29 Testicular Cancer Maria Pearse

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29 Testicular Cancer

Maria Pearse and Gerard C. Morton

M. Pearse, MD, MB, ChB, FRANZCR

Division of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada

G. C. Morton, MD, MRCPI, FRCPC

Assistant Professor, Division of Radiation Oncology, Toronto- Sunnybrook Regional Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada

29.1

Introduction

The majority of testicular tumors occur in young men with a peak incidence at 30 years of age.

Although testicular tumors are uncommon, the incidence is increasing (Thompson et al. 1999; Stone et al. 1991; Power et al. 2001; Dos et al. 1999), with most cases occurring in white males (Daniels et al.

1981). While nonseminomatous germ cell tumors (NSGCTs) are primarily treated with surgery and systemic chemotherapy, radiation treatment con- tinues to have a major role in the management of seminoma.

Over 95% of testicular malignancies are germ cell tumors. These are separated into two histological subgroups – seminoma and non-seminoma.

NSGCTs include teratoma, embryonal carcinoma, endodermal (yolk sac) tumors, choriocarcinoma and mixed tumors.

There is increasing evidence that intratubular germ cell neoplasia (IGCN) is a precursor of all types of germ cell tumors except spermatocytic seminoma and infantile testicular cancer. In patients with invasive germ cell tumors, IGCN is identified adjacent to the invasive component in 90–99% of cases (Coffin et al. 1985; Dieckmann and Skakkebaek 1999; Jacobsen et al. 1981), and approximately 5%

of patients with unilateral germ cell neoplasms have IGCN in the contralateral testicle (Dieckmann and Loy 1996).

With the advent of effective cisplatin chemotherapy, the role of radiotherapy in NSGCTs has dramatically diminished. Radiotherapy still plays an important role in the treatment of stage I and II seminoma, IGCN and residual disease following chemotherapy. Radiotherapy is also utilized in the palliation of distant metastases.

CONTENTS

29.1 Introduction 739

29.2 Anatomy and Natural History 740 29.2.1 Anatomy 740

29.2.2 Natural History 740

29.3 Seminoma: General Management 740 29.3.1 Staging 741

29.3.1.1 Stage I Seminoma 741 29.3.1.2 Stage II Seminoma 742 29.4 Radiotherapy Treatment 742 29.4.1 Target Volume and Field Borders 742 29.4.2 Simulation and Beam Arrangement 743 29.4.3 Dose and Fractionation 745

29.4.3.1 Stage I Seminoma 745 29.4.3.2 Stage II Seminoma 745 29.4.4 Organs at Risk 745 29.4.5 Treatment Delivery 746 29.4.5.1 Testicular Shielding 746 29.4.5.2 Treatment verification 746

29.5 Intratubular Germ Cell Neoplasia 746 29.6 Special Considerations 747

29.6.1 Scrotal Invasion/Scrotal Interference 747 29.6.2 Contralateral Germ Cell Tumors 747 29.6.3 Management of a Residual Mass Following Chemotherapy 748

29.6.4 Prophylactic Contralateral Pelvic Lymph Node Irradiation 748

29.7 Treatment Sequelae 748 29.7.1 Acute Side Effects 748 29.7.2 Late Side Effects 749

29.7.3 Impaired Spermatogenesis 749 29.7.4 Second Malignant Neoplasms 749 References 750

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29.2

Anatomy and Natural History

29.2.1 Anatomy

Evaluation of lymphangiograms, surgical series of retroperitoneal lymph node dissections and anatomical studies in cadavers have provided valuable information on the lymphatic drainage of the testis (Ray et al. 1974). In the developing embryo, the testes originate from the genital ridge located near the second lumbar vertebra. Accompanied by their blood supply and lymphatics, they descend into the scrotum via the inguinal canal. As a result, the primary lymphatic drainage from the testis is to the retroperitoneal lymph nodes. The lymphatic vessels first drain into the collecting trunks at the hilum of the testicle. These lymphatic trunks accompany the testicular artery, vein and spermatic cord to the internal ring, and then continue proximally to the retroperitoneal lymph nodes. The retroperitoneal lymph nodes are situated anterior to the T11 to L4 vertebral bodies, although are concentrated at the L1–L3 level. On the left, the lymphatics drain primarily into the pre-aortic and para-aortic lymph nodes around the left renal hilum and thence to the inter-aortocaval nodes. On the right, the first echelon of nodes is in the inter-aortocaval region, followed by the pre-aortic and para-aortic lymph nodes. Early lymphographic studies demonstrated rapid crossover from right to left as well as from left to right. Clinically, however, contralateral spread is mainly seen with right-sided tumors and rarely with left-sided.

From the retroperitoneal nodes, the lymph drains into the cisterna chyli, thoracic duct, posterior mediastinum and the left supraclavicular fossa. The thoracic duct drains into the left subclavian vein in the left supraclavicular region. In 5–10% of patients, drainage into the right supraclavicular area can occur.

Aberrant lymphatic drainage may occur. Her- niorrhaphy alters the drainage of the testicle. The testicular lymphatic vessels anastomose with the regional lymph vessels resulting in drainage into the ipsilateral inguinal and iliac lymph nodes (Perez et al. 2005). In addition, the testicular trunks may abandon the spermatic vessels at the internal inguinal ring and pass posteriorly and superiorly into the external iliac lymph nodes. The scrotum drains directly into the inguinal and external iliac lymph nodes.

29.2.2

Natural History

In the majority of patients, pathological examination of the radical orchidectomy specimen reveals the tumor confined to the testis. Occasionally, in advanced disease invasion of the epididymis, rete testis or spermatic cord can occur. Rarely, the tumor extends through the tunica albuginea to involve the scrotum.

Seminoma has an orderly and predictable pat- tern of spread. Locoregional lymphatics are the first site of metastatic disease. From the retroperitoneal lymph nodes, seminoma spreads proximally to involve the next echelon, the mediastinal lymph nodes, and then the supraclavicular lymph nodes.

Very occasionally, metastases from retroperitoneal lymph nodes can drain directly via the thoracic duct to the supraclavicular fossa, resulting in supraclavicular metastases in the absence of mediastinal disease.

Hematogenous metastases are rare in pure seminoma, being much more common with NSGCT.

Lung is the most common site of distant disease, although bone, liver and brain may also be involved.

29.3

Seminoma: General Management

If the clinical and radiological features are consis- tent with a testicular tumor, a radical orchidectomy is performed. Via an inguinal incision, the testicle and spermatic cord are removed en bloc with high ligation of the spermatic cord at the deep inguinal ring. An inguinal approach is used to minimize the risk of aberrant lymphatic spread and local contami- nation. A transscrotal approach risks development of alternative lymphatic drainage to the inguinal and pelvic lymph nodes. In addition, the spermatic cord remains in place from the external to the internal inguinal ring.

Laboratory investigations include a complete blood count, renal and liver function tests and serum tumor markers including alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH). To assess the extent of metastatic disease, a chest X-ray and computed tomography (CT) scan of the abdomen and pelvis are obtained.Of patients diagnosed with seminoma, 80% have stage I disease at presentation.

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29.3.1 Staging

A number of staging systems for testicular cancer are used. The commonly used American Joint Committee on Cancer (AJCC) 2002 classification is outlined in Table 29.1. This staging system incorporates the features of the primary tumor (T), nodes (N), metastases (M) and level of serum tumor marker (S). The nodal staging is based on the greatest dimension of the largest involved lymph node and does not take into account the total bulk of lymphadenopathy, a well-recognized prognostic factor.

29.3.1.1

Stage I Seminoma

Following orchidectomy alone, relapse occurs in 12–20% of patients with stage I seminoma. The majority of these relapses occur in the para-aortic lymph nodes (Horwich et al. 1992a; Maier et al.

1968; Miki et al. 1998; von der Masse et al. 1993;

Warde et al. 1993). Management approaches include adjuvant radiotherapy and surveillance. Although adjuvant chemotherapy is not considered standard treatment for stage I seminoma, single agent carboplatin chemotherapy is presently under investiga- tion.

Table 29.1. American Joint Committee on Cancer (AJCC) (2002) Staging for Testicular Neoplasms Primary Tumor (T) (pathological classification)

Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor (e.g., histological scar in testis) Tis Intratubular germ cell neoplasia (carcinoma in situ)

pT1 Tumor limited to testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albu- ginea but not the tunica vaginalis

pT2 Tumor limited to testis and epididymis with vascular/lymphatic invasion or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

pT3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion pT4 Tumor invades scrotum with or without vascular/lymphatic invasion

Lymph Node (N)

N0 No regional node metastasis

N1 Metastasis within a lymph node mass 2 cm or less in greatest dimension; or multiple nodes no more than 2 cm in greatest dimension

N2 Metastasis within a lymph node mass that is >2 cm but not more than 5 cm in greatest dimension or multiple lymph nodes 2–5 cm, any one mass greater than 2 cm but not more than 5 cm in greatest dimension

N3 Metastasis within a lymph node mass that is more than 5 cm in maximum diameter Distant Metastasis (M)

M0 No distant metastasis

M1a Non-regional lymph node or pulmonary metastasis M1b Non-pulmonary visceral metastasis

Serum Tumor Markers (S)

Sx Serum tumor markers not performed S0 Serum tumor markers within normal limits S1 LDH <1.5xN and HCG <5,000 and AFP <1,000

S2 LDH 1.5–10xN or HCG 5,000–50,000 or AFP 1,000–10,000 S3 LDH >10xN or HCG >50,000 or AFP >10,000

Staging Groupings

From the TNM system, patients are grouped into either stage 1, 2 or 3 IA T1 N0 M0 S0

IB T2–4 N0 M0 S0 IS Any T N0 M0 S1–3 IIA Any T N1 M0 S0/1 IIB Any T N2 M0 S0/1 IIC Any T N3 M0 S0/1 IIIA Any T, any N M1a S0/1 IIIB Any T, any N M1a S2 IIIC Any T, any N M1b or S3

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The standard post-operative management of patients with stage I seminoma has been adjuvant radiotherapy to the para-aortic and ipsilateral pelvic lymph nodes (the “dog-leg” or “hockey stick”

radiation field). In view of the exquisite radiosen- sitivity of seminoma, this treatment results in an excellent recurrence-free survival of 97% and a disease-specific survival greater than 99% (Perez et al. 2005). Several retrospective reviews have reported similar disease-free and overall survival (OS) in patients with stage I seminoma treated with para-aortic radiotherapy alone (Kiricuta et al. 1996; Melchior et al. 2001; Santoni et al.

2003; Sultanem et al. 1998; Taylor et al. 2001;

Read and Johnston 1993). The Medical Research Council performed a randomized controlled trial comparing dog-leg and para-aortic irradiation in stage I seminoma (Fossa et al. 1999). At a median follow-up of 4.5 years, there was no difference in the 3-year relapse-free survival (RFS) or OS. Less than 2% of patients in the para-aortic alone arm relapsed in the pelvis. Radiotherapy was better tolerated in the para-aortic alone arm with a reduction in the severity and frequency of acute gastrointestinal and hematological toxicity. The post-treatment peptic ulcer rate was similar in both arms, but sperm counts within the first 18 months were significantly higher in the para-aortic alone arm. Reducing the clinical target volume (CTV) to include the para-aortic lymph nodes alone is an option for many patients.

Prior to radiotherapy, sperm analysis and sperm banking may be carried out in patients who wish to preserve fertility.

29.3.1.2

Stage II Seminoma

Only 10–20% of patients are diagnosed with stage II disease, mostly of small volume.

Patients with stage IIA and IIB disease treated with radiotherapy alone have an excellent disease- free survival (88–93%) and OS (95–100%) (Bauman et al. 1998b; Chung et al. 2004; Classen et al. 2003b;

Schmidberger et al. 1997; Warde et al. 1998). How- ever, following radiotherapy alone, the relapse rate ranges between 20% and 50% in patients with stage IIC disease (Warde et al. 1998) and between 33%

and 100% in patients with retroperitoneal adenopa- thy greater than 10 cm (Anscher et al. 1992; Ball et al. 1982; Speer et al. 1995; Thomas 1997; Warde et al. 1998).

Although radiotherapy provides adequate local control for patients with bulky stage II disease, the risk of distant relapse is high. Primary chemotherapy is therefore the treatment of choice providing excellent local control and treating possible distant micrometastases. In addition, radiotherapy in bulky stage II disease may be technically difficult, particularly if nodal disease covers a significant portion of the kidney.

29.4

Radiotherapy Treatment

29.4.1

Target Volume and Field Borders

For stage I disease, the CTV consists of the inter-aortocaval, pre-aortic and para-aortic nodes. The left renal hilar nodes are included for left-sided tumors.

The ipsilateral external iliac and common iliac nodes may also be included, particularly if there is concern about aberrant drainage. Inclusion of the inguinal scar, inguinal lymph nodes or hemiscrotum is not warranted in the routine treatment of stage I disease. For stage II disease, a gross tumor volume is identified from diagnostic imaging, and the CTV also includes the ipsilateral pelvic nodes.

The planning target volume (PTV) includes the CTV plus a margin to account for positional and set-up uncertainties. To cover the known location of the retroperitoneal and iliac lymph nodes with an appropriate margin, standard anatomical field borders have been used. This is commonly referred to as the “dog-leg” or “hockey stick” field. The superior border is placed between the T9 and T10 vertebral bodies, with the inferior border at the top of the obturator foramen. The field is approximately 10–12 cm wide and usually covers the transverse processes (Fig. 29.1). On the left, the lateral border is extended to include the left renal hilum and customized shielding is positioned to reduce the amount of kidney irradiated (Fig. 29.2). At the mid L4 level the field is extended laterally to cover the ipsilateral external iliac nodes. Shielding is placed forming the “dog-leg” configuration. Multi- leaf collimators now largely replace lead blocks to define the field shape.

Once these borders are placed, the planning CT can be used to ensure adequate coverage of the target. Distance from the PTV to the field border is 8–15 mm depending on field size, energy, separa-

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Fig. 29.1a,b. Radiotherapy fi eld – stage I seminoma, right-sided tumor. The fi eld includes the para-aortic and right pelvic lymph nodes (“dog-leg” fi eld). a The superior border placed at the T9/T10 interspace, lateral borders at the edge of the transverse processes and inferior border above the obturator foramen. b A soft tissue image showing the location of the vessels within the radiotherapy fi eld

a b

tion and shielding. Originally, separate para-aortic and iliac fields were used to encompass this large volume and were matched at the L5/S1 junction. As the iliac nodes are anterior to the para-aortic nodes, this technique allowed differential weighting of the fields. A “dog-leg” field has the advantage of avoid-

ing a field junction between the iliac and para-aortic nodes.

If retroperitoneal nodes alone are to be treated, the superior and lateral borders are as described above, although some use a lower superior border, e.g., T10/11. The inferior border is placed at the L5/

S1 disc space (Fig. 29.3).

In stage II disease, the PTV includes the CTV plus an appropriate margin. A modified “dog-leg” field covers the macroscopic retroperitoneal nodal disease and optionally the contralateral common iliac nodes if there is low-lying retroperitoneal adenopa- thy (Fig. 29.4). Organs at risk, including the kidney and liver, can be identified. Shielding is customized to allow adequate coverage of disease, while reducing the dose to normal tissues. If the retroperitoneal lymphadenopathy is greater than 4 cm in size, a two-phase technique is used. The first phase encom- passes the PTV as described above. A second phase includes the gross disease with a tight margin.

29.4.2

Simulation and Beam Arrangement

The patient is simulated in the supine position with arms at his sides. This simple position is comfort- able. Testicular shielding (often in the form of a clam-shell device) is used. Foot stocks and knee

Fig. 29.2. Radiotherapy ﬁ eld – stage I seminoma, left-sided tumor. The ﬁ eld is extended to include the left renal hilar lymph nodes

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taken from the seventh thoracic vertebra to 2 cm below the ischial tuberosities. Utilization of a CT- based planning technique enables visualization of the location of the lymph node regions, adjacent tissues and critical normal structures including the kidneys and liver. In addition, the beams eye view (BEV) allows evaluation of the coverage of the PTV, and shielding can be appropriately placed. If a planning CT is not available, an intravenous urogram is performed to identify the position of the kidneys.

Tattoos are placed at the center, superior and inferior borders of the field. A lateral tattoo is also placed at mid-plane. The interplanar distance is measured at the central tattoo using a sliding rod if a planning CT is not available.

Treatment is delivered with a linear accelerator using an anterior and posterior parallel opposed pair. The beams are equally weighted. Both fields are treated daily, 5 days per week. Depending on the separation, 6- to 18-MV photons are utilized. If the separation is greater than 24 cm, an energy of greater than 6 MV provides less dose inhomogeneity. The patient is treated with either an isocentric, source axis distance (SAD) technique or, alterna- tively, a standard source skin distance (SSD) technique. In most patients, standard SSD is adequate, although if the field is longer than 40 cm, the patient is treated with extended SSD. With extended SSD, the patient may need to change position between fields. If extended SSD is employed, the width of the

Fig. 29.3a,b. Para-aortic nodes alone. a The superior border is placed either at the T10/T11 interspace (although some use T9/

T10), with the inferior border at the L5/S1 interspace. The lateral borders are at the edge of the transverse processes. The left renal hilum is included for left-sided tumors. b A soft tissue image showing the location of the vessels within the radiation ﬁ eld

a b

Fig. 29.4. Radiotherapy ﬁ eld – stage II seminoma. The ﬁ eld is extended to cover the para-aortic nodal disease and often the contralateral proximal external iliac lymph nodes

or ankle restraints may be used to immobilize the patient and decrease external movement. A volu- metric planning CT scan is acquired with the patient in this position. Contiguous 5-mm CT slices are

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penumbra is increased, and this must be taken into account when selecting the field borders.

Rarely dose inhomogeneity due to contour obliq- uity occurs and a compensator is placed in the beam. For a 10-MV beam at 100 cm SSD, a difference in separation of 7 cm results in a variation in dose of approximately 10%. A compensator or wedge is recommended if there is a variation in dose of 10%

or greater.

For stage II disease, a parallel opposed anterior and posterior pair is used. However, depending on the location of the mass and the position of organs at risk relative to the mass, a CT planned technique with oblique fields may result in a reduced dose to normal structures.

29.4.3

Dose and Fractionation

29.4.3.1

Stage I Seminoma

Radiation doses between 25 Gy and 40 Gy at 1.25–

2.0 Gy per fraction have been most commonly used in the past. A 1986 consensus statement recommended an adjuvant dose of 25 Gy in 20 fractions (Thomas 1986), which still remains the standard.

More recently, several authors have reported similar RFS, OS and infield failure rates with lower doses (Giacchetti et al. 1993; Gurkaynak et al. 2003;

Logue et al. 2003; Niewald et al. 1995). The U.K.

Medical Research Council (MRC TE18) completed a randomized controlled trial of 30 Gy in 15 fractions

over 3 weeks or 20 Gy in 10 fractions over 2 weeks.

RFS was similar in both groups. Acutely, there was significantly more moderate or severe lethargy and inability to carry out normal work in the group that received 30 Gy. However, by 12 weeks, there were no differences between the two groups (Jones et al.

2001).

Radiation dose is generally prescribed to a point in the mid-line, and ideally a homogeneous dose distribution is obtained with a variation in the coverage of the PTV of –5% and +7% (Fig. 29.5).

29.4.3.2

Stage II Seminoma

1. Retroperitoneal lymphadenopathy less than 4 cm.

25 Gy in 20 fractions is delivered over 4 weeks.

2. Retroperitoneal lymphadenopathy greater than 4 cm.

– Phase I – 25 Gy in 20 fractions is delivered over 4 weeks.

– Phase II – 10 Gy in 5–8 fractions is delivered to the residual mass.

29.4.4

Organs at Risk

Table 29.2 shows the organs in the treatment field and their tolerance doses (TDs) (Emami et al. 1991) for treatment delivered at 1.8–2 Gy per fraction. The dose resulting in a 5% risk of nephritis at 5 years is 23 Gy (TD 5/5=23 Gy, whole kidney) or 27 Gy at 1.25 Gy per fraction.

It is also necessary to minimize the radiation dose to the remaining testis. In these relatively young men, fertility and hormonal function are important. For the endpoint of infertility, the TD5/5 for the testis at standard fractionation is around 1 Gy.

Fig. 29.5. Stage I seminoma. Axial computed tomography (CT) slice at the level of the kidneys showing the isodose distribution (parallel opposed ﬁ elds). The 95% isodose curve covers the CTV

Table 29.2 Tolerance doses TD 5/5 Volume

Organ 1/3 2/3 3/3 Endpoint Kidney 50 30 23 Clinical nephritis Liver 50 35 30 Liver failure

Small bowel 50 40 Obstruction/perforation/fistula Stomach 60 55 50 Ulceration/perforation Heart 60 45 40 Pericarditis

Bladder 80 65 Symptomatic bladder contrac- ture and volume loss From Emami et al. (1991)

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29.4.5

Treatment Delivery

29.4.5.1

Testicular Shielding

During a fractionated course of radiotherapy to the retroperitoneal and ipsilateral iliac lymph nodes, the dose to the remaining testis ranges between 0.3 Gy and 1.5 Gy. A variety of factors contribute to this dose. A component is from leakage from the head.

External scatter is generated from the collimator, field-shaping blocks and air. A significant proportion of the scattered dose is produced internally within the patient. A number of effective shielding devices have been described (Bieri et al. 1999; Fraass et al.

1985; Kubo and Shipley 1982). Most departments use simple forms of gonadal shielding such as the clam-shell device. The testis is placed in the 1-cm thick lead gonadal cups. This technique reduces the amount of internal scatter to the remaining testis to approximately 1% of the mid-plane dose. Shielding devices are available that shield both the penis and testis, although shielding the penis does not impact on the gonadal dose. In addition, these shielding devices are large, more cumbersome and less con- venient when compared with the clam-shell device.

Bieri et al. (1999) reported a greater than 50%

reduction in testicular dose with gonadal shielding, and Gordon et al. (1997) noted the testicular dose was 5.1% of the target dose for patients with no or pipe cap type shields and 1.6% for patients with clam-shell type shields.

In addition to shielding, distance from the field is an important factor. Jacobsen et al. (1997) report a significant correlation between the symphysis-to- testicle distance and gonadal dose. The authors sug- gest the ideal placement of the testicle is at 30 degrees rotation from the patient’s long axis. This allows the testicle to lie in the scrotum as distally as possible from the field edge.

29.4.5.2

Treatment verification

An electronic portal image or port film is obtained on day 1 and optionally at weekly intervals to verify the field placement. This is compared with the simulation film or digitally reconstructed radiograph, which is important to verify the geo- metric set-up. The patient is reviewed weekly to assess toxicity.

29.5

Intratubular Germ Cell Neoplasia

Untreated, 50% of patients with IGCN will progress to invasive disease at 5 years (von der Masse et al. 1986b) and 70% at 7 years (Classen et al. 1998).

In view of this, treatment is usually recommended.

Both orchidectomy and radiotherapy yield excellent local control rates (Dieckmann et al. 1993;

Dieckmann and Loy 1994; von der Masse et al.

1986a), and it is often the clinical situation that dictates which approach is employed. Unilateral disease is treated with orchidectomy. In the situation of bilateral disease or in patients with IGCN in a solitary testis, an organ preservation approach using radiotherapy is the preferred option. Initial reports using chemotherapy were promising (von der Masse et al. 1985). However, recently several authors have reported the persistence or recurrence of IGCN in patients treated with primary chemotherapy (Christensen et al. 1998; Dieckmann 1988; von der Masse et al. 1988). Residual germ cell cancer is often found in orchidectomy speci- mens after cisplatin-based chemotherapy (Greist et al. 1984).

Intratubular germ cell neoplasm is a radiosensitive tumor. The aim of treatment is to eradicate the IGCN while preserving hormone function. The CTV is the whole testis.

At simulation, the patient is supine, with the thighs abducted and soles together (this is commonly referred to as the “frog-leg” position). A lead shield is placed posteriorly to shield the perineum and immobilize the testis. The penis is taped out of the field, usually over the symphysis pubis.

The optimal radiotherapy technique to treat the testis is not defined. A number of different modali- ties have been employed. Due to the position of the testis and scrotum, a direct anterior field is preferred.

Although parallel opposed beams provide a more homogeneous dose distribution, in this setting, the addition of a posterior beam would irradiate a large area of perineum resulting in extra toxicity.

Historically, a direct orthovoltage beam was commonly used to treat the testis. Although this provided a simple technique, there were several disadvantages. For a standard orthovoltage beam, the maximum dose is at or very close to the skin.

The 90% depth dose for 270 KV is at approximately 2 cm. In view of this, a single direct field does not adequately treat to the depth required, and the posterior testis is underdosed. In addition, the high skin dose results in an increase in the skin reaction.

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A direct electron beam has the advantage of a rapid fall off in dose with depth, reducing the dose to the perineum. A testicular ultrasound is acquired with the patient in the treatment position. This ultrasound provides a measurement of the thick- ness of the testis in the anterior–posterior plane.

This measurement is used to determine the depth required for treatment. The electron energy is then selected. Commonly, the energy ranges between 9 and 15 megaelectron volts (MeV). A customized lead cut out is made to ensure that the testis with a 1-cm margin is treated and any adjacent tissue is shielded.

Bolus is used to provide a homogeneous dose distribution, avoiding hot spots, and a rapid fall off in dose at the field edge. The bolus covers the entire testis, which also provides backscatter, thereby improving the dosimetry.

A direct cobalt beam has also been used as a treatment modality in this setting. As with orthovoltage, the depth dose characteristics of a cobalt beam results in under dosing of the posterior part of the target volume. For a 10×10-cm field, the Dmax

is at approximately 5 mm and 93% at approximately 2 cm. A further disadvantage is the relatively wide penumbra when compared with that of a linear accelerator. This must be taken into account when defining the lateral field borders.

In summary, the optimal treatment modality and technique for irradiation of the testis is unclear.

However, electrons appear to have the advantage of delivering an adequate dose at depth. The curved contour of the testis can be adjusted for using bolus resulting in a homogeneous dose distribution.

Treatment with low dose radiotherapy (18–20 Gy) is able to eradicate IGCN and preserve hormone function avoiding life-long hormone supplementa- tion (Dieckmann et al. 1993). There is, however, evidence that with longer-term follow-up some impairment of androgen synthesis occurs (Dieckmann and Loy 1994; Dieckmann and Skakkebaek 1999).

In addition, patients with contralateral IGCN have a higher rate of baseline Leydig cell dysfunction than patients with a normal contralateral testis: 11/24 (45.8%) and 2/30 (6.6%), respectively (Petersen et al. 1999).

IGCN is a radiosensitive tumor and there is emerging evidence that doses less than 20 Gy in 10 fractions may be adequate to eradicate this tumor.

Sedlmayer et al. (2001) reported eradication of IGCN in nine patients treated with 13 Gy in 10 fractions. Petersen et al. (2002) evaluated radiation doses of 14 Gy, 16 Gy, 18 Gy and 20 Gy delivered at 2 Gy per fraction, 5 days per week. IGCN was eradi-

cated in all patients treated with doses of 16 Gy or more. However, Classen et al. (2003a) compared a dose of 18 Gy in 9 fractions with 16 Gy in 8 fractions.

One patient relapsed with IGCN after 16 Gy and two other patients had persistent spermatogonia following 16 Gy and 18 Gy.

Although patient numbers in the above-men- tioned series are small and the follow-up period short, the data suggests that 16 Gy or more may eradicate a high proportion of IGCN. However, in a study by Dieckmann et al. (2002), two patients sub- sequently developed a germ cell cancer (one patient a seminoma and the other patient a mixed seminoma and embryonal carcinoma) despite a total dose of 20 Gy. These tumors occurred at 5 years and 7 years after completion of radiotherapy. At present, 20 Gy in 10 fractions over 2 weeks is a widely accepted fractionation schedule for IGCN.

29.6

Special Considerations

29.6.1

Scrotal Invasion/Scrotal Interference

Although most patients present with T1 disease, testicular GCT can invade locally to involve the rete testis, epididymis and spermatic cord. As the tunica albuginea acts as a natural barrier, direct invasion of the scrotum is rare and occurs late. Historically, the hemiscrotum and inguinal lymph nodes were included in the treatment portal in patients with tunica albuginea invasion or scrotal interference.

This practice has now been abandoned, as the risk of relapse is low and treatment would result in high dose to the remaining testis. However, if scrotal invasion occurs, adjuvant radiotherapy to the hemiscrotum and ipsilateral inguinal lymph nodes is recommended. The scrotal field is matched to the tattoo at the inferior border of the dog-leg field. Electrons are commonly used and a lead cut out is custom made to limit the dose to the remaining testis.

29.6.2

Contralateral Germ Cell Tumors

The prevalence of bilateral testicular cancer ranges between 1.5% and 5% (Bokemeyer et al. 1993;

Fossa et al. 1989; Hamilton et al. 1986; Hay et al. 1984; Ohyama et al. 2002; Vallis et al. 1995).

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Although synchronous tumors occur, the majority are metachronous occurring at a median time inter- val of 5–8 years (Bokemeyer et al. 1993; Hay et al.

1984; Ohyama et al. 2002). A similar incidence of a second testicular tumor is observed in patients on surveillance (Bokemeyer et al. 1993).

Standard treatment is radical orchidectomy.

Following this procedure, the patient is sterile and requires life-long hormone replacement. Organ- sparing techniques have been reported. Kazem and Danella (1999) described two patients that developed seminoma in the contralateral testis.

Both patients were treated with an organ-sparing technique. Local excision of the tumor was followed by radiotherapy to the remaining testis.

One patient received 19.8 Gy in 11 fractions and the other 20 Gy in 10 fractions. After more than 3 years, both patients have no evidence of disease.

Androgen production is preserved but reduced and virility is retained. The authors conclude that this approach provides an alternative to radical orchidectomy with the advantage of avoiding long-term hormone replacement.

29.6.3

Management of a Residual Mass Following Chemotherapy

Following chemotherapy for metastatic seminoma, a residual mass may persist in up to 80% of patients (Duchesne et al. 1997; Horwich et al. 1992b, 1997;

Motzer et al. 1988; Peckham et al. 1985; Puc et al.

1996; Schultz et al. 1989). A variety of strategies have been proposed including surveillance, surgery and radiotherapy. Pathological examination of the resected specimen reveals viable tumor in only 10–20% of patients. Surgery is technically difficult following chemotherapy as a desmoplastic reaction occurs and the residual mass is densely adherent.

In view of these factors, surveillance with careful monitoring of the residual mass has been suggested (Clemm et al. 1986).

A number of authors have observed that the size of the residual mass (>3 cm) predicts the risk of viable tumor (Fossa et al. 1989; Herr et al. 1997; Motzer et al. 1987; Puc et al. 1996), although this is not sup- ported by others (Horwich et al. 1992b; Schultz et al. 1989). The radiographic appearance of the residual mass (well defined versus poorly defined) has also been reported to predict residual tumor. In a series by Ravi et al. (1999), 6 of 11 (54.5%) patients with a well-defined residual mass of 3 cm or more

had positive histology versus only 1 of 14 (7.1%) patients with a poorly defined mass of similar size.

None of the patients with a residual mass less than 3 cm had a viable tumor.

Routine radiotherapy is not recommended and does not improve OS (Duchesne et al. 1997). How- ever, if the residual mass increases in size and surgery is not technically feasible, radiotherapy is the preferred option. If radiotherapy is employed, a CT planned technique allows accurate delineation of the gross tumor volume and organ at risk. In the post-chemotherapy setting, the CTV is generally limited to the gross disease identified on imaging.

Technique is individualized. The total dose is 35–

40 Gy in 1.6- to 2-Gy fractions, depending on bulk and location of disease.

29.6.4

Prophylactic Contralateral Pelvic Lymph Node Irradiation

The contralateral pelvic lymph nodes may be included in the CTV for patients with stage II disease if retrograde spread is a concern, although the risk of contralateral iliac lymph node involvement is extremely low (Mason and Kearsley 1988).

29.7

Treatment Sequelae

29.7.1

Acute Side Effects

Low dose infradiaphragmatic radiotherapy is well tolerated acutely. From the available literature, some nausea occurs in up to 100% of patients (Aass et al. 1992; Bauman et al. 1998a; Khoo et al. 1997;

Sommer et al. 1990; Vallis et al. 1995), with vomiting and diarrhea in up to 80% of patients (Aass et al. 1992; Bauman et al. 1998a; Khoo et al. 1997;

Vallis et al. 1995). These side effects are generally mild in most patients, with the incidence of grade- 3 and grade-4 acute toxicity ranging between 1.5%

(Sommer et al. 1990) and 2.5% (Vallis et al. 1995).

Most of the data reporting toxicity was collected in an era when higher total dose and dose per fraction were used. These rates of nausea, vomiting and diarrhea are not typically seen today with the current total dose and fractionation regime.

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29.7.2

Late Side Effects

Late effects are uncommon. Analyzing the records of 1,026 patients treated with infradiaphragmatic radiotherapy, Coia and Hanks (1988) observed the 3-year actuarial complication rate was 4% for major complications and 14% for any complication.

With increasing dose, there was a statistically sig- nificant increase in complications (P<0.01). The risk of major bowel complications increased from 1%

for doses less than 35 Gy to 3% for doses of 35 Gy or more (P=0.03). Gastrointestinal injury includ- ing peptic ulceration, hemorrhage, chronic diarrhea and intestinal obstruction were the most frequent complications (Coia and Hanks 1988).

Table 29.3 shows the incidence of late effects following infradiaphragmatic radiotherapy in patients treated for testicular GCT. The incidence of second malignancies and radiation-induced impairment in spermatogenesis is discussed separately.

Peptic ulceration is relatively common, occurring in up to 16% of patients at a median follow-up of 12 months (Akimoto et al. 1997). It is more often seen with a higher dose and in patients with prior abdominal surgery, a prior history of dyspepsia or in those who had significant acute toxicity (Hamilton et al. 1986; Aass et al. 1992). Others have reported no late toxicity (Sommer et al. 1990; Zagars and Babaian 1987).

29.7.3

Impaired Spermatogenesis

Following radiotherapy or chemotherapy for testicular germ cell tumors, impairment of spermatogenesis can occur. A number of authors have reported that less than 50% of patients have a normal sperm count following radical orchidectomy even without radiotherapy (Gordon et al. 1997; Hahn et al. 1982;

Hansen et al. 1990; Jacobsen et al. 1997; Nijman et al. 1987).

A radiotherapy-induced reduction in sperm count can take several weeks. The spermatogonia are more radiosensitive than the differentiated stages and, at low doses of radiation, aspermia occurs at approximately 10–12 weeks (Hahn et al. 1982).

The gonadal dose impacts on the recovery of sperm count (Gordon et al. 1997; Hahn et al. 1982;

Hansen et al. 1990). Gordon et al. (1997) reported recovery within 12 months if the gonadal dose was less than 0.79 Gy, but this was delayed for more than

Table 29.3. The incidence of late complications following infradiaphragmatic radiotherapy for testicular cancer

Complication Incidence

Peptic ulcer disease 0–16%

Chronic diarrhea 0–2.6%

Dyspepsia 0–27.7%

Aass et al. (1992); Akimoto et al. (1997); Hamilton et al.

(1986); Sommer et al. (1990); Yeoh et al. (1993); Zagars and Babaian (1987)

2 years in patients who received a gonadal dose of more than 0.79 Gy. In a further study, Hahn et al. (1982) observed that recovery took between 21 weeks and 41 weeks with doses below 60 rad and 47–88 weeks with doses of 60–148 rad. Other factors that may prolong the recovery time include age over 25 years, low pretreatment sperm count and the addition of chemotherapy (Hansen et al. 1990).

Nevertheless, there are several reports in the literature describing survivors of testicular cancer father- ing healthy infants (Centola et al. 1994; Gordon et al. 1997; Hahn et al. 1982; Akimoto et al. 1997). In a series by Akimoto et al. (1997), 79% of patients who wanted to have children after postorchidectomy radiotherapy were successful.

29.7.4

Second Malignant Neoplasms

Following exposure to ionizing radiation, there is a latent period prior to the development of a second malignant neoplasm (Fossa et al. 1990; Hay et al.

1984; Moller et al. 1993; Smith and Doll 1982).

The incidence of solid tumors increases with time from exposure.

The relative risk of second cancer ranges between 1.5 and 7.5 (Bokemeyer and Schmoll 1995). Patients diagnosed with testicular cancer may already be at an increased risk of developing a second malignancy (Kleinerman et al. 1985). Although some reports find no difference in the incidence of second malignant neoplasm within or outside the radiation field (Hanks et al. 1992; Hay et al. 1984), most second cancers occur within or at the margins of the radiation field (Fossa et al. 1990; Jacobsen et al. 1993).

The increased risk of solid malignancies following radiotherapy for testicular cancer appears to be higher at certain sites, notably the genitouri- nary tract (Fossa 2004; Hay et al. 1984; Moller et al. 1993; Wanderas et al. 1997), gastrointestinal tract (Bokemeyer and Schmoll 1995; Fossa 2004; Moller et al. 1993; Travis et al. 1997;

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Table 29.4. The relative risk of second malignancy in survivors of testicular cancer

Site of second malignancy Author Relative risk

All sites Moller et al. (1993) 1.6

Wanderas et al. (1997) 3.54 Travis et al. (1997) 1.43 Van Leeuwen et al. (1993) 1.6 Hanks et al. (1992) 3.4

Hay et al. (1984) 1.55

Fossa et al. (1990) 1.58

Bladder Moller et al. (1993) 2.1

Wanderas et al. (1997) 2.1 Travis et al. (1997) 2.02

Kidney Moller et al. (1993) 2.3

Gastric cancer Moller et al. (1993) 2.1

Wanderas et al. (1997) 2.46 Travis et al. (1997) 1.95 Van Leeuwen et al. (1993) 3.7

Pancreatic cancer Moller et al. (1993) 2.3

Travis et al. (1997) 1.5

Gallbladder Horwich and Bell (1994) 8.3

Colon Moller et al. (1993) 1.5

Travis et al. (1997) 1.27

Rectum Travis et al. (1997) 1.41

Leukemia Horwich and Bell (1994) 6.2

Van Leeuwen et al. (1993) 5.1 Moller et al. (1993) 2.4 Travis et al. (1997) 2.13 Non-Hodgkin’s lymphoma Travis et al. (1997) 1.88 Connective tissue/sarcoma Jacobsen et al. (1993) 4.0

Travis et al. (1997) 3.16 Wanderas et al. (1997) 9.2 Non-melanomatous skin cancer Moller et al. (1993) 2.0

Melanoma Travis et al. (1997) 1.69

Fossa et al. (1990) 3.89

Unknown primary Hay et al. (1984) 8.36

Lung Wanderas et al. (1997) 2.19

Thyroid Travis et al. (1997) 2.92t

van Leeuwen et al. 1993; Wanderas et al. 1997) and in connective tissue (Fossa 2004; Travis et al.

1997; Wanderas et al. 1997) (Table 29.4). The risk of leukemia is also increased following radiotherapy (Fossa 2004; Hay et al. 1984; Horwich and Bell 1994; van Leeuwen et al. 1993). Other rare second cancers may also occur. Amin et al. (2001) reported two cases of malignant peritoneal mesothelioma many years after previous abdominal radiation therapy for testicular carcinoma. Saiki et al. (1997) described a patient with metastatic testicular cancer who developed a glioblastoma multiforme after radiotherapy for a brain metastasis.

Cytotoxic treatment is associated with an increased risk of second malignant neoplasm. Not only do patients treated for testicular cancer have an increased incidence of second malignancy, most of these malignancies are significant neoplasms resulting in an increased mortality (Bokemeyer and Schmoll 1993; Hanks et al. 1992; Zagars et al. 2004). In view of this serious late complication of radiotherapy, long-term follow-up is necessary.

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