodal treatment) [17e19]. Hypofractionated RT is recommended to prostate only [20, 21]. • Brachytherapy radiation alone [11, 12]. For prostate gland volume more than 60 cc, recommend neoadjuvant hormonal therapy for 3e6 months. Low-Risk (T1eT2a and gl < 6/GG1 and PSA <10) • Life expectancy <10 years: observation • Life expectancy >10 years: • Active surveillance [8, 9, 10]. • Radical prostatectomy, with the option of the bilateral pelvic LN dissection [8, 9, 10], • Radiation therapy options involve EBRT (no nodal treatment) [17e19]. Hypofractionated RT is recommended to prostate only [20, 21]. • Brachytherapy radiation alone [11, 12]. For prostate gland volume more than 60 cc, recommend neoadjuvant hormonal therapy for 3e6 months. Favorable Intermediate-Risk (T2b-c or gl 3 þ 4/GG2 or PSA 10e20* and percent positive cores <50%)

*cannot have >1 intermediate risk factor

• Life expectancy <10 years: observation or EBRT or brachytherapy • Life expectancy >10 years: • Radical prostatectomy with a pelvic node dissection option [8, 9, 10]. • EBRT initially to prostate and proximal seminal vesicle, followed by a boost dose to prostate only (no nodal treatment) [17e19]. Hypofractionated RT is recommended to prostate  SV [21e23]. • Brachytherapy alone [11e13]. Unfavorable Intermediate-Risk (T2b-c or gl 3 þ 4/GG2 or gl 4 þ 3/GG3 or PSA 10e20) • Life expectancy <10 years: observation or EBRT or brachytherapy • Life expectancy >10 years: • Radical prostatectomy with a pelvic node dissection option. III. CLINICAL RADIATION ONCOLOGY

PROSTATE CANCER

441

• EBRT initially to prostate and proximal seminal vesicle, followed by a boost dose to prostate [17e19]. Consider pelvic node RT for gl score 4 þ 3 (15, 16). • Brachytherapy alone or EBRT combination with brachytherapy boost can be considered for these patients [11e13]. • Recommend short-term ADT (4e6 months). Hormonal therapy is given with bicalutamide 50 mg orally every day
4 months, goserelin 3.6 mg every month
4e6 months [24, 26, 27]. High-risk (T3a or gl 8/GG > 4 or gl 4 þ 5/GG5 or PSA >20) Very high-risk (T3beT4, or primary gl five or >4 cores gl 8e10/GG 4e5) Regional (Nþ) • EBRT to pelvic nodes, seminal vesicle, and prostate, followed by boost dose to prostate and seminal vesicle, followed by boost dose to prostate [17e19]. Treat pelvic node [15, 16]. • EBRT combination with brachytherapy boost can be considered for this group of patient (13, 14). Treat pelvic node. • Long-term ADT (28 months) with 2 months before and 2 months during the RT with bicalutamide and goserelin as above, followed by adjuvant hormonal therapy with goserelin 10.8 mg every 3 months
2 years is recommended [25, 26, 28]. • Consider chemotherapy with docetaxel in addition to ADT [29, 30]. Docetaxel dose is 75 mg/m2
6 cycles with or without prednisone. • Consider abiraterone combined with ADT [31]. Abiraterone dose is 1000 mg/day for
2 years. Postprostatectomy Radiation Therapy The definition of a failure after radical prostatectomy: PSA >¼0.2 ng/mL followed by a second PSA also >¼0.2 ng/mL (AUA definition) • Adjuvant RT is recommended for ECE, positive SV, and positive margin. RT is given after urinary incontinence resolves, may take up to 1 year [32, 33]. • Salvage RT is recommended for persistent PSA, rising PSA after initial undetectable PSA from RP, gross disease by imaging or biopsy. Salvage RT is recommended while PSA is still low <1 ng/mL [34, 35, 37]. • Androgen deprivation is indicated for patients with a rising PSA after RP and specifically for patients with pT3 disease, high PSA (>0.7), positive margins, high Gleason score (8e10), positive nodes [35, 36]. ADT duration is 6e24 months with bicalutamide or goserelin. PosteRadiation Rising PSA The definition of failure after RT: a rise of the PSA >¼2 ng/mL above PSA nadir (Phoenix definition). • Patients who meet the phoenix definition of biochemical failure after RT should have repeat staging workup. If patient has no distant metastasis, then consider prostatectomy or salvage brachytherapy, cryotherapy, or HIFU. • Alternatively, androgen ablation therapy can be considered. III. CLINICAL RADIATION ONCOLOGY

442

19. GENITOURINARY CANCERS

Metastatic Disease • ADT and docetaxel 75 mg/m2
6 cycles with or without prednisone [23, 24]. • ADT and abiraterone is recommended [25]. • LHRH agonist and antiandrogen with Casodex 50 mg orally every day
1 month and Zoladex 10.8 mg subcutaneously every 3 months until PSA failure. • LHRH antagonist with degarelix initial dose 120 mg SC for two doses (i.e., two separate injections totaling 240 mg), then, after 28 days, begin maintenance dose of 80 mg SC q28 days. • Patients with bony metastasis should be considered for bisphosphonate treatment. Hormonal Refractory Prostate Cancer • Abireterone with prednisone • Systemic chemotherapy with docetaxel and prednisone every3 weeks for
6 cycles; alternatively, estramustine, etoposide, paclitaxel
4 cycles is the recommended treatment. • Enzalutamide 160 mg/d can be considered. • Ketoconazole 400 mg t.i.d. with or without glucocorticoids can be considered. • Provenge, a cancer vaccine for metastatic hormone refractory prostate cancer patients. Treatment involves three courses in a month with weeks in between courses. • Patients with bony metastasis should be considered for bisphosphonate treatment.

Radiation Therapy Technique 3D Technique • Patient is supine, arms on chest, on Vac-Lok, IV contrast, mark anus, perform urethrogram, bladder full, rectum empty, patient CT simulated. Borders are: superior at bottom of SI joint; inferior border is 1 cm below urethrogram beak, lateral at 2 cm on bony pelvis; anterior to symphysis pubis, posterior at S3/S4. Boost prostate with a margin of 1 cm (rectal margin 0.5 cm) to a total final dose, depending on the risk stratification of the prostate cancer. If treating more than 72 Gy, patients must have image-guided radiation therapy (IGRT). Treat small pelvis with four-field box and prostate boost with six-field conformal radiation therapy. Figs. 19.2 and 19.3. • For post-op patients, it is necessary for the incontinence to resolve, which takes about 3 months. Patient position is same as above, small bowel contrast in place. Borders are superior, 10 cm above inferior border; inferior, 1 cm below urethrogram beak, lateral 10 cm across; anterior, 1 cm behind symphysis; posterior, cm posterior to most anterior portion of anterior rectal wall. Boost with small bowel block and 10
10 field to a total final dose. • Brachytherapy is done in selected patients with small prostate glands of <60 cc. In patients receiving brachytherapy alone, the implant is done with ultrasound guidance. Postimplant dosimetry should be performed within 1 month.

III. CLINICAL RADIATION ONCOLOGY

PROSTATE CANCER

443

FIGURE 19.2 (A) DRR for prostate cancer, 3D AP field, showing superior border at the bottom of SI joint and inferior border 1 cm below the urethral beak. Lateral borders have a 2-cm margin on the bony pelvis. (B) DRR for prostate cancer, 3D right lateral field, showing the anterior border is anterior to the symphysis pubis and the posterior border is at S3/S4.

FIGURE 19.3 (A) DRR for prostate cancer, cone down 3D AP field, showing treating seminal vesicles and the prostate with a 1-cm margin. (B) DRR for prostate cancer, cone down 3D right lateral field, showing treating seminal vesicles and the prostate with a 1-cm margin. IMRT Technique • Simulation: Patient is supine, bladder full; rectum empty (a 3 cm diameter or less). Consider fiducials (placed before SIM). Knee and ankle fix for immobilization. MRI prostate with CT simulation for contouring (typically use T2 sequence). • Planning technique: 6-MV photons, use equally spaced 7e9 coplanar IMRT beams or two arcs with VMAT (6 MV or 15 MV). Daily IGRT is recommended.

III. CLINICAL RADIATION ONCOLOGY

444

19. GENITOURINARY CANCERS

• Contouring: • Prostate is contoured using the MRI for more precise delineation. Attention should be given to contouring the prostatic apex. • Rectum is drawn from ischial tuberosity to the top of the seminal vesicles. Sigmoid colon is drawn to the top of the pelvic inlet (11e15 cm from ischial tuberosity). • Nodal volume is contoured using a 7 mm around vessels from L5/S1 interspace to top of pubis (include the obturator nodes) • To reduce the rectal toxicity, rapid dose fall-off posteriorly is important; the 50% isodose line should not cover the entire circumference of the rectum. See Figs. 19.4 and 19.5. Volumes Intact prostate volume GTV ¼ prostate þ extracapsular extension Low/favorable intermediate risk CTV1 ¼ GTV þ proximal 1 cm SV CTV2 ¼ GTV Select unfavorable intermediate risk/high risk CTV1 ¼ GTV þ entire SV þ pelvic elective LNs CTV2 ¼ GTV þ entire SV CTV3 ¼ GTV PTV ¼ CTV þ0.8 cm margin with rectal margin 0.5 cm SBRT PTV ¼ Prostate  proximal 1 cm SVs with 5 mm superior and lateral, 3 mm anterior and posterior F Full bladder

PTV

CTV LN

SV

Emptty rectum

CTV LN

SV Prostat

FIGURE 19.4 Prostate cancer CT images showing target volumes SV, prostate, LNs, CTV, PTV and critical structures bladder, and rectum.

III. CLINICAL RADIATION ONCOLOGY

445

PROSTATE CANCER

PPTV1, 2, 3 Bladder Small bowel

Rectum

Femoral heads

FIGURE 19.5 Prostate cancer CT images showing two-arc VMAT planning isodose lines conforming to PTVs and DVH meeting all constraints. The prescription dose is PTV1 45 Gy, PTV2 55.8 Gy, PTV3 79.2 Gy.

Postprostatectomy Prostate Bed Volume* GTV ¼ none CTV ¼ prostate bed (as below) þ pelvic LN (for salvage RT) Superior level of cut end of vas deferens or 3e4 cm above top of symphysis (vas may retract postoperatively; include seminal vesicle remnants if pathologically involved) Inferior 8e12 mm below vesicourethral anastomosis (may include more if concern for apical margin, can extend to slice above penile bulb if vesicourethral anastomosis not well visualized) Anterioposterior edge of pubic bone, posterior 1e2 cm of bladder wall. Posterioanterior rectal wall (may need to be concave around lateral aspects), mesorectal fascia. Lateral levator ani muscles, obturator internus, sacrorectogenitopubic fascia (if concern about extraprostatic disease at base may extend to obturator internus) PTV ¼ CTV þ 0.8 cm margin with rectal margin 0.5 cm. *(Michalski JM, Lawton C, El Naqa I, Ritter M, O’Meara E, Seider MJ, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys (2010) 76(2):361e8)

Pelvic Elective LNs: External iliac, internal iliac, presacral and periprostatic LNs (superior border for the LNs at L5/S1, inferior border of external iliac is at the superior border of femoral head, inferior border of internal iliac LN at the top of SV, inferior border of obturator LN is at the top of the pubis presacral LN anterior border is 1 cm anterior to the sacrum, superior and inferior border is at S1eS3)

III. CLINICAL RADIATION ONCOLOGY

446

19. GENITOURINARY CANCERS

Brachytherapy Technique Brachytherapy is performed in select patients. • Ideal criteria include patients with prostate glands of 30e60 cc, with AUA score of <¼15, no pubic arch interference. • Monotherapy: patients with very low risk, low risk, and favorable intermediate risk • Boost therapy: patients with unfavorable intermediate risk and high risk • Implants can be done with low-dose rate (LDR) or HDR, and CT or US guidance is used. • Large prostate gland of >60 cc recommend short course of ADT of 4e6 months. Low-Dose Rate Brachytherapy This is a permanent brachytherapy technique. Pre-op bowel preparation is needed, appropriate anesthesia is required. TRUS images are used for preplanning. PTV is 3e5 mm margin around the prostate. In the OR intra-op TRUS-guided images are matched with the pre-op images. Preloaded needles are inserted through the template until the correct location is established. Seeds are then deposited, and needles are withdrawn. The patient is discharged from the hospital the same day or the next day after he is able to urinate. When treating with LDR, postimplant dosimetry should be done within 1 month (Figs. 19.4 and 19.5). High-Dose Rate Brachytherapy This is a temporary brachytherapy technique. Afterloading catheters are inserted using template under TRUS guidance. CT simulation is done with the catheters in place. Treatment planning is done via computer optimization of the dwell times. HDR Ir 192 sources are used for treatment using a computer-driven afterloading machine. The catheters and the template are removed after each treatment. After appropriate radiation safety monitoring, the patient is discharged home the same day. Doses for External Beam Radiation Therapy and Brachytherapy Definitive RT Low/intermediate risk PTV1 ¼ 180e200 cGy/fx to 54e55.8 Gy PTV2 ¼ 180e200 cGy/fx 75.6e80 Gy High risk PTV1 ¼ 180e200 cGy/fx to 45e46 Gy PTV2 ¼ 180e200 cGy/fx to 54e55.8 Gy PTV3 ¼ 180e200 cGy/fx to 79.2e80 Gy Hypofractionated RT PTV1 ¼ 250 cGy/fx to 78 Gy or 270 cGy/fx to 70.2 Gy SBRT 6.5 Gy/fx in five fxs to 32.5 Gy or 7.25 cGy/fx to 36.25 Gy (NRG Gu005)

III. CLINICAL RADIATION ONCOLOGY

PROSTATE CANCER

Post-op RT 180 cGy/fx to 66.6e72 Gy Gross disease: 180 cGy/fx to 73.8e75.6 Gy Brachytherapy mono dose I-125: mono dose 145 Gy Pd-103: mono dose 125 Gy Goals: V100 > 95%e99%, V150 < 70%, V200 <20%, D90 >90e100% HDR Ir-192: 9.5 Gy in four fxs to 38 Gy or 13. 5 Gy/fx in two fxs to 27 Gy Goals: V100 > 90e9%, V150 <40%, D90 > 90% Brachytherapy boost dose (EBRT40e50 Gy) I-125: 110 Gy Pd-103: 90e100 Gy HDR Ir-192: 4 Gy/fx in four fxs to 16 Gy or 10.5 Gy/fx to 21 Gy Constraints Standard Fractionation (180e200 cGy/fx) Rectum: V72 Gy<10cc, V65 Gy<17%, V40Gy<35% Anus: V60 Gy<1cc, V35Gy<40% Bladder: V65 Gy<25%, V40 Gy<50% Femoral heads: V50 Gy<10% Bowel: V50 Gy<5%, V40 Gy<20% Penile bulb: V15 Gy < 10% Corporal bodies: V7 Gy<10% Moderate Hypofractionation (270 cGy/fx) Rectum: V65 Gy<10cc, V50 Gy<17%, V31 Gy<35% Anus: V48 Gy<1cc, V32 Gy<40% Bladder: V50 Gy<25%, V31 Gy<50% Femoral heads: V40 Gy< 10% Bowel: V40 Gy<5%, V30 Gy<20% Penile bulb: V12 Gy<10% Corporal bodies: V 5.5 Gy < 10% Combination EBRT

+ Brachytherapy (HDR) Boost

Rectum: V41 Gy<10cc, V40 Gy<17%, V30 Gy<35% Anus: V35Gy<1cc, V20Gy<40% Bladder: V40Gy<25%, V30 Gy<50% Femoral heads: V31 GY <10% Bowel: V50 Gy<5%, V40 Gy<20% Penile bulb: V10 Gy<10% Corporal bodies: V4.5Gy<10%

III. CLINICAL RADIATION ONCOLOGY

447

448

19. GENITOURINARY CANCERS

Brachytherapy LDR: Rectum D0.1 cc <200 Gy, D2 cc <100%, RV <1 cc; urethra V100 <60%, D30 <130%, Dmax <150% HDR: Rectum V75 <1 cc; urethra V120 <0.8 cc

Outcome • After radiation, PSA is halved in 2e3 months. PSA remains detectable in majority of patients after RT with no clinical evidence of failure. It can take years for patients to reach nadir. • Biochemical disease-free survival (bDFS) for low-risk patients is 80e90þ%, intermediate risk 75%e85%, high risk 60% • For post-op patients treated with adjuvant or salvage radiation, the 5-year freedom from biochemical failure overall is 56%, 71% for PSA 0.01e2 ng/mL, 63% for PSA 0.21e0.5, 54% for PSA 0.51e1, 43% for PSA 1.01e2, and 37% for PSA>2.

Complications EBRT • Likely: Fatigue, urinary frequency/urgency, dysuria, diarrhea/loose stools, gas, occasionally rectal irritation/inflammation or exacerbation of hemorrhoids • Less likely: Permanent changes in bowel habits, rectal bleeding, proctitis, bowel or rectal damage requiring surgical correction, hematuria, cystitis • Erectile dysfunction in long term • Second malignancy (bladder 0.1%e3.8%, rectal 0.3%e1.2%)* *Wallis CJD, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ 2016;352. https://doi.org/10.1136/bmj.i851 (Published 02 March 2016).

Brachytherapy • Urinary frequency, dysuria, hematuria • Urinary retentiondresolves within 3 days • Obstructive symptomsdresolve within 12 months Hormone Therapy Toxicity • Fatigue, hot flashes, energy changes, decreased energy, increased appetite, weight gain, risk of metabolic syndrome, risk of DM/CAD, risk of bone density loss • Bicalutamide also carries the risk of gynecomastia • Treated with tamoxifen or prophylactic breast RT

Follow-Up • Every 3 months for the first year, every 6 months for the second year, and every 12 months thereafter. • DRE and PSA measurement with each visit. • PSA failure after EBRT: PSA rise by > 2 ng/mL above the nadir. Nadir after EBRT may take up to 3 years (after brachytherapy up to 5 years). Transient rise of PSA may happen after EBRT/brachytherapy. • Patients receiving androgen ablation treatment should be considered for a baseline bone density study. III. CLINICAL RADIATION ONCOLOGY

449

TESTICULAR CANCER

TESTICULAR CANCER The estimated incidence in the United States is 9310 with 400 estimated deaths in 2018. Testicular cancer is most common between the ages of 20 and 34. Lymph drainage is to the PA nodes between the T11-L4 vertebrae. The left testicle drains to the left renal vein, and the right testicle drains to the inferior vena cava below the renal vein level.

Workup Risk Factors • Prior testicular cancer • Cryptorchidism • Klinefelter’s syndrome Symptoms and Signs • Painless heavy feeling of the testicles, low back pain • Testicular mass in almost all patients • Check for adenopathy in supraclavicular fossa, axilla, inguinal region, with attention to cryptorchidism • Gynecomastia (associated with high HCG and choriocarcinoma) Investigations • CBC and routine chemistries • LDH: the serum level of LDH has prognostic value in patients with metastatic disease and is included for staging. • Serum markers • HCG (half-life ¼ 1 day); HCG is secreted by syncytiotrophoblast. It is elevated in SGCT-pure seminoma and NSGCT-embryonal and choriocarcinoma. • AFP (half-life ¼ 5 days); AFP is elevated in nonseminomatous embryonal, teratoma, teratocarcinoma, yolk sac tumor; AFP is not elevated in pure seminoma, choriocarcinoma, or germinoma. • Serum tumor markers are obtained immediately after orchiectomy and if elevated should be performed serially after orchiectomy according to the normal decay for HCG and AFP to assess for persistent serum tumor marker elevation. • Testicular ultrasound differentiates tumor from cyst, spermatocele, varicocele. • Evaluate contralateral testis for subclinical tumor. • Chest X-ray with or without CT chest, CT of the abdomen and pelvis, brain MRI, if clinically indicated. • Semen analysis and banking of sperm, if adequate quality, for patient’s fertility desires.

TNM Staging (Testicular Cancer) pTX

Primary tumor cannot be assessed

pTis

Germ cell neoplasia (carcinoma in situ)

pT1

Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis (Continued)

III. CLINICAL RADIATION ONCOLOGY

450

19. GENITOURINARY CANCERS

pT2

Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer covering the external surface of tunica albuginea with or without lymphovascular invasion

pT3

Tumor invades the spermatic cord with or without vascular/lymphatic invasion

pT4

Tumor invades the scrotum with or without vascular/lymphatic invasion

*Except for pTis and pT4, extent of primary tumor is classified by radical orchiectomy. N0

No regional lymph node metastasis

N1

Metastasis with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension

N2

Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension

N3

Metastasis with a lymph node mass more than 5 cm in greatest dimension

M0

No distant metastasis

M1

Distant metastasis

M1a

No retroperitoneal nodal or pulmonary metastasis

M1b

Nonpulmonary visceral metastases

Stage Grouping Stage I

pT1e4

N0

M0

SX

Stage IA

pT1

N0

M0

S0

Stage IB

pT2

N0

M0

S0

pT3

N0

M0

S0

pT4

N0

M0

S0

Stage IS

Any pT/Tx

N0

M0

S1e3 (postorchiectomy)

Stage II

Any pT/Tx

N1e3

M0

SX

Stage IIA

Any pT/Tx

N1

M0

S0

Any pT/Tx

N1

M0

S1

Any pT/Tx

N2

M0

S0

Any pT/Tx

N2

M0

S1

Stage IIB

III. CLINICAL RADIATION ONCOLOGY

451

TESTICULAR CANCER

Stage I

pT1e4

N0

M0

SX

Stage IIC

Any pT/Tx

N3

M0

S0

Any pT/Tx

N3

M0

S1

Stage III

Any pT/Tx

Any N

M1

SX

Stage IIIA

Any pT/Tx

Any N

M1a

S0

Any pT/Tx

Any N

M1a

S1

Any pT/Tx

N1e3

M0

S2

Any pT/Tx

Any N

M1a

S2

Any pT/Tx

N1e3

M0

S3

Any pT/Tx

Any N

M1a

S3

Any pT/Tx

Any N

M1b

Any S

Stage IIIB

Stage IIIC

Required for staging: Serum tumor markers (S) S0

Marker study levels within normal limits

S1

LDH < 1.5
Na AND hCG (mIu/ml) < 5000 AND AFP (ng/mL) < 1000.

S2

LDH 1.5e10
N OR hCG (mIu/ml) 5000e50,000 OR AFP (ng/mL) 1000e10,000

S3

LDH > 10
N OR hCG (mIu/ml) > 50,000 OR AFP (ng/mL) > 10,000

M, (distant metastasis); N, (regional lymph nodes); TNM, T (tumor). a

N indicates the upper limit of normal for the LDH assay.

Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.

Treatment Seminoma Initial surgical management is radical orchiectomy with high spermatic cord ligation, followed by RT if indicated. Sperm banking should be discussed with the patient before any RT is initiated. • Stage I treatment options: • Observation for compliant patient (preferred). • Post-op chemotherapy carboplatin
1e2 cycles with AUC of 7 [39] • Post-op RT to PA LNs (38). Note: Contraindication for RT, such as horseshoe kidney or inflammatory bowel disease, these patients should undergo observation after orchiectomy.

III. CLINICAL RADIATION ONCOLOGY

452

19. GENITOURINARY CANCERS

• Stage IIA: Post-op RT to PA and ipsilateral pelvis followed by boost to gross LNs. • Stage IIB treatment options: • Postop chemotherapy PEB
3 cycles or EP
4 cycles • Post-op RT to PA and ipsilateral pelvis followed by boost to gross LN (s) Stage IIC/III: Chemotherapy PEB (cisplatin, etoposide, bleomycin) 20/100 mg/m2/ 30 units per week every 4 weeks
3e4 cycles. After chemotherapy, residual tumors of 3 cm or more or progressive disease may require surgery or RT. • Unresectable: In patients with a massive primary tumor that cannot be resected, the treatment is with RT alone to a field that includes the hemiscrotum, the PA nodes, ipsilateral pelvis, and groin (especially if the scrotum is involved). Nonseminoma Initial surgical management is radical inguinal orchiectomy with high spermatic cord ligation. • Stage I: IA: Surveillance. IB: Retroperitoneal lymph node dissection (RPLND) or chemotherapy PEB
1 cycle. • Stage IIA: RPLND is performed. If patients have persistently elevated markers after RPLND, then PEB
3 cycles are given. • Stage IIB, IIC, III: No RPLND, chemo PEB every 4 weeks
4 cycles. • Residual mass after chemotherapy: Resections are recommended for these patients. If the patient has a residual mass and negative markers but the mass is unresectable, then the patient can either be observed or have radiation therapy. If, after initial complete response or partial response to chemotherapy, the mass grows, then the recommendation is to resect the mass. • Mixed tumor: Postorchiectomy-elevated AFP indicates mixed tumor, which should be treated as nonseminoma.

Radiation Therapy Technique 3D Technique Patient is supine, arms by side, testicles in clam shell, IV contrast, CT simulated. Borders: Superior T10/T11; inferior for PA field L5/S1; if treating dogleg, then top of symphysis pubis; laterals for PA field 2 cm from vertebral edge (cover left renal hilum for left-sided tumor); if treating dogleg, then ipsilateral border 2 cm on pelvic bone; contralateral at transverse process up to L5/S1, then diagonally parallel with ipsilateral border then vertically to medial border of obturator and block humeral head. See Figs. 19.6 and 19.7. With coffee table and extended tray block 5 cm beyond field, there is about 0.5% dose to the testis (fractionated tolerance dose for sterility is 1e2 Gy). Recovery of sperm count is dependent on dose and can take up to a year or more. Volumes GTV ¼ gross disease (none after surgery) or nodal mass

III. CLINICAL RADIATION ONCOLOGY

TESTICULAR CANCER

453

FIGURE 19.6 The left panel shows a stage I testicular cancer treated adjuvant RT, paraaortic field 3D AP view with the superior border at T11/T12, and the inferior border at L5/S1. The right panel shows axial CT with isodose distribution for a 3D-CRT treatment plan.

DRR for stage IIA testicular cancer, 3-D AP field, showing a dogleg field. The superior border is at T10/T11 and the inferior border is at the symphysis pubis.

FIGURE 19.7

CTV1 ¼ GTV (none after surgery) þ grossly involved LNs with 2e3 cm margin þ elective retroperitoneal LNs with 1.2e1.9 cm expansion on the inferior vena cava and aorta CTV2 ¼ cone down to nodal mass with 2e3 cm margin PTV ¼ CTV þ 0.5 cm

III. CLINICAL RADIATION ONCOLOGY

454

19. GENITOURINARY CANCERS

Elective LNs Stage I: paracaval, precaval, and interaortocaval LNs for right sided tumors and at least the preaortic and lateral aortic nodes for left-side tumors. Contour the inferior vena cava and aorta from bottom of T11 to L5/S1 where the blood vessels end þ1.2e1.9 cm expansion on vessels. Stage II: stage I elective LNs and ipsilateral common iliac, external and proximal internal iliac veins and arteries down to the upper border of the acetabulum þ1.2e1.9 cm expansion on vessels. Doses PTV1 ¼ 150e200 cGy/fx to 20e25.5 Gy PTV 2: Stage IIA ¼ 150e200 cGy/fx to 30 Gy Stage IIB ¼ 150e200 cGy/fx to 36 Gy Constraints Kidney: V20 < 30%, if horseshoe kidney then RT is contraindicated.

Outcome Seminoma local relapse of tumor <3 cm is 6%; 3e6 cm is 18%; >6 cm is 36%. Stage I disease-free survival is 97%, OS is 100%, stage IIA,B disease-free survival is 90%, stage IIC is 85%.

Complications • • • • • • •

Nausea/vomiting and diarrhea Transient azoospermia Decrease in fertility RT dose 15e20 cGy: temporary reduction in sperm count RT dose 20e200 cGy: transient azoospermia RT dose >200 cGy: permanent azoospermia Second malignancy: 5% at 15 years

Follow-Up • Every 3 months for the first year, every 4 months for the second and third years, every 6 months for the fourth and fifth years, and every 12 months thereafter • AFP and bHCG with every visit • Chest X-ray, CT of the abdomen and pelvis with every visit

ANNOTATED BIBLIOGRAPHY RENAL CELL CANCER Ref 1. Siva et al. (2017). Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017;120:623e30. This was a prospective interventional clinical trial with 37 patients with T1eT2 primary renal cell carcinoma underwent SABR. Dose was 26 Gy in one fx if primary tumor <5 cm

III. CLINICAL RADIATION ONCOLOGY

455

BLADDER CANCER

in maximal dimension, or 14 Gy/fx to 42 Gy in three fxs if primary tumor ¼>5 cm. At median follow-up of 24 months, the data showed that Two-year outcomes: Freedom from local progression: 100% Distant progression: 89% Overall survival: 92% No grade 4, 5 toxicity, grade 3 toxicity 3%, grade 1e2 toxicity 78% The study results show that SABR for primary RCC was feasible and well tolerated. The data showed encouraging cancer control, functional preservation, and early survival outcomes in an inoperable cohort. Ref 2. Siva et al. (2018). Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: a report from the international radiosurgery oncology consortium for kidney (IROCK). Cancer March 1, 2018;124(5):934e42. Data from 233 patients treated with SABR from nine international data sets from a consortium were pooled. Median dose was 25 Gy in one fx, of those treated with >1 fx median dose was 40 Gy in four fx. Four year outcomes: Local control: 97.8% Cancer-specific survival: 91.9% Progression-free survival: 65.4% Grade 3, 4 toxicity 1.3%, grade 1, 2 toxicity 35.6% The authors concluded that SABR is well tolerated and locally effective for primary RCC. In addition, they found that patients treated with single fraction SABR had less distant progression/death from RCC.

BLADDER CANCER Neoadjuvant/Adjuvant Chemotherapy Ref 3. International Collaboration of Trialists (2011). International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30,894 trial. J Clin Oncol 1;29(16)2171e7. BA06 Trial. In this trial, 976 patients with muscle-invasive bladder cancer (T2 gr 3, T3, T4, N0/Nx, M0) were randomized no neoadjuvant chemo versus CMV chemo
3 cycles followed by cystectomy and/or radiotherapy. Each institution selected its preferred local treatment option (radiotherapy/ cystectomy) to reduce individual bias in selection of treatments for specific patients. At median follow-up of 8 years, the data showed the following: 10-Year Overall Survival No neoadjuvant chemo

30

Neo adjuvant chemo

36

P value

0.037

III. CLINICAL RADIATION ONCOLOGY

456

19. GENITOURINARY CANCERS

The trial showed that CMV chemotherapy improves OS outcome as first-line adjunctive treatment for invasive bladder cancer and should be viewed as state of the art compared with cystectomy or radiotherapy alone for deeply invasive bladder cancer. Ref 4. Kitamura H et al. (2014). Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan clinical oncology group study JCOG0209. Ann Oncol;25(6):1192e8. JCOG0209 Trial. In this trial, 130 patients with muscle-invasive bladder cancer (T24aN0M0) patients were randomized to receive two cycles of neoadjuvant MVAC followed by radical cystectomy or radical cystectomy alone. At median follow-up of 55 months, the data showed the following:

pT0 (%)

5-Year Progression-Free Survival (%)

5-Year Overall Survival (%)

No neoadjuvant chemo

9

56.4.

62.4

Neoadjuvant chemo

34

67.9

72.3

P value

<0.01

0.04

0.07

This trial showed that a significantly increased pT0 proportion and favorable OS of patients who received neoadjuvant MVAC chemotherapy. Ref 5. Sternberg CN et al. (2015). Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or NþM0 urothelial carcinoma of the bladder (EORTC 30,994): an intergroup, open label, randomized phase 3 trial. Lancet Oncol;16(1):76e86. EORTC 30994. In this trial, 284 patients with muscle-invasive bladder cancer were randomized to immediate versus deferred combination chemotherapy MVAC
6 cycles after radical cystectomy. After a median follow-up of 7 years, the data showed the following: 5-Year Progression-Free Survival (%)

Overall Survival (%)

Deferred chemo

31.8

no

Immediate chemo

47.6

diff

P value

<0.0001

ns

The data did not show a significant improvement in OS with immediate versus deferred chemotherapy after radical cystectomy.

III. CLINICAL RADIATION ONCOLOGY

457

BLADDER CANCER

ChemoRT Bladder Conservation Ref 6. Mitin T et al. (2016). Long-term outcomes among patients who achieve complete or near-complete responses after the induction phase of bladder preserving combined modality therapy for muscle-invasive bladder cancer: a pooled analysis of NRG Oncology/RTOG 9906 and 0233. Int J Radiat Biol Phys;94(1):67e74. RTOG 9906 Trial. A pooled analysis was performed on 119 patients with muscle-invasive bladder cancer enrolled on NRG 9906 and RTOG 0233, who were classified as having a complete (T0) or near complete (Ta or Tis) response after induction chemoRT and completed consolidation with a total RT dose or at least 60 Gy. At median follow-up of 5.9 years, the data showed the following: Bladder Recurrence-Free Survival (%)

5-Year Disease-Free Survival (%)

5-Year Overall Survival (%)

Near complete response

72

67

61

Complete response

68

85

72

P value

0.70

0.11

0.12

The analysis shows that the outcomes are similar between patients who achieve a complete response (T0) or near-complete response (Ta or Tis) after the induction phase of bladderpreservation trimodality therapy and suggests that it is reasonable to continue with bladderpreservation therapy in patients who achieve near-complete response to the induction phase. Ref 7. Emma H et al. (2017). BC200l long-term outcomes: a phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer. J Clin Oncol February 2017;35(6_suppl):280. BC 2001 Trial. In this study, 458 patients with MIBC (pT2-T4a N0 M0) were randomized in a 2
2 factorial design (stratified by center and use of neoadjuvant chemotherapy [neoCT]) to CRT versus RT alone and/or to standard RT (sRT) (to tumor and whole bladder with 1.5 cm margin) versus reduced high-dose volume RT (rvRT) (tumor þ1.5 cm margin treated to 100 (þ/5)% target dose and remaining bladder to 80% target dose). RT was 64 Gy/32 fx in 6.5 weeks (wks) or 55 Gy/20 fx in 4 wks (as per center policy). CRT was mitomycin C (12 mg/m2 iv bolus, MMC) day one of RT and 5-fluorouracil (5-FU) continuous infusion at 500 mg/m2/24 h for 10 days in total corresponding to fx 1e5 (wk 1) and fx 16e20 (wk 4) of RT. At median follow-up of 118 months, the results showed the following: 5-Year LRC (%)

2-Year Salvage Cystectome (%)

Overall Survival (%)

RT

49

17

no

cRT

63 ss

11

diff (Continued)

III. CLINICAL RADIATION ONCOLOGY

458

19. GENITOURINARY CANCERS

5-Year LRC (%)

2-Year Salvage Cystectome (%)

P value

Overall Survival (%)

0.03

sRT

no

no

rvRT

diff

diff

This study showed that in medically inoperable bladder cancer, (1) CRT using MMC-5FU is well tolerated and significantly improves local recurrence DFS compared with RT alone with good bladder function and no increase in late toxicity and (2) reducing dose to uninvolved bladder has minimal effect on either local control or toxicity.

PROSTATE CANCER Conservative Treatment Ref 8. Bill-Axelson et al. (2014). Radical prostatectomy or watchful waiting in early prostate cancer. N Eng J Med;370:932e942. In this study, 695 patients with localized prostate cancer were randomly assigned to watchful waiting versus radical prostatectomy. The results at median follow-up of 23.2 years showed the following: Death from (%)

All cumulative (%)

Prostate Cancer (%)

Death (%)

Watchful waiting

28.7

68.9

Prostatectomy

17.7

56.1

P value 0.006

0.001

<0.001

This study showed that extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy. Ref 9. Hamdy et al. (2016). 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Eng J Med;375(15):1415e24. PROTECT Trial. In this trial, 643 men between 50 and 69 years of age were randomized active monitoring, radical prostatectomy, and external beam radiotherapy for treatment of clinically localized prostate cancer. RT given 200 cGy/fx to 74 Gy. RT patients also received 3e6 months of neoadjuvant and concurrent ADT. At median follow-up of 10 years, the data showed the following: Incidence of Metastasis (%)

Prostate CancereSpecific Survival (%)

Observation

6.3

98.8

RP

2.4

99

RT þ ADT

3 ss

99.6 ss III. CLINICAL RADIATION ONCOLOGY

459

PROSTATE CANCER

This trial revealed that at 10 years, prostate cancerespecific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and RT were associated with lower incidences of disease progression and metastases than active monitoring. Ref 10. Wilt TJ et al. (2017). Follow-up of prostatectomy versus observation for early stage prostate cancer. N Eng J Med;377(2):132e42. PIVOT trial. In this trial, 731 patients with localized prostate cancer were randomized to observation or radical prostatectomy. At median follow-up of 12.7 years, the data showed the following: Death Due to Prostate Cancer (%)

Total Death

Observation

11.4

66.8

Surgery

7.4

61.3

P value

0.06

0.06

The trial showed after nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation.

Brachytherapy Ref 11. Kittel et al. (2015). Long-term efficacy and toxicity of low-dose-rate 125I prostate brachytherapy as monotherapy in low-, intermediate-, and high-risk prostate cancer. IJROBP;92(4):884e93. In this study, 1989 patients with low, intermediate, or high-risk prostate cancer were treated with prostate seed implant with 125I and followed on a prospective registry at a single institution. PSI dose was 144 Gy. Median follow-up was 5.8 years. 10-Year Outcomes (All Groups) (%) bRFS

81.5

DMFS

91.5

OS

76.1

PCSM

2.5

LDR monotherapy is an effective treatment even for select high or unfavorable intermediaterisk patients. Long-term toxicity rates were low. Ref 12. Hauswald et al. (2016). High-dose-rate monotherapy for localized prostate cancer: 10 year results. IJROBP;94(4):667e75.

III. CLINICAL RADIATION ONCOLOGY

460

19. GENITOURINARY CANCERS

In this study, 448 men with low, intermediate-risk prostate cancer treated with HDR monotherapy and a median dose of 43.5 Gy in six fractions. Median follow-up was 6.5 years. 10-year PSA PFS (progression-free survival) ¼ 97.8% 10-year OS ¼ 76.7% LC 99.7% DMFS 98.9% CSS 99.1% HDR monotherapy for low- and intermediate-risk prostate cancer is safe and effective. Ref 13. Morris WJ et al. (2017). Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and- intermediate-risk prostate cancer. Int J Radiat Oncol Biol;98(2):275e85. ASCENDE Trial. In this trial, 398 men had high-tier intermediate and high-risk prostate cancer were randomized to a standard arm with 12 months of androgen deprivation therapy (ADT), pelvic RT to 46 Gy, followed by a dose-escalated external beam RT (DE-EBRT) boost of 32 Gy, or an experimental arm of a low-dose brachytherapy (LDR-PB) boost of I-125 dose of 115 Gy. At median follow-up of 6.5 years the data showed the following: 9-Year bPFS (%)

9-Year IntermediateRisk bPFS (%)

9-Year HighRisk bPFS (%)

DE-EBRT

62

70

58

LDR-PB

83

94

78

P value

<0.001

<0.001

0.05

This study showed that compared with 78 Gy EBRT, men randomized to LDR-PB were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years. Ref 14. Ennis et al. (2018). Brachytherapy-based radiotherapy and radical prostatectomy are associated with similar survival in high-risk localized prostate cancer. JCO;36(12):1192e6. In this study, 42,765 prostate cancer patients with high risk, localized disease from National Cancer Data Base treated with radical prostatectomy, EBRT þ ADT or EBRT þ BT  ADT. At median follow-up of 36 months, the data showed the following: HR Compared With RP Unweighted EBRT þ ADT

1.95

EBRT þ BT  ADT

1.45

This study showed that high-risk prostate cancer patients treated with EBRT þ BT  ADT have similar survival to those treated with radical prostatectomy.

III. CLINICAL RADIATION ONCOLOGY

461

PROSTATE CANCER

Lymph Node Treatment Ref 15. Roach et al. (2013). Radiation therapy oncology group (RTOG) 9413: a randomized trial comparing whole pelvic radiation therapy (WPRT) to prostate only (PORT) and neoadjuvant hormonal therapy (NHT) to adjuvant hormonal therapy (AHT). Int J Radiat Oncol Biol October 1, 2013;87(2 supplement):S106e7. RTOG 9413 Trial. This is a phase III trial comparing whole pelvis RT followed by a cone-down boost to boost RT only and comparing neoadjuvant to adjuvant TAB. 1300 patients with any T stage, LN risk >15%, PSA <100, ineligible for 9408 randomized to four arms as NHT þ RT: small field RT dose 70.2 Gy versus NHT þ RT: large field, RT dose 50.4 þ 19.8 ¼ 70.2 Gy versus RT þ AHT: small field, 70.2 Gy versus RT þ AHT: large field, 50.4 þ 19.8 ¼ 70.2 Gy. PSA failure was defined as two consecutive rises or a PSA >4 at last follow-up after a nadir. At a median follow-up of 10 years, the results showed the following:

BF (%)

Progression-Free Survival (%)

Overall Survival (%)

NHT þ PORT

e

e

No

NHT þ WPRT

Improved

Improved

Diff

P value

0.01

0.03

Ns

The RTOG 9413 continues to demonstrate that NHT þ WPRT improve biochemical failure compared with NHT þ PORT. Ref 16. Pommier P et al. (2016). Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Update of the long-term survival results of the GETUG -01 randomized study. Int Radiat Oncol Biol;96(4):759e69. GETUG 01 Trial. In this trial, 446 patients with T1b-T3, N0pNx, M0 patients were randomized to prostateonly versus pelvic nodes þ prostate. Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for high-risk (T3 or gleason score <6, or PSAx3 upper normal limit of laboratory) patients. The total RT dose increased from 66 to 70 Gy during the course of the study. At median follow-up of 11.4 years, the data showed the following:

LR

Overall survival HR

All

NHT þ PORT

84

71.2

73.6

NHT þ WPRT

87.7

71

74.9

P value

0.79

0.56

0.53

The trial showed that pelvic nodes irradiation did not statistically improve event-free survival or OS in the whole population.

III. CLINICAL RADIATION ONCOLOGY

462

19. GENITOURINARY CANCERS

Dose Escalation With Higher Radiation Dose Treatment Ref 17. Pasalic et al. (2018). A Twenty-Y Update on the Outcome of a Randomized Dose-Escalation Trial for Prostate Cancer. IJROBP; vol 102. num 35. supp 2018, abs 61, S31. In this study, 301 patients with T1b-T3 prostate cancer randomized to EBRT with 70 Gy versus 78 Gy. RT given initially four fields to 46 Gy, then six fields conformal to boost dose, specified to isocenter. PSA failure defined as nadir þ2. At median follow-up was 14.3 years, the data showed the following: Grade >2 toxicity (%)

Freedom From Biochemical/ Clinical Failure (%)

DSF (%)

Overall Survival (%)

GI

GU

70 Gy

53.8

68.4

No

13

8

78 Gy

74.3

82.3

diff

26

13

P value

0.0018

0.074

n/a

ns

ns

This study confirmed that dose escalation improved freedom from biochemical failure and clinical progression, however, had no impact on OS. Although GI toxicity was higher in the high-dose arm, GU toxicity was less and no significant. Ref 18. Heemsbergen WD et al. (2014). Long-term results of the Dutch randomized prostate cancer trial: impact of dose-escalation on local, biochemical, clinical failure and survival. Radiother Oncol;110(1):104e9. Dutch Trial. In this study, 664 patients with T1b-T4N0 prostate cancer were randomized between 68 and 78 Gy. RT used was 3D-CRT. Hormonal treatment was permitted and was at the discretion of the treating physician. At median follow-up of 110 months, the data showed the following:

Biochemical Failure(%)

LF (%)

Prostate Cancer death

Overall Survival (%)

68 Gy

e

e

No

No

78 Gy

20% less

50% less

diff

diff

P value

<0.05

<0.05

ns

ns

The study observed significantly less biochemical failure and LF in the high-dose arm; however, similar rates of prostate cancer death and OS were observed in both arms. Ref 19. Dearnalaley DP et al. (2014). Escalated-dose versus control-dose conformal radiotherapy for prostate cancer:long-term results from MRC RT01 randomized controlled trail. Lancet Oncol;15(4):464e73. MRC Trial.

III. CLINICAL RADIATION ONCOLOGY

463

PROSTATE CANCER

In this trial, 843 patients with T1beT3a prostate cancer with PSA of less than 50 ng/mL were randomly assigned to 200 cGy/fx to 64 Gy versus 74 Gy. All patients received neoadjuvant ADT for 3e6 month before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. At median follow-up of 10 years, the data showed the following:

Biochemical Progression-Free Survival (%)

Overall Survival (%)

64 Gy

43

71

74 Gy

55

71

P value

0.0003

0.96

This study showed that escalated dose conformal RT with neoadjuvant ADT showed an advantage in biochemical PFS, but this advantage did not translate into an improvement on OS.

Hypofractionated Radiation Treatment Ref 20. Lee WR et al. (2014). Randomized phase III noninferiority study comparing two radiotherapy fractionated schedules in patients with low risk prostate cancer. J Clin Oncol;34(20):2325e32. RTOG 0415 Trial. In this trial, 1115 men with low-risk (T1b-2c, gleason score two to six, PSA <10) prostate cancer were randomized to C-RT (180 cGy/fx to 73.8 Gy) versus H-RT (250 cGy/fx to 70 Gy). At median follow-up of 5.8 years the data showed the following:

Biochemical Recurrence (%)

5-Year Disease-Free Survival (%)

5-Year Overall Survival (%)

Late GI Grade 2 e3 (%)

C-RT

8.1

85.3

93.2

13.8

H-RT

6.3

86.3

92.5

22.4

P value

<0.001

<0.001

0.008

0.0021

This study showed that men with low-risk prostate cancer, the efficacy of 70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions in 8.2 weeks, although an increase in late GI adverse events was observed in patients treated with H-RT. Ref 21. Dearnaley D et al. (2016). Conventional versus hypofractionated highdose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHip trial. Lancet Oncol;17(8):1047e60. CHHip Trial.

III. CLINICAL RADIATION ONCOLOGY

464

19. GENITOURINARY CANCERS

In this trial, 3216 men with localized prostate cancer (pT1b-T3aN0M0) were randomized to conventional (74 Gy given in 37 fractions) or one of two hypofractionated schedules (60 Gy in 20 fractions or 57 Gy in 19 fractions), all given with IMRT. Patients were given RT with 3e6 months of neoadjuvant and concurrent androgen suppression. At median follow-up of 62.4 months the data showed the following: Toxicity Grade >2

5-Year (%) bFS/cFS

Overall Survival (%)

GI

GU

74 Gy

88.3

no

13.7

9.1

60 Gy

90.6 (0.0018)

diff

11.9

11.7

57 Gy

85.9 (0.48)

no diff

11.3

6.6

This study showed that hypofractionated RT using 60 Gy in 20 fractions in noninferior to conventional fractionations using 74 Gy for localized prostate cancer. Ref 22. Catton C et al. (2017). Randomized trial of hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol June 2017; 35(17):1884e90. PROFIT Trial. In this trial, 1206 men with intermediate-risk prostate cancer (T1-2a, gleason score <6, and PSA 10.1e20 ng/mL, or T1-2, gleason score 7, and PSA <20 ng/mL), were randomized to 200 cGy/fx to 78 Gy versus 300 cGy/fx to 60 Gy. ADT was not permitted with therapy. At median follow-up of 6 years, the data showed the following:

Biochemical Disease-Free Survival (%)

Prostate Death

All (pt) Death

Late Toxicity (%) GI > gr3

GU > gr3

78 Gy

85

12

78

1.5

2.8

60 Gy

85ns

10ns

76

2.7ns

2

This trial showed that the hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Ref 23. Widmark et al. (2018). Ultrahypofractionation for prostate cancer: outcome from the Scandinavian phase 3 HYPO-RT-PC trial. Radiother Oncol April 2018;127(1):S-314; Abstract OC-0599 at ESTRO 37. In this study, 1200 men with intermediate-risk prostate cancer patients with tumor stages of T1c-T3a, prostate-specific antigen (PSA) levels of 20 or below, and one or two of three risk factors: stage T3a, a Gleason tumor score of seven or higher, or a PSA level greater than 10.

III. CLINICAL RADIATION ONCOLOGY

465

PROSTATE CANCER

Patients were randomized to one of two treatment arms: 200 cGy/fx to 78 Gy in 8 weeks versus 6.1 Gy/fx to 42.7 Gy in 2.5 weeks. ADT was not allowed among study participants. At median follow-up of 60 months the data showed the following:

Late Grade 2 (%)

5-Year FFS (%) Biochemical/Clinical

Urinary

Bowel

CF 78 Gy

83.8

3.5

2.3

UeHF42.7 Gy

83.7

2.5

1.2

P value

ns

0.75

0.69

The authors deemed that the UeHF regimen is noninferior to conventional fractionation.

Neoadjuvant and Adjuvant Hormonal Treatment Ref 24. Pisansky TM et al. (2015). Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trail 9910. J Clin Oncol;33(4):332e9. RTOG 9910 Trial. In this trial, 1579 men with intermediate-risk prostate cancer were randomly assigned 8 weeks of AS followed by RT with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). At median follow-up of 10 years, the data showed the following: 10-Year PSA Failure (%)

10-Year Disease-Free Survival (%)

10-Year Overall Survival (%)

8 weeks þ RT

27

95

66

28 weeks þ RT

27

96

67

P value

0.77

0.45

0.62

This study showed that extending AS from 8 to 28 weeks before RT did not improve outcomes in intermediate-risk group prostate cancer patients. Ref 25. Mason MD et al. (2015). Final report of the Intergroup randomized study of combined androgen-deprived therapy radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate cancer. J Clin Oncol;33(19):2143e50. Intergroup Trial. In this trial, 1205 patients with locally advanced prostate cancer (T3-4,N0/Nx, M0 or T1-2 with either PSA more than 40 ug/L or PSA of 20e40 ug/L plus gleason score of 8e10, were randomly assigned to lifelong ADT alone or to ADT þ RT. The RT dose was 64e69 Gy in

III. CLINICAL RADIATION ONCOLOGY

466

19. GENITOURINARY CANCERS

35e39 fractions to the prostate and pelvis or prostate alone. At a median follow-up of 8 years, the data showed the following: PSA (%) Progression-Free

Disease (%) Progression-Free

10-Year Overall Survival (%)

ADT

27

46

49

ADT þ RT

63

74

55

P value

ss

ss

0.001

The analysis of this study showed that benefit of survival is maintained at a median followup of 8 years and firmly establishes the role of RT in the treatment of locally advanced prostate cancer. Ref 26. Fossa SD et al. (2016). Ten and 15-year prostate cancer-specific mortality in patients with nonmetastatic locally advanced or aggressive intermediate prostate cancer, randomized to lifelong endocrine treatment alone or combined with radiotherapy: final results of Scandinavian Prostate Cancer Group-7. Eur Urol;70(4): 684e91. Scandinavian Trial. In this trial, 875 patients with high-risk or intermediate PCa were randomized to ET (endocrine treatment) or ET þ RAD. After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET þ RAD started prostate radiotherapy (70 Gy) at 3 mo. At median survival of 12 years, the data showed the following:

15-Year PCa-Specific Mortality Rate (%) ET

34

ET þ RAD

17

P value

<0.001

The study analysis showed that adding radiation therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer. Ref 27. Dubray et al. (2016). Does short-term androgen depletion add to high dose radiotherapy (80 Gy) in localized intermediate risk prostate cancer? Final analysis of GETUG 14 randomized trial (EU-20503/NCT00104741). J Clin Oncol May 2016;34(15_suppl):5021. In this study, 377 patients with intermediate-risk localized prostate adenocarcinoma patients randomly assigned to high-dose conformal radiotherapy (prostate 80 Gy/40 fractions; seminal vesicles 46 Gy/23 fractions) either alone (group RT) or in combination with 4-month androgen

III. CLINICAL RADIATION ONCOLOGY

467

PROSTATE CANCER

deprivation (flutamide þ triptorelin starting 2 months before radiotherapy, group AD-RT). At median follow-up of 84 months, the data showed the following:

Biochemical-Free Survival (%)

Overall Survival (%)

RT

76

94

ADT þ RT

84

93

P value

0.02

0.54

This study revealed that 4 months of androgen blockade improves event-free survival at 5 years in pts with intermediate-risk prostate adenocarcinoma when treated with high dose radiotherapy. Ref 28. Lawton AF et al. (2017). Duration of androgen deprivation in locally advanced prostate cancer: Long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol 98(2):296e303. RTOG 9202 Trial. In this study, 1500 patients with LAPC T2c-T4 with PSA <150 ng/mL were randomized. All patients received flutamide and Zoladex
2 months before and
2 months during RT and were randomized to no further therapy (STAD) or 2 years of additional Zoladex (LTAD). A radiation dose of 65e70 Gy was given to the prostate and a dose of 44e50 Gy to the pelvic LNs. At median follow-up of 19.6 years the results showed the following:

Local (RR%) Progression

Distant (RR%) Metastases

Disease-Free Survival (%)

Overall Survival (%)

STAD

e

e

e

e

LTAD

46 reduced

36 reduced

29 improved, 12 improved

P value

0.02

<0.0001

<0.0001

0.03

This study showed that LTAD and RT are superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care. RRdrelative reduction.

Hormonal Treatment and Chemotherapy Ref 29. Sandler HM et al. (2015). A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). J Clin Oncol;33(18), suppl-published online. RTOG 0521 Trial.

III. CLINICAL RADIATION ONCOLOGY

468

19. GENITOURINARY CANCERS

In this trial, 612 patients with high risk prostate cancer (1) gl seven to eight, any T stage, PSA >20 or (2) gl 8, >2 T, any PSA, or (3) gl 9e10, any T stage, any PSA (all had PSA <150). RT dose 75.6 Gy. CT consisted of 6, 21-day cycle of docetaxel þ prednisone starting 28 days after RT. At median follow-up of 5.5 years, the data showed the following:

5-Year Disease-Free Survival (%)

4-Year Overall Survival (%)

AS þ RT

66

89

AS þ RT þ CT

73

93

P value

0.05

0.03

This study analysis showed that for high risk, localized PCa, adjuvant CT improved OS at 4 years. Toxicity was acceptable. Ref 30. James ND et al. (2016). Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet;387(10024):1163e77. STAMPEDE Trial. In this trial 2962 patients with high risk, locally advanced, metastatic or recurrent prostate cancer were randomized hormone therapy for at least 2 years þ RT (SOC) versus SOC þ ZA versus SOC þ Doc versus SOC þ ZA þ Doc. Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisone 10 mg daily. At median follow-up of 43 months, the data showed the following: Median Overall Survival (Months) SOC

71

SOC þ ZA

Not reached

SOC þ Doc

81ss

SOC þ ZA þ Doc

76ss

The analysis of this trial showed that adding Zoledronic acid no evidence of survival improvement and should not be part of standard care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival. Docetaxel should be part of standard of care for adequately fit men commencing longterm hormone therapy. Ref 31. James ND et al. (2017). Abiraterone for prostate cancer not previously treated with hormone therapy. N Eng J Med 2017;377:338e51. STAMPEDE Trial.

III. CLINICAL RADIATION ONCOLOGY

469

PROSTATE CANCER

In this trial, 1917 patients with high risk locally advanced or metastatic prostate cancer patients, hormone naïve, were randomized to ADT alone or ADT þ abiraterone acetate (1000 mg daily) and prednisone (5 mg daily). Local RT was mandatory for node negative, nonmetastatic disease and encouraged for those with positive nodes. Treatment continued for 2 years or until any type of progression. At median follow-up of 40 months, the data showed the following: 3-Year Overall Survival (%)

Toxicity Grade 3, 4

ADT

76

33

ADT þ Abiraterone

83

47

This study concluded that among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisone was associated with higher rates of OS than ADT alone.

Postoperative Radiation Treatment Postoperative Radiation Treatment and Hormone Therapy Ref 32 Bolla M et al. (2012). Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomized controlled trial (EORTC trial 22911). Lancet;380(9858):2018e27. EORTC 22911 Trial. In this study, 1005 patients with prostate cancer, s/p prostatectomy with pN0 M0 tumors and one or more pathological risk factorsdcapsule perforation, positive surgical margins, invasion of seminal vesiclesdwere randomized to wait-and-see policy versus immediate postoperative radiotherapy (60 Gy conventional irradiation delivered over 6 weeks). At median follow-up of 10.6 years, the results showed the following:

Biochemical Progression-Free Survival (%)

Late Adverse Effects (%)

Surgery alone

39.4

59.7

Surgery þ post-op RT

61.8

70.8

P value

<0.000

0.001

The study analysis shows that conventional postoperative irradiation significantly improves biochemical PFS and local control compared with a wait and see policy. Ref 33. Wiegel T et al. (2014). Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol;66(2):243e50. ARO/AUO Trial.

III. CLINICAL RADIATION ONCOLOGY

470

19. GENITOURINARY CANCERS

In this trial, 388 patients after RP, with pT3pN0 prostate cancer were randomized to WS (wait and see) or three-dimensional conformal ART with 60 Gy. At median follow-up of 113 months the data showed the following:

10-Year Progression-Free Survival (%)

Mets-Free (%) Survival

Overall Survival (%)

WS

35

No

No

ART

56

Diff

Diff

P value

<0.0001

The analysis showed that compared with WS, ART reduced the risk of PFS in pT3 PCa. Ref 34. Tendulkar et al. (2016). Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. JCO; 34(30):3648e54. In this study, 2460 patients node-negative patients with a detectable post-RP prostatespecific antigen (PSA) treated with Salvage RT with or without concurrent ADT were obtained from 10 academic institutions. At median follow-up of 5 years, the data showed the following:

PreRT PSA

5-Year FFBF (%)

All patients

56

0.01e0.2

71

0.21e0.5

63

0.51e1

54

1.01e2

43

>2

37

The authors conclude that early salvage radiation with a low preradiation PSA was associated with improved FFBF, DM. On MVA, pre-RT PSA, Gleason score, ECE, SVI, margin status, ADT, and dose were associated with FFBF. Ref 35. Carrie C et al. (2016). Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomized, multicenter, open-label phase 3 trial. Lancet Oncol;17(6):747e56. GETUG Trial. In this trial, 743 patients who underwent radical prostatectomy, who has stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0.2 to less than two ug/ L after prostatectomy were randomly assigned RT of 200 cGy/fx to 66 Gy or RT þ short-term

III. CLINICAL RADIATION ONCOLOGY

471

PROSTATE CANCER

androgen suppression using 10.8 mg goserelin by SC injection on the first day of irradiation and 3 months later. The data showed the following:

5-Year Progression-Free Survival RT

62

RT þ ADT

80

P value

<0.0001

The study showed that adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Ref 36. Shipley WU et al. (2017). Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med;376(5):417. RTOG 9601 Trial. In this trial, 760 patients who has undergone prostatectomy with a lymphadenectomy, with a tumor stage of T2 (confined to prostate but with a positive surgical margin) or T3 (histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2e4 ng/mL to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after RT. At median follow-up of 13 years the data showed the following: Metastatic (%) Prostate Cancer

Overall Survival (%)

Post-op RT

23

71.3

Post-op RT þ antiandrogen

14.5

76.3

P value

0.005

0.04

The study showed that addition of 24 months of antiandrogen therapy with daily bicalutimide to salvage RT resulted in significantly higher rates of long-term OS and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. Ref 37. Pollak et al (2018). Short Term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial. Presented at ASTRO 60th Annual Meeting, San Antonio, TX, October 2018. RTOG 0534 Trial. In this study 1,792 men who had persistently detectable or rising PSA levels were randomly placed into three treatment groups: prostate bed radiation therapy (PBRT) alone, PBRT plus short-term androgen deprivation (hormone) therapy (STAD), and PBRT plus pelvic lymph node radiotherapy (PLNRT) plus STAD. Hormone therapy consisted of four-to-six months of

III. CLINICAL RADIATION ONCOLOGY

472

19. GENITOURINARY CANCERS

androgen deprivation. The RT dose was 45 Gy to the PLNRT and 64.8e70.2 Gy to the PBRT. The data at 5 years showed that

FFP (%)

Distant mets (pts)

OS (%)

PBRT

71

45

no

PBRTþSTAD

81

38

statistical

PBRTþSTADþPLNRT

87

25

difference

p value

<0.0001

0.014

-

This study reveled that PLNRTþ PBRTþSTAD superior to PBRT alone; PBRTþSTAD superior to PBRT alone; PLNRTþPBRTþSTAD superior to PBRTþSTAD for prostate cancer patients in salvage RT.

TESTICULAR CANCER Ref 38. Jones et al. (2005). Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol;23(6):1200e8. In this study 625 patients with stage I seminoma were randomly assigned 20 Gy/10 fx over 2 weeks or 30 Gy/15 fx during 3 weeks after orchidectomy. RT given was PA field with dogleg field for prior inguinal surgery. The results at 5 years showed the following: Relapse-Free Survival (%)

Moderate/Severe Lethargy (%)

30 Gy

97

20

20 Gy

96.4 ns

5

The study showed that treatment with 20 Gy in 10 fractions is unlikely to produce relapse rates more than 3% higher than for standard 30-Gy radiation therapy, and reductions in morbidity enable patients to return to work more rapidly. Ref 39. Oliver RT et al. (2011). Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30,982 study (ISRCTN27163214). J clin Oncol; 29(8):957e62. EORTC 30,981. In this trial, 1447 patients with stage I seminoma postsurgery randomly assigned between RT and one infusion of carboplatin dosed at seven
(glomerular filtration rateþ25) on the basis of EDTA and 90% of this dose if determined on the basis of creatinine clearance. RT was given to PA field to a dose between 20 and 30 Gy. At a median follow-up of 6.5 years, the data showed the following:

III. CLINICAL RADIATION ONCOLOGY

473

TESTICULAR CANCER

RFR (%)

Contralat (%) GCT-Free

RT

96

99.8

Carboplatin

94.7

98.8

P value

0.36

0.03

This trial confirmed the noninferiority of single-dose carboplatin (at 7xAUC dose) versus RT in terms of RFR and establishes a statistically significant reduction in the medium-term risk of second GCT produced by treatment.

III. CLINICAL RADIATION ONCOLOGY