Chapter 35: Testicular Cancer

Darren R. Feldman; George J. Bosl

INTRODUCTION

Listen

Epidemiology

| Download (.pdf) | Print

Incidence:

8,820 estimated new cases for 2014 in the United States

5.5 per 100,000 males per year

Deaths:

Estimated 380 in 2014

Median age:

33 years

Siegel R et al. CA Cancer J Clin 2013;63:11–30

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

| Download (.pdf) | Print

Epidemiology

Frequency of Stage at Presentation

Seminoma

Nonseminoma

Stage I

85%

60%

Stage II

10%

20%

Stage III

20%

Frequency of IGCCCG Risk Groups at Diagnosis for Patients Requiring Chemotherapy

IGCCCG Risk Group

Seminoma

Nonseminoma

All

Good

90%

56%

60%

Intermediate

10%

28%

26%

Poor

N/A

16%

14%

IGCCCG, International Germ Cell Cancer Collaborative Group; GCT germ cell tumor

Biggs M, Schwartz S. “Cancer of the Testis.” In Ries SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988–2001. 2007:165–170

Bosl G et al. In Devita V, Lawrence T, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins, 2008:1463–1485

International Germ Cell Cancer Collaborative Group (IGCCCG). J Clin Oncol 1997;15:594–603

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Pathology

| Download (.pdf) | Print

Pathology

Germ Cell Tumors (95%)

Non–Germ Cell Tumors (5%)

Seminoma
1. Classic
2. Spermatocytic
Nonseminoma
1. Embryonal carcinoma
2. Teratoma
  1. Teratoma (Mature or Immature)
  2. Teratoma with malignant transformation
3. Choriocarcinoma
4. Yolk sac (endodermal sinus) tumor

Note: Most common nonseminoma histology is a mixture of ≥2 histologies. Pure teratoma represents a fully malignant GCT

Sex cord-stromal (gonadal stromal) tumors
1. Leydig cell
2. Sertoli cell tumor
3. Granulosa cell
Both germ cell and gonadal stromal elements
1. Gonadoblastoma
Adnexal and paratesticular tumors
1. Mesothelioma
2. Carcinoma of rete testis
Miscellaneous neoplasms
1. Carcinoid
2. Lymphoma
3. Sarcoma
4. Other

Work-up

| Download (.pdf) | Print

Work-up

Suspicious Testicular Mass (by History or Exam)

Confirmed Testicular Mass (by Ultrasound)

Seminoma or Nonseminoma (S/P Orchiectomy)

History and physical

STM if not yet done

STM

AFP, hCG, and LDH (serum tumor markers [STM])

CBC, complete metabolic profile

CT A/P + either CXR or CT chest

CT C/A/P if >4 weeks since prior

Scrotal ultrasound

Bone scan or MRI Brain, only if clinically indicated

Discussion of sperm banking if further treatment (surgery, chemotherapy, or XRT) is required

Staging

| Download (.pdf) | Print

Staging

T: Primary Tumor Staging

pTx

Primary tumor cannot be assessed

pT0

No evidence of primary tumor

pTis

Intratubular germ cell neoplasia (testicular intraepithelial neoplasia)

pT1

Tumor limited to testis and epididymis without lymphovascular invasion (LVI); tumor may invade tunica albuginea but not tunica vaginalis

pT2

Tumor limited to the testis and epididymis with LVI or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

pT3

Tumor invades the spermatic cord with or without LVI

pT4

Tumor invades the scrotum with or without LVI

| Download (.pdf) | Print

Staging

N: Regional Lymph Nodes Clinical Staging

Regional lymph nodes (LN) cannot be assessed

No regional LN metastasis

LN mass ≤2 cm in greatest dimension; or multiple LN, none >2 cm

LN mass >2 cm but not >5 cm in greatest dimension; or multiple LN, any 1 mass >2 cm but not >5 cm

Lymph node mass >5 cm in greatest dimension

| Download (.pdf) | Print

Staging

N: Regional Lymph Nodes Pathologic Staging

Regional LN cannot be assessed

No regional LN metastasis

Metastasis with a lymph node mass ≤2 cm in greatest dimension and ≤5 lymph nodes positive, none >2 cm

Positive LN >2 cm but <5 cm in greatest dimension; or >5 positive LN, none >5 cm; or evidence of extranodal extension

Positive lymph node >5 cm in greatest dimension

| Download (.pdf) | Print

Staging

M: Metastatic Disease Staging

Distant metastasis cannot be assessed

No distant metastasis

Distant metastasis

M1a

Nonregional nodal or pulmonary metastasis

M1b

Nonpulmonary visceral metastases

| Download (.pdf) | Print

Staging

S: Serum Tumor Markers Staging

Markers not available or not performed

Marker levels within normal limits

LDH <1.5× upper limit of normal (ULN) and human chorionic gonadotropin, beta subunit (hCG) <5000 mIU/L and alpha-fetoprotein (AFP) <1000 ng/mL

LDH 1.5–10× ULN or hCG 5000–50,000 mIU/L or AFP 1000–10,000 ng/mL

LDH >10× ULN or hCG >50,000 mIU/L or AFP >10,000 ng/mL

Caveats Regarding Staging

| Download (.pdf) | Print

Caveats Regarding Staging

Except for pTis and pT4, extent of tumor is classified by radical orchiectomy. Use pTx in absence of orchiectomy
Histology (seminoma vs. nonseminoma) is incorporated into the risk classification system but not AJCC stage
Serum tumor markers (STM) for staging and IGCCCG risk prognostication should be drawn after orchiectomy or other tissue diagnosis but before chemotherapy. Elevated preoperative STM must be repeated postorchiectomy after marker half-life has been evaluated

TNM Stage Grouping

IGCCCG Risk Group Classification

Stage

TNM

Risk Group (5-Year DFS)

Seminoma (Criteria)

Nonseminoma (Criteria)

pTis, N0, M0, S0

Good

Nonseminoma (56% of cases)

5-y PFS 89%

5-y survival 92%

Seminoma (90% of cases)

5-y PFS 82%

5-y survival 86%

Any primary site. Absence of nonpulmonary visceral metastasis. Normal AFP, any level hCG or LDH

Must fulfill all of the following criteria:

Primary site not mediastinum (Testis/retroperitoneal primary); absence of nonpulmonary visceral metastasis; markers S0 or S1

pT1–4, N0, M0, Sx

pT1, N0, M0, S0

pT2–T4, N0, M0, S0

Any pT/Tx, N0, M0, S1–3

Any pT/Tx, N1–3, M0, Sx

Intermediate

Nonseminoma (28% of cases)

5-y PFS 75%

5-y survival 80%

Seminoma (10% of cases)

5-y PFS 67%

5-y survival 72%

Any primary site. Presence of nonpulmonary visceral metastasis

Normal AFP, any level hCG or LDH

Must fulfill all of the following criteria:

Primary site not mediastinum (Testis/retroperitoneal primary); absence of nonpulmonary visceral metastasis; and markers S2

IIA

Any pT/Tx, N1, M0, S0–1

IIB

Any pT/Tx, N2, S0–1

IIC

Any pT/Tx, N3, S0–1

III

Any pT/Tx, Any N, M1a, Sx

IIIA

Any pT/Tx, Any N, M1a, S0–1

Poor

Nonseminoma (16% of cases)

5-y PFS 41%

5-y survival 48%

Seminoma (seminomas are not classified as poor prognosis)

N/A—Seminomas are never poor risk

Must fulfill at least 1 of the following criteria:

Primary site mediastinum; or presence of nonpulmonary visceral metastases; or markers S3

IIIB

Any pT/Tx, Any N, M1a, S2

Any pT/Tx, N1–3, M0, S2

IIIC

Any pT/Tx, N1–N3, M0, S3

Any pT/Tx, Any N, M1a, S3

Any pT/Tx, Any N, M1b, Any S

International Germ Cell Cancer Collaborative Group (IGCCCG). J Clin Oncol 1997;15:594–603

Expert Opinion

I. Caveats

A testicular mass is malignant until proven otherwise. Radical inguinal orchiectomy is the indicated surgical procedure for all testicular masses; transscrotal orchiectomy and testicular biopsy are not recommended
Patients with seminoma and an elevated AFP level or any nonseminomatous histology, including teratoma, should be treated as a nonseminoma
Patients with pure testicular teratoma should be treated as a fully malignant nonseminoma
Primary mediastinal site and level of serum tumor markers (STMs) do not affect prognosis for seminoma patients
Sperm banking should be discussed with patients after orchiectomy before initiation of any further therapy
There is ≈2% lifetime risk of developing a contralateral testicular tumor; self-exam and MD exam are recommended at regular intervals. Such tumors are treated as new primary GCTs

II. Treatment Recommendations by AJCC Stage and Histology

A. Nonseminomas

Stage I

Stage IA: surveillance is the preferred option for compliant patients. The risk of recurrence is ≈20% and if the disease recurs, >95% patients can be cured with chemotherapy (CT) using EP or BEP. For noncompliant patients, nerve-sparing retroperitoneal lymph node dissection (RPLND) may be preferred
Stage IB: risk of relapse is ≈50%. RPLND, surveillance, or 1–2 cycles of BEP are all options. RPLND results in the least likelihood of patients receiving chemotherapy
Stage IS: CT should be administered (EP × 4 or BEP × 3 for S1; BEP × 4 for S2–S3)

Stage II (S0 and S1 STM only; S2 and S3 STM qualify as Stage IIIB and IIIC, respectively)

If adenopathy >2 cm or bilateral or STM are persistently elevated after orchiectomy, BEP × 3 or EP × 4 should be given
If adenopathy <2 cm and unilateral/unifocal and STM are normal, RPLND or CT (EP × 4 or BEP × 3) can be considered depending on clinical circumstances. Following postchemotherapy RPLND, patients with complete resection should receive 2 cycles of EP or BEP if findings reveal pathologic stage IIB (pN2)

Stage III

Treatment is based on IGCCCG risk classification
Patients in the good-risk category should be given either EP × 4 or BEP × 3
Patients in the intermediate- or poor-risk categories should be given BEP × 4
VIP × 4 (etoposide, ifosfamide, cisplatin) is as effective as BEP × 4 in patients with poor-risk GCT, but VIP is associated with greater toxicity (primarily hematologic). VIP can be considered for patients in whom bleomycin is contraindicated (ie, pulmonary disease)

Residual masses

In general, all sites of residual masses after completion of CT should be resected, if possible. PET is not routinely indicated for evaluation of post-CT residual masses

B. Seminomas

Stage I

The risk of recurrence is 15–20%. The 3 treatment options are active surveillance, adjuvant radiation therapy (RT), and adjuvant carboplatin
Surveillance is becoming the preferred option for compliant patients since RT and carboplatin overtreat ≥80% of patients. RT increases the risk of secondary cancers and data on the long-term risks with carboplatin are lacking
RT, 2000–2500 cGy is an option for non-compliant patients but recognition of the increased incidence of secondary intra-abdominal malignancies has rapidly led to less frequent use. Carboplatin may be an alternative option for non-compliant patients but long-term follow-up is lacking such that the frequency of late relapses and late toxicity have not been established. For these reasons, the authors do not use carboplatin in their practice [Bosl SJ, Patil S. J Clin Oncol 2011;29:949]

Stage II

Stage IIA: RT (3000–3500 cGy) to retroperitoneal and ipsilateral pelvic lymph nodes. CT (EP × 4 or BEP × 3) is an acceptable alternative to RT [Garcia-del-Muro X et al. J Clin Oncol 2008;26:5416]
Small Stage IIB (single node <3 cm): either RT (≥3600 cGy) or CT with EP × 4 or BEP × 3
Large (>3 cm) or multinodal Stage IIB, all Stage IIC and Stage III: Treatment is with chemotherapy based on IGCCCG risk stratification. EP × 4 or BEP × 3 are used for good-risk seminoma, BEP × 4 is used for intermediate-risk disease. Seminoma patients are never poor-risk

Residual masses

Surgery is more difficult with seminoma and carries a higher complication rate
PET scan is recommended to evaluate residual masses >3 cm. Additional treatment (surgical or medical) or diagnostic procedure may be indicated for PET-positive residual masses >3 cm. PET-negative lesions >3 cm require no further treatment, just active surveillance. Some patients with lesions <3 cm may benefit from PET scan evaluation. Since teratoma is rarely an issue with seminoma, false-negative results are uncommon

III. Salvage Therapy

We divide patients into 2 categories:
1. Patients with a favorable prognosis with conventional chemotherapy: This group includes patients with a retroperitoneal or gonadal primary nonseminoma or a seminoma of any primary site who previously achieved a complete response (CR) or partial response (PR) with negative markers lasting >6 months to first-line therapy. We treat these patients with TIP, based on the 63% durable disease-free survival rate. These patients may be able to be cured without being subjected to the toxicity of high-dose chemotherapy. VIP and VeIP are additional options. Investigational treatments should also be considered
2. Patients with an unfavorable prognosis with conventional chemotherapy: All patients who do not fit into the group above including (a) patients with mediastinal primary nonseminomas and (b) patients who do not achieve a CR or durable PR with negative markers. These patients should be treated with high-dose chemotherapy, which gives them the best chance of long-term survival (40–60%) [Feldman DR et al. J Clin Oncol 2010;28:1706]. Chance of cure with conventional chemotherapy is <10%. Investigational treatments should be considered

IV. Chemotherapy for Special Populations

Viable GCT upon resection after completing first-line chemotherapy: Administer 2 additional cycles of adjuvant chemotherapy with EP
Late relapses: defined as relapse after ≥2 years of being in remission after chemotherapy. These tumors tend to be more chemoresistant and difficult to cure than relapses occurring ≤2 years after completing treatment. Surgery is the treatment of choice when possible. When surgery is not possible, TIP (50% durable CR rate in 14 patients) and cisplatin plus epirubicin (30% durable CR rate in 21 patients) are 2 regimens that have shown promise. High-dose chemotherapy may be indicated in selected patients. Referral to a specialist center is recommended. Investigational treatments should be considered
Intermediate- or poor-risk patients with severe lung disease: VIP can be substituted for BEP with equivalent efficacy but increased hematologic toxicity
Pulmonary toxicity developing during BEP × 3 for good-risk disease: If DLCO or TVC decrease by ≥25% or there is physical exam or CXR evidence of bleomycin toxicity, then discontinuation of bleomycin is indicated with continuation of treatment with EP. Patients who require discontinuation of bleomycin prior to completing 3 full cycles of BEP can be given additional cycles of EP until a total of 4 cycles of chemotherapy have been administered (personal correspondence, Lawrence Einhorn, December 2008)

V. Mesna Dosing Schedules

Ifosfamide 1200 mg/m² per day for 5 days
1. Mesna 120 mg/m² by short intravenous infusion when ifosfamide administration commences, followed immediately afterward by Mesna 1200 mg/m² per day given by continuous intravenous infusion for 5 consecutive days (total dosage/5 days = 6120 mg/m²)
2. Mesna 1200 mg/m² per day given intravenously for 5 consecutive days prepared as an admixture (in the same container) with ifosfamide (total dosage/5 days = 6000 mg/m²)
3. Mesna 400 mg/m² per dose given intravenously when ifosfamide administration commences, and at 4 and 8 hours after ifosfamide for 3 doses per day such that equal total doses of mesna and ifosfamide are given daily; ie, 1200 mg/m² per day (total dosage/5 days = 6000 mg/m²)
Ifosfamide 1500 mg/m² per day for 4 days
1. Mesna 1500 mg/m² per day prepared as an admixture (in the same container) with ifosfamide (total dosage/4 days = 6000 mg/m²)
2. Mesna 500 mg/m² per dose given intravenously with ifosfamide, and then at 4 hours and 8 hours after ifosfamide to equal the total amount of ifosfamide given daily; ie, 1500 mg/m² (total dosage/4 days = 6000 mg/m²)
3. Mesna 500 mg/m² per dose given intravenously when ifosfamide administration commences followed by Mesna 1000 mg/m² per dose given orally at 4 and 8 hours after ifosfamide (for total of 2500 mg/m² mesna per day; total dosage/4 days from IV + oral routes = 10,000 mg/m²)

VI. Follow-up Schedules

Follow-up guidelines based on disease stage, histology (seminoma vs. nonseminoma) and treatment type (radiation, chemotherapy, surgery, surveillance) have been published by various groups, primarily based on expert opinion rather than direct evidence from clinical trials. One commonly used set of guidelines is published by the National Comprehensive Cancer Network (NCCN) (http://www.nccn.org). Other guidelines are also available

For follow-up schedules, the authors consider the starting point to be the first day of definitive treatment (surgery, radiation, or chemotherapy) resulting in expected cure. For patients with metastatic disease who receive chemotherapy followed by surgery, the first day of the first cycle is considered to be the start of year 1 unless adjuvant therapy is required for persistent viable disease. When adjuvant chemotherapy is required, the start date of adjuvant therapy is used to mark the start of year 1

De Santis M et al. J Clin Oncol 2004;22:1034–1039

Einhorn LH et al. N Engl J Med 2007;357:340–348

Motzer RJ et al. Cancer 1991;67:1305–1310

Rabbani F et al. Urology 2003;62:1092–1096

FIRST-LINE TREATMENT REGIMENS: ETOPOSIDE + CISPLATIN (EP)

Listen

First-Line Treatment Regimens: Etoposide + Cisplatin (EP)

Bosl GJ et al. J Clin Oncol 1988;6:1231–1238

Hydration for cisplatin: Administer intravenously 0.9% sodium chloride injection, USP (0.9% NS) to insure a urine output of at least 100 mL/hour prior to each dose of cisplatin. Hydration should be continued until the patient has completed chemotherapy and is able to take adequate oral liquids to prevent dehydration. Monitor and replace electrolytes/magnesium as needed

Etoposide 100 mg/m² per day; administer intravenously diluted in 0.9% NS to a concentration within the range of 0.2–0.4 mg/mL over 60 minutes, for 5 consecutive days, days 1–5, every 21 days for 3–4 cycles (total dosage/cycle = 500 mg/m²)

Cisplatin 20 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS over 30–60 minutes for 5 consecutive days, on days 1–5, every 21 days for 3–4 cycles (total dosage/cycle = 100 mg/m²)

EP × 3 indicates 3 treatment cycles; EP × 4 indicates 4 cycles

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–5: HIGH. Potential for delayed emetic symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Toxicity

MSKCC^✫

Indiana

Neutropenia day 1

Delay by 1 week unless WBC ≥2500/mm³ and ANC ≥500/mm³^✫; consider granulocyte colony-stimulating factor (G-CSF) with next cycle

No delay. Hold etoposide on day 5 if ANC still ≤2500/mm^3†,‡; consider G-CSF with next cycle

Febrile Neutropenia (FN) or prior irradiation

Add G-CSF

Add G-CSF or reduce etoposide dosage by 25%^†

FN despite G-CSF

Consider prophylactic antibiotic next cycle

Reduce etoposide dosage by 25%^‡

Serum creatinine (Cr) ≥3.0 mg/dL (≥265.2 µmol/L)

Delay until Cr <3.0 mg/dL & CrCl creatinine clearance ≥50 mL/min (≥0.83 mL/s), then give full dose or substitute carboplatin if Cr does not return to <3.0 mg/dL or CrCl ≥50 mL/min

Delay until Cr <3.0 mg/dL^‡

^✫Motzer R et al. Cancer 1990;66:857–861

^†Einhorn L et al. J Clin Oncol 1989;7:387–391

^‡Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Patient Population Studied

Patients with good-risk GCT not previously treated with chemotherapy

Bajorin D et al. J Clin Oncol 1993;11:598–606

Bosl GJ et al. J Clin Oncol 1988;6:1231–1238

Culine S et al. Ann Oncol 2007;18:917–924

Kondagunta GV et al. J Clin Oncol 2005;9290–9294

Efficacy (EP × 4 for Good-Risk Patients)

| Download (.pdf) | Print

Efficacy (EP × 4 for Good-Risk Patients)^✫

Author

Year

CR/FR

DurFR

OS^†

Median Follow-up (months)^†

Bosl

1988

93%

82%

Bajorin

1993

134

90%

87%

Kondagunta^✫

2005

289

98%

92%

94%

Culine

2007

126

97%

86%

93%

CR/FR, complete or favorable response; DurFR, durable favorable response; OS, overall survival; NR, not reported

Favorable response: CR of any duration or PR with negative markers lasting ≥2 years

^✫Not a randomized controlled trial

^†OS and Median Follow-up are 4-year actuarial rates

Toxicity

| Download (.pdf) | Print

Toxicity

Bajorin D et al. J Clin Oncol 1993;11:598–606

Hematologic Toxicity

Percent (%)

Fever and neutropenia

Required RBC transfusion

Required platelets transfusion

Nonhematologic Toxicity

| Download (.pdf) | Print

Nonhematologic Toxicity

% G1

% G2

% G3

% G4

Ototoxicity

Neuropathy

Mucositis

Transaminitis

Raynaud phenomenon^✫

None

^✫Raynaud phenomenon reported in separate trial of EP × 4 for good-risk patients (de Wit R et al. J Clin Oncol 1997;15:1837–1843)

Therapy-Related Deaths N (%)

2 (1.5%)

Therapy Monitoring

Every cycle: CBC with differential, comprehensive metabolic profile, and serum tumor markers
Response evaluation: CT scan chest, abdomen, and pelvis and tumor markers after completion of cycle 4

REGIMEN: BLEOMYCIN, ETOPOSIDE, AND CISPLATIN (BEP)

Listen

Regimen: Bleomycin, Etoposide, and Cisplatin (BEP)

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Hydration for cisplatin: 0.9% NS; administer intravenously to insure a urine output of ≥100 mL/hour prior to each dose of cisplatin and continue until the patient has completed chemotherapy and is able to take adequate oral liquids to prevent dehydration. We give 500 mL of 0.9% NS over 1 hour before cisplatin while premedications and etoposide are infused, and an additional 500 mL of 0.9% NS over 1 hour after cisplatin. Electrolytes/magnesium replaced as needed. Other hydration schedules are feasible

Bleomycin 30 units/week; administer by intravenous injection, weekly for 3–4 cycles (ie, 9–12 weeks; total dose/9-week course = 270 units; total dose/12-week course = 360 units)

Etoposide 100 mg/m² per day; administer intravenously diluted in 0.9% NS to a concentration within the range of 0.2–0.4 mg/mL over 30–60 minutes for 5 consecutive days on days 1–5, every 21 days for 3–4 cycles (total dosage/cycle = 500 mg/m²)

Cisplatin 20 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS over 30–60 minutes for 5 consecutive days on days 1–5, every 21 days for 3–4 cycles (total dosage/cycle = 100 mg/m²)

BEP × 3 indicates 3 consecutive cycles; BEP × 4 indicates 4 consecutive cycles

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–5: HIGH. Potential for delayed symptoms

Emetogenic potential on days with bleomycin alone: MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Toxicity (BEP × 3)

| Download (.pdf) | Print

Toxicity (BEP × 3)

Hematologic Toxicity

Percent (%)

Leukocytes <1000/mm³

Fever and leukopenia (<2000/mm³ and T ≤38°C)

Platelet count is <25,000/mm³

Nonhematologic Toxicity

% G1

% G2

% G3

% G4

Pulmonary

Ototoxicity

—

Sensory Neuropathy

—

Fatigue

—

Raynaud phenomenon^✫

^✫Raynaud phenomenon reported in regimen of BEP × 4 (not BEP × 3) for good-risk patients (de Wit R et al. J Clin Oncol 1997;15:1837–1843)

de Wit R et al. J Clin Oncol 2001;19:1629–1640

Patient Population Studied

Bleomycin, Etoposide, and Cisplatin × 3 (BEP × 3)

Indication/population studied: Good-risk GCT patients not previously treated with chemotherapy

Culine S et al. Ann Oncol 2007;18:917–924

de Wit R et al. J Clin Oncol 2001;19:1629–1640

Einhorn L et al. J Clin Oncol 1989;7:387–391

Loehrer P et al. J Clin Oncol 1995;13:470–476

Toner G et al. Lancet 2001;357:739–745

Bleomycin, Etoposide, and Cisplatin × 4 (BEP × 4)

Indication/population studied: Patients with intermediate- or poor-risk GCT not previously treated with chemotherapy

de Wit R et al. Br J Cancer 1995;71:1311–1314

Hinton S et al. Cancer 2003;97:1869–1875

Motzer R et al. J Clin Oncol 2007;25:247–256

Nichols C et al. J Clin Oncol 1991;9:1163–1172

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Toxicity (BEP × 4)

| Download (.pdf) | Print

Toxicity (BEP × 4)

Hematologic Toxicity

% G3

% G4

Any hematologic toxicity

Nonhematologic Toxicity

% G3/G4

Nausea/vomiting

Neurologic

Infection

Pulmonary

Therapy-Related Deaths

N (%)

Pulmonary or pulmonary hemorrhage

3 (2)

Sepsis

3 (2)

Cerebral hemorrhage

1 (1)

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Efficacy (BEP × 3; Good Risk): Randomized Phase III Trials

| Download (.pdf) | Print

Efficacy (BEP × 3; Good Risk): Randomized Phase III Trials

Author

Year

CR/FR

DurFR

Median Follow-up (months)

Einhorn

1989

98%

92%

94%

NR^✫

Loehrer

1995

94%

86%

95%

de Wit

2001

397

97%

90%

97%

NR^†

Toner

2001

88%

90%

96%

Culine

2007

132

95%

91%

96%

53^‡

CR/FR, complete or favorable response; DurFR, durable favorable response; OS, overall survival; NR, not reported

Favorable response: CR of any duration or PR with negative markers lasting 2 years

^✫All patients had ≥1 year follow-up

^†DurFR and OS assessed at 2 years

^#DurFR and OS assessed at 4 years

Efficacy (BEP × 4: Intermediate- and Poor-Risk): Randomized Phase III Trials

| Download (.pdf) | Print

Efficacy (BEP × 4: Intermediate- and Poor-Risk): Randomized Phase III Trials

Author

Year

CR/FR

DurFR

Median Follow-up (months)

Nichols

1991

73%

61%

74%

de Wit

1995

105

72%

80%

NR^✫

Hinton

2003

115

55%

63%

Motzer

2007

111

55%

48%

72%

NR^†

CR/FR, complete or favorable response; DurFR, durable favorable response; OS, overall survival; NR, not reported

Favorable response: CR of any duration or PR with negative markers lasting ≥2 years

^✫DurFR and OS assessed at 5 years

^†DurFR assessed at 1 year and OS at 2 years

Treatment Modifications

| Download (.pdf) | Print

Treatment Modifications

Adverse Events

Treatment Modifications

Myelosuppression not improving during the first 4 days of therapy

Omit day 5 etoposide. Administer full dose cisplatin

Febrile neutropenia

Add filgrastim during ongoing cycle and subsequent cycles so as to administer full dose chemotherapy

Febrile neutropenia while receiving filgrastim

Reduce etoposide dosage by 25%

Clinical (rales or inspiratory lag) or radiographic evidence of pulmonary toxicity or fibrosis

Discontinue bleomycin

Repeated treatment cycles should begin on schedule without regard for the degree of myelosuppression noted on the day of scheduled treatment. Daily CBC is obtained to document marrow recovery

Therapy Monitoring

Every cycle: CBC with differential, comprehensive metabolic profile, serum tumor markers, and evaluation for bleomycin pulmonary toxicity (Indiana—lung exam¹^,2, MSKCC—PFTs³)
After completion of BEP × 3 or BEP × 4, repeat CT scan of chest, abdomen, and pelvis, and tumor markers

¹Loehrer P et al. J Clin Oncol 1995;13:470–476

²Nichols CR et al. J Clin Oncol 1998;16:1287–1293

³Bosl GJ et al. J Clin Oncol 1988;6:1231–1238

SALVAGE TREATMENT REGIMENS REGIMEN: PACLITAXEL + IFOSFAMIDE + CISPLATIN (TIP × 4)

Listen

Salvage Treatment Regimens Regimen: Paclitaxel + Ifosfamide + Cisplatin (TIP × 4)

Kondagunta GV et al. J Clin Oncol 2005;23:6549–6555

Indications:

First-line salvage chemotherapy for patients who relapsed after a complete response or partial response with negative markers lasting >6 months
Other patients who are not candidates for high-dose chemotherapy or have progressed after high-dose therapy and have not received paclitaxel

Premedication for paclitaxel: Dexamethasone 20 mg/dose; administer orally or intravenously for 2 doses at 14 and 7 hours prior to paclitaxel, plus diphenhydramine 50 mg and cimetidine 300 mg; administer both intravenously 1 hour prior to paclitaxel

Paclitaxel 250 mg/m²; administer intravenously in 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) to yield a final concentration within the range of 0.3 and 1.2 mg/mL over 24 hours on day 1, every 21 days for 4 cycles (total dosage/cycle = 250 mg/m²)

Hydration: 1000 mL 0.9% NS; administer intravenously over 2 hours on days 2–5 before or during ifosfamide administration. Consider additional intravenous fluid if medically appropriate until the patient has completed chemotherapy and is able to take adequate oral liquids to prevent dehydration. Monitor and replace electrolytes/magnesium as needed

Ifosfamide 1500 mg/m² per day; administer intravenously in 0.9% NS or D5W to produce a concentration within the range of 0.6 and 20 mg/mL, over 2–3 hours for 4 consecutive days on days 2–5, every 21 days for 4 cycles (total dosage/cycle = 6000 mg/m²)

Mesna 500 mg/m² per dose; administer intravenously in D5W to yield a concentration of 20 mg/mL, for 3 doses/day starting just before or coincident with the start of ifosfamide, with repeated doses at 4 and 8 hours after ifosfamide for 4 consecutive days on days 2–5, every 21 days for 4 cycles (total daily dosage = 1500 mg/m²; total dosage/cycle = 6000 mg/m²) (See Expert Opinion for alternative administration schemes)

Cisplatin 25 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS, over 30–60 minutes for 4 consecutive days on days 2–5, every 21 days for 4 cycles (total dosage/cycle = 100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1: LOW

Emetogenic potential on days 2–5: HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Discontinue daily filgrastim use if WBC ≤10,000/mm3 on 2 consecutive daily measurements

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider use during neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir)

See Chapter 47 for more information

Dose Modifications

| Download (.pdf) | Print

Dose Modifications

Toxicity

Modification

ANC <450/mm³ on day 1

Delay until ANC >450/mm³

Platelet count <75,000/mm³ on day 1

Delay until platelet count is >75,000/mm³

Platelets <10,000/mm³ or platelets <50,000/mm³ with bleeding

Transfuse platelets to >10,000/mm³ if no bleeding, and to >50,000/mm³ if bleeding

Hgb <8 g/dL

Transfuse RBC to keep Hgb >8 g/dL

Kondagunta GV et al. J Clin Oncol 2005;23:6549–6555

Therapy Monitoring

CBC with differential weekly
Comprehensive metabolic profile and serum tumor markers once to twice per cycle
Response assessment: CT scan of chest, abdomen, and pelvis, and tumor markers after completion of 4 cycles

Patient Population Studied (N = 46)

GCT patients fulfilling all of the following 3 criteria:

Gonadal primary tumor
Prior therapy with cisplatin-based treatment totaling 6 or fewer cycles
Prior CR or PR with negative markers lasting >6 months from completion of first-line chemotherapy

Kondagunta GV et al. J Clin Oncol 2005;23: 6549–6555

Toxicity

| Download (.pdf) | Print

Toxicity

Hematologic Toxicity

Percent (%)

Febrile neutropenia

Nonhematologic Toxicity

Percent (%)

Grade 3 neuropathy

Grade 4 or 5 nephrotoxicity

Grade 3 elevation of transaminases

Therapy-related deaths

Kondagunta GV et al. J Clin Oncol 2005;23:6549–6555

Efficacy (N = 46)

| Download (.pdf) | Print

Efficacy (N = 46)

Percent (%)

Chemotherapy alone

Chemotherapy + surgery

PR, marker negative

Other

Relapse From CR

Continuously NED^✫

Two-year overall survival

CR (complete response): disappearance of all clinical, radiographic, and biochemical evidence of disease for at least 4 weeks

IR (incomplete response): failure to achieve CR to chemotherapy with or without surgery, including patients who were observed to have failure of serum tumor marker normalization

NED (no evidence of disease)

^✫Median follow-up of 68 months

SALVAGE TREATMENT REGIMENS REGIMEN: VINBLASTINE + IFOSFAMIDE + CISPLATIN (VeIP × 4)

Listen

Salvage Treatment Regimens Regimen: Vinblastine + Ifosfamide + Cisplatin (VeIP × 4)

Loehrer PJ Sr et al. J Clin Oncol 1998;16:2500–2504

Indications:

First-line salvage chemotherapy for patients who relapsed after achieving a complete response or partial response with negative markers lasting >6 months
Other patients who progressed on or after first-line therapy who are not candidates for high-dose chemotherapy or progressed after high-dose therapy

Vinblastine 0.11 mg/kg per day; administer by intravenous injection over 1–2 minutes on 2 consecutive days, on days 1 and 2, every 3 weeks for 4 cycles (total dosage/cycle = 0.22 mg/kg)

Hydration: Administer 0.9% NS intravenously to insure a urine output of ≥100 mL/hour prior to each dose of cisplatin. Continue intravenous hydration until a patient has completed chemotherapy and is able to take adequate oral liquids to prevent dehydration

Suggested: 0.9% NS 500 mL over 1 hour before cisplatin and an additional 500 mL of 0.9% NS over 1 hour after cisplatin. Electrolytes/magnesium replaced as needed. Other hydration schedules are feasible

Cisplatin 20 mg/m² per day; administer intravenously in 25–250 mL of 0.9% NS over 30–60 minutes for 5 consecutive days on days 1–5, every 3 weeks for 4 cycles (total dosage/cycle = 100 mg/m²)

Ifosfamide 1200 mg/m² per day; administer intravenously in 0.9% NS or D5W sufficient to produce a concentration within the range of 0.6 and 20 mg/mL, over 30–60 minutes for 5 consecutive days on days 1–5, every 3 weeks for 4 cycles (total dosage/cycle = 6000 mg/m²)

Mesna 500 mg/m² per dose; administer intravenously in 25–50 mL 0.9% NS or D5W, over 15–30 minutes starting simultaneously with ifosfamide, followed by Mesna 1200 mg/m² per day by continuous intravenous infusion in a volume of 0.9% NS, D5W (or dextrose and saline combinations) sufficient to produce a concentration of 20 mg/mL over 24 hours for 5 consecutive days on days 1–5, every 3 weeks for 4 cycles (total dosage/cycle = 6500 mg/m²). (See Expert Opinion for alternative administration schemes)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–5: HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for one dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Discontinue daily filgrastim use if WBC >10,000/mm³ on 2 consecutive daily measurements

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider use during neutropenia and for anticipated mucositis
Antiviral—antiherpes antivirals (eg, acyclovir)

See Chapter 47 for more information

Dose Modification

| Download (.pdf) | Print

Dose Modification

Toxicity

Modification

Neutropenia on day 1

No delay. Omit ifosfamide on day 5 if ANC still ≤2500/mm³

Thrombocytopenia and bleeding, febrile neutropenia (FN), or prior irradiation

Reduce etoposide and vinblastine dosages by 25%^✫

Platelet count <100,000/mm³ on day 5

Omit day 5 of ifosfamide^✫

Serum creatinine >2 mg/dL (>176.8 µmol/L)

Decrease ifosfamide dosage by 25%^✫

>10 RBCs/HPF

Hold ifosfamide and continue mesna and hydration until <10 RBCs/HPF

^✫Loehrer PJ Sr et al. J Clin Oncol 1998;16:2500–2504

Therapy Monitoring

Weekly CBC with differential
Comprehensive metabolic profile and serum tumor markers once to twice per cycle
Response assessment: CT scan of chest, abdomen, and pelvis, and tumor markers after completion of 4 cycles

Patient Population Studied (N = 145)

Second-line therapy for GCT patients who progressed during or after first-line chemotherapy

Loehrer PJ Sr et al. J Clin Oncol 1998;16:2500–2504

Toxicity

| Download (.pdf) | Print

Toxicity

Hematologic Toxicity

Percent (%)

Febrile neutropenia

Required RBC transfusions

Required platelet transfusions

Nonhematologic Toxicity

Percent (%)

Renal insufficiency (Cr >4 mg/dL, 353.6 μmol/L)

Irreversible renal insufficiency

Secondary hematologic malignancies

Treatment-related deaths

Efficacy

| Download (.pdf) | Print

Efficacy

Response

Percent (%)

Chemotherapy alone

Chemotherapy + surgery

Relapse From CR

Continuously NED

Progression-Free (PFS) and Overall Survival (OS)

Median PFS

4.7 years

Median OS

1.3 years

OS at 2 years

38%

OS at 7 years

32%

CR (complete response): complete disappearance of all objective evidence of disease (clinical and radiographic) with normalization of hCG and AFP for at least 1 month

IR (incomplete response): any response that did not meet criteria of CR

NED (no evidence of disease) after VeIP + surgery

SALVAGE TREATMENT REGIMENS REGIMEN: ETOPOSIDE + IFOSFAMIDE + CISPLATIN (VIP × 4)

Listen

Salvage Treatment Regimens Regimen: Etoposide + Ifosfamide + Cisplatin (VIP × 4)

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Indication:

Initial therapy for intermediate- or poor-risk GCT patients who are not candidates for BEP (usually because of pulmonary compromise)

Order of administration: etoposide → cisplatin → ifosfamide/mesna

Hydration: 1000 mL 0.9% NS; administer intravenously over 2 hours. Consider additional intravenous fluid if medically appropriate until the patient has completed chemotherapy and is able to take adequate oral liquids to prevent dehydration. Monitor and replace electrolytes/magnesium as needed

Etoposide 75 mg/m² per day; administer intravenously diluted in 0.9% NS to a concentration within the range of 0.2–0.4 mg/mL over 60 minutes for 5 consecutive days on days 1 to 5, every 21 days for 4 cycles (total dosage/cycle = 375 mg/m²)

Cisplatin 20 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS over 30–60 minutes for 5 consecutive days on days 1–5, every 21 days for 4 cycles (total dosage/cycle = 100 mg/m²)

Ifosfamide 1200 mg/m² per day; administer intravenously in 0.9% NS or D5W sufficient to produce a concentration within the range of 0.6 and 20 mg/mL, over 30–120 minutes for 5 consecutive days on days 1–5, every 21 days for 4 cycles (total dosage/cycle = 6000 mg/m²)

Mesna 120 mg/m²; administer by intravenous injection on day 1 just before or coincident with the start of ifosfamide administration, followed by Mesna 1200 mg/m² per day; administer by continuous intravenous infusion over 24 hours for 5 consecutive days on days 1–5, every 21 days for 4 cycles (total dosage/cycle = 6120 mg/m²). (See Expert Opinion for alternative administration schemes)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–5: HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Discontinue daily filgrastim use if WBC >10,000/mm³ on 2 consecutive daily measurements

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider use during neutropenia and for anticipated mucositis
Antiviral—antiherpes antivirals (eg, acyclovir)

See Chapter 47 for more information

Therapy Monitoring

Every cycle: CBC with differential, comprehensive metabolic profile, and serum tumor markers
Response evaluation: CT scan of chest, abdomen, and pelvis, and tumor markers after completion of cycle 4

Patient Population Studied (N = 135)

Primarily intermediate- or poor-risk GCT patients not previously treated with chemotherapy

Nichols C et al. J Clin Oncol 1998;16:1287–1293

Toxicity

| Download (.pdf) | Print

Toxicity

Hematologic Toxicity

% G3

% G4

% G5

Any hematologic toxicity

Nonhematologic Toxicity

% G3/G4

Nausea/vomiting

Neurologic

Infection

Genitourinary

Therapy-Related Deaths

Percent (%)

Sepsis

Cerebral hemorrhage

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Dose Modification

| Download (.pdf) | Print

Dose Modification

Toxicity

MSKCC

Indiana

Neutropenia day 1

Delay cycle by 1 week

No delay. Hold etoposide on day 5 if ANC still ≤2500/mm³^✫

Thrombocytopenia and bleeding (TB), febrile neutropenia (FN), or prior irradiation

TB—delay until platelet count is ≥100,000/mm³

FN—add G-CSF

Reduce etoposide dosage by 25%^✫

Serum creatinine >3 mg/dL (>265.2 μmol/L)

Delay cisplatin until Cr <3 mg/dL, continue etoposide and ifosfamide on schedule.^✫ Substitute carboplatin for cisplatin if Cr does not return to <3.0 mg/dL

^✫Nichols CR et al. J Clin Oncol 1998;16:1287–1293

Efficacy

| Download (.pdf) | Print

Efficacy

Percent (%)

CR to chemotherapy alone

CR to chemotherapy + surgery

Partial response

Favorable response^✫

Failure-free survival at 2 years^†

Overall survival at 2 years

^✫Includes patients with partial response and negative markers without relapse for ≥2 years

^†Includes patients with partial responses (marker-negative or marker-positive) who did not have progression within 2 years

Nichols CR et al. J Clin Oncol 1998;16:1287–1293

IGCCCG Classification

Good Risk (N = 13)

Intermediate Risk (N = 39)

Poor Risk (N = 92)

92%

77%

62%

PFS

92%

72%

56%

Hinton S et al. Cancer 2003;97:1869–1875 (Long-term follow-up of patients in Nichols study (cited above) but with patients reclassified by IGCCCG risk status. Median follow-up for both OS and PFS was 7.3 years)

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Chapter 35: Testicular Cancer

Send Email

Citation

Jump to a Section

INTRODUCTION

Expert Opinion

FIRST-LINE TREATMENT REGIMENS: ETOPOSIDE + CISPLATIN (EP)

REGIMEN: BLEOMYCIN, ETOPOSIDE, AND CISPLATIN (BEP)

SALVAGE TREATMENT REGIMENS REGIMEN: PACLITAXEL + IFOSFAMIDE + CISPLATIN (TIP × 4)

SALVAGE TREATMENT REGIMENS REGIMEN: VINBLASTINE + IFOSFAMIDE + CISPLATIN (VeIP × 4)

SALVAGE TREATMENT REGIMENS REGIMEN: ETOPOSIDE + IFOSFAMIDE + CISPLATIN (VIP × 4)

Pop-up div Successfully Displayed