Pediatric Seminoma

Germ cell tumors account for 95% of testicular tumors and include seminomas, teratomas, choriocarcinomas, and mixed tumors. Seminomas comprise approximately 50% of all germ cell tumors. Seminomas are generally believed to arise from the germinal epithelium of the seminiferous tubules because "seminoma cells" are morphologically similar to spermatogonia and also because seminomas are frequently found within the seminiferous tubules in early stages.

Most researchers believe that seminomas can arise from any or all of the spermatocytic elements because undifferentiated seminomas can resemble primordial germ cells, spermatogonia, or spermatocytes. Unlike the nonseminomatous germ cell tumors, pure seminoma tends to remain localized or tends to involve only lymph nodes. Seminoma is confined to the testis in 85% of patients at presentation. It initially spreads to draining lymph nodes in the retroperitoneum and then spreads proximally to involve the next echelon of draining lymphatics in the mediastinum and supraclavicular fossa. Seminoma can spread hematogenously to involve lung parenchyma, bone, liver, or brain (ie, stage IV). Less than 5% of patients present with stage III or stage IV disease.[3]

 

The cause of germ cell tumors is unknown. Familial clustering has been observed.

Prior testicular cancer is a major risk factor for a contralateral malignancy. The cumulative risk 25 years after original diagnosis is 3.6% for patients with seminoma.

Cryptorchidism, especially when bilateral, is a predisposing factor in the development of germ cell tumors arising from the testis. In fact, 7-10% of testis tumors occur in association with cryptorchidism.[4]  Orchiopexy performed before puberty reduces the risk of germ cell tumors and improves the ability to observe the testis.[5]  However, 25% of the cancers found in association with cryptorchidism occur in the contralateral, normally descended testis, which suggests that a developmental defect is responsible for both the maldescent and the tumor. The risk of an individual with cryptorchidism developing testicular cancer is directly related to the degree of maldescent. The risk is 1 in 20 if the testis is intra-abdominal and is 1 in 80 if it is within the inguinal canal. Hypospadias and hydrocele are other genitourinary anomalies that have been associated with testicular cancers.

Presence of chromosomal abnormalities including del(1p36), i(12p), loss of chromosomes 11,13 and 18; gain in chromosomes 7, 8 or X.  In germ cell tumors, deletions of chromosomes 1p, 4q, and 6q and gains of chromosomes 1q, 3, and 20q have been reported.

Klinefelter syndrome is associated with the development of mediastinal germ cell tumors.[6]

Human immunodeficiency virus (HIV) infection may be associated with an increased risk of germ cell tumors. Other possible associations include mumps, orchitis, history of testicular trauma, immunosuppression after organ transplant, and prior vasectomy.[5]

A Children's Oncology Group study suggests that maternal vitamin supplementation may reduce the risk of pediatric germ cell tumors in their offspring.[7]

No clear association between seminoma or other testicular germ cell tumors and previous exposure to diethylstilbestrol has been identified.

A meta-analysis by Bräuner et al showed that maternal exposure to environmental endocrine-disrupting chemicals was associated with a higher risk of testicular cancer, including seminomas, in male offspring. In addition, high exposure during pregnancy to grouped organochlorines and organohalogens was related to a higher risk of both seminomas and nonseminomas in the offspring.[8]

Testicular teratomas and malignant testicular germ cell tumors (GCTs) are seen in early childhood. These are often composed of pure yolk sac tumor which are also called endodermal sinus.

United States statistics

Germ cell tumors are the most common solid tumor in men aged 15-35 years.[4] The worldwide incidence has more than doubled over the past 40 years, and approximately 7500 cases are diagnosed annually in the United States. Seminomas account for nearly 50% of these cases.

International statistics

Among children in Saudi Arabia, seminomas are the most common testicular cancer, representing 39% of all cases in those aged 1-14 years.[9]

Race-, sex-, and age-related demographics

Geographic distribution of testicular cancer widely varies, with the highest rates among North American whites, Scandinavians, and Western Europeans. The lowest rates occur among Asians, Africans, Puerto Ricans, and North American Blacks. Recent data show a White-to-Black incidence ratio of approximately 5:1, and a report from the US military showed a relative White-to-Black incidence ratio of 40:1.

In children and adolescents, the pattern of racial distribution for testicular cancer is different. A review of the Surveillance, Epidemiology, and End Results (SEER) data from 1973-2000 reported that Asians and Pacific Islanders had the highest incidence of testicular cancer at 7.6 per million, whereas American Indians and Alaskan Natives had an incidence of 1.4 per million children. The rates for Caucasian and African American children were the same at 5.1 per million.[10]

Seminomas arise from the male testicle.

As noted above, germ cell tumors are the most common solid tumors in men aged 15-35 years. Seminoma (the most common germ cell tumor) occurs most commonly in the fourth decade of life. Children represent only 2-5% of all patients with testicular cancer. Seminoma is considered a postpubertal tumor, although it has been reported in a patient as young as 8 years.

Prognosis depends on several factors including stage of the disease and decline in tumor marker (ie, alpha feto protein and beta-hCG) in response to therapy.

• Early-stage seminoma: Relapse occurs in approximately 4% of patients with stage I and 10% of patients with stage IIA or stage IIB seminoma. Subsequent treatment with chemotherapy cures more than 90% of patients whose disease relapses after radiotherapy. Therefore, approximately 99% of patients with early-stage seminoma are cured.

• Advanced seminoma: With the development of effective cytotoxic chemotherapy, many patients with advanced (70-80%), recurrent (50-60%), or even metastatic (20-30%) seminomas are cured of their disease. Further studies of alternative chemotherapy regimens and high-dose regimens with stem cell support are ongoing.

• A combined study of five US trials and two UK trials for malignant extracranial GCTs merged by the Malignant Germ Cell Tumor International Collaborative (MaGIC) is available. For this collaboration, data from 519 young patients, incorporating age at diagnosis, stage, and site of primary tumor, pretreatment AFP level and histology were combined. Of these, patients aged 11 years and older with stages III to IV extragonadal disease or ovarian stage IV disease had a less than 70% likelihood of long-term disease-free survival. This ranged from 40% (extragonadal stage IV) to 67% (ovarian stage IV). AFP levels and histologies, other than pure yolk sac were found to be negative factors, but did not achieve statistical significance at the 0.05 level.[11]

Morbidity/mortality

With advances in radiologic staging, serum tumor marker surveillance, and platinum-based chemotherapy for advanced disease, overall survival (ie, cure) rates for patients with seminoma have increased to more than 90%. Nearly 100% of patients with stage I testicular seminoma are cured. Potential adverse effects/morbidity related to therapy for this malignancy are discussed below; in general, morbidity includes infertility, second cancers, chemotherapy-related nausea and vomiting, nephrotoxicity, and cardiovascular toxicity or peptic ulcer disease from mediastinal or retroperitoneal irradiation, if this is used, respectively.

Complications

Patients treated with orchiectomy and adjuvant radiotherapy are at increased risk for subfertility, even though the contralateral testis is not located directly within the radiotherapy field.[12]  Scrotal shielding during radiation treatments reduces the dose of scattered radiation and should be employed routinely.

Second malignancies have been reported following orchiectomy and postoperative adjuvant radiotherapy for seminoma.[13]  Although such malignancies are uncommon, the actuarial risk increases with time from diagnosis; second cancer sites have included the rectum, small intestine, stomach, and bladder.

Potential long-term complications of cisplatin/etoposide chemotherapy include loss of high-frequency hearing, nephrotoxicity, hypomagnesemia/Raynaud phenomenon, subfertility, and acute nonlymphocytic leukemia.

Although cardiovascular toxicity has been reported following treatment of seminoma with orchiectomy and adjuvant radiotherapy, it was associated with the use of radiotherapy fields that treated the mediastinum and supraclavicular fossae. These fields are no longer routinely treated because the incidence of recurrence in these areas is low for patients with stage I, stage IIA, or stage IIB disease.

Patients diagnosed with testicular seminoma have an increased risk of developing a contralateral testis tumor. These patients should be taught methods of testicular self-examination. This form of screening should be performed monthly so that a second primary tumor can be identified at the earliest possible stage.

The most common presenting symptom in a patient with seminoma is a painless testicular mass. Other symptoms can include testicular pain (45%) or heaviness.[5]

A history of previous testicular trauma is common, although usually coincidental. The trauma typically draws the patient's attention to the mass.[6]

Seminoma that has spread to retroperitoneal lymph nodes can cause back pain or abdominal discomfort. Widely disseminated metastatic disease to lungs, liver, bone, or brain is rare but may produce systemic symptoms.

A history of cryptorchidism or other genitourinary anomalies can be elicited in some patients.

When a testicular mass is suspected, the physical examination should include transillumination of the scrotum, which can differentiate a solid mass from a fluid-filled hydrocele or varicocele.

The contralateral testis should be carefully examined because patients with seminoma have a higher risk of contralateral testis cancer than the general population of healthy males.

Pay careful attention to possible sites of lymph node metastases. Specifically, the abdomen should be examined to rule out the presence of large abdominal masses (suggesting bulky paraaortic/retroperitoneal lymphadenopathy), and both supraclavicular fossae should be palpated to rule out metastatic lymphadenopathy in those locations.

A general physical examination that includes lungs, liver, nervous system, and musculoskeletal structures can aid in ruling out widespread metastatic disease.

Measurements of alpha-fetoprotein (AFP), human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH) are important in the management of patients with testicular tumors. In fact, these tests are incorporated in the current staging system for testicular tumors (see Staging).[14]  Alpha fetoprotein is elevated in over 90% of the cases with yolk-sac origin.

Both AFP and beta-hCG are suggestive of malignancy when elevated before orchiectomy. The rate of decline after orchiectomy indicates the likelihood of residual tumor. Tumor marker levels are used to assess response to treatment and to predict the likelihood of complete remission. In regular follow-up, tumor marker levels indicate recurrence, often in the absence of symptoms, physical findings, or abnormal findings on imaging studies.

• Beta-human chorionic gonadotropin

  • Beta-hCG is a glycoprotein typically produced by the placenta.

  • Elevations in beta-hCG levels are found in the serum of approximately 15% of patients with seminoma.

  • The half-life of beta-hCG is approximately 22 hours.

• Alpha-fetoprotein

  • AFP is a glycoprotein typically associated with the human fetus and is the fetal equivalent of albumin. AFP is found in nonseminomatous germ cell tumors, as well as in hepatocellular carcinomas, cirrhosis, hepatitis, and pregnancy. It is of note that AFP is normally elevated at birth with gradual decline up to 6-9 months postpartum.

  • The half-life of AFP is approximately 5 days.

  • Elevated AFP levels are rare in pure seminomas and indicate that nonseminomatous elements are also present (ie, mixed tumor).[15]

• Lactate dehydrogenase: The LDH level is an independent prognostic factor in patients with germ cell tumors (including seminoma). It is thought to reflect tumor burden.

Plain chest radiography and CT scanning of the abdomen and pelvis are the most important radiologic investigations in determining the extent of disease in patients with seminoma.[16]

•  Imaging studies of the chest should be done to rule out pulmonary parenchymal metastases.

• CT scanning of the abdomen or MRI are to be performed for identifying the presence and extent of retroperitoneal lymphadenopathy and is necessary in all patients; it has largely replaced bipedal LAG in the radiographic staging of patients with seminoma. Retroperitoneal lymph nodes measuring 1-2 cm are confirmed to be pathologically involved with metastatic tumor in approximately 70% of cases.

• Although radiologists skilled in the technique are increasingly difficult to find, bipedal LAG is uniquely able to define abnormal lymph nodes by both size and internal architecture, unlike CT scanning. In addition, LAG is useful to the radiation oncologist, who is able to minimize irradiation of normal tissues when such a study is available to facilitate portal design. Currently, this test is not widely used because of the difficulty in finding radiologists who are experts in this technique.

• Further radiologic investigation are obtained to rule out metastatic disease (eg, CT or MRI of the primary site as well as brain in select patients).

The typical testicular tumor is intratesticular and may produce one or more discrete hypoechoic masses or diffuse abnormalities with microcalcifications that can be detected using scrotal ultrasonography. Calcifications are more frequent in seminoma than in nonseminomatous tumors.

Grossly, seminomas are pale gray–to-yellow nodules that are uniform or slightly lobulated. Pure seminomas are subdivided into 3 subtypes based on histopathologic characteristics.

• Classic seminomas (85%) demonstrate a monotonous sheet of large cells with abundant cytoplasm and round hyperchromatic nuclei with prominent nucleoli. A lymphocytic infiltrate or granulomatous reaction with giant cells or both is frequently present. Trophoblastic giant cells capable of producing hCG are present in 15-20% of tumors. Mitoses are infrequent.

• Anaplastic seminoma (10%) is an older term used to describe seminomas with 3 or more mitotic figures per high-power field. This finding has no clinical or prognostic significance because the response of anaplastic seminomas to standard therapy is equivalent to that of classic seminomas.

• Spermatocytic seminoma (5%) is a rare histologic variant that is not associated with carcinoma in situ. These well-differentiated tumors usually contain cells resembling secondary spermatids or spermatocytes. Spermatocytic seminomas rarely metastasize, and they occur almost exclusively in elderly men.[3] The only recommended treatment is orchiectomy.

Testicular seminoma is staged according to the American Joint Committee on Cancer (AJCC) 2010 staging guidelines.[17] This is a TNM staging system comprising separate categorizations for the primary tumor, regional lymph nodes, distant metastases, and serum tumor markers; these 4 categories are used to determine the stage of the patient's disease. Modern treatment decisions are based, in part, on the subdivisions of this staging system. Formal staging is a complex process involving particular required and allowable tests and procedures; the following is a quick overview. (For full staging information, see the AJCC Staging Manual.)

• Primary tumor staging

  • Tis - Intratubular germ cell neoplasia (carcinoma in situ)

  • T1 - Tumor limited to testis/epididymis without vascular or lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

  • T2 - Tumor limited to testis/epididymis with vascular or lymphatic invasion or tumor extending through tunica albuginea with involvement of the tunica vaginalis

  • T3 - Tumor invading spermatic cord with or without vascular/lymphatic invasion

  • T4 - Tumor invading scrotum with or without vascular/lymphatic invasion

• Regional lymph node staging

  • N0 - No regional lymph node metastases

  • N1 - Metastasis with lymph node(s) 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension

  • N2 - Metastasis with lymph node(s) larger than 2 cm but not larger than 5 cm in greatest dimension, or multiple lymph nodes, any 1 mass larger than 2 cm, but not more than 5 cm, in greatest dimension

  • N3 - Metastasis with lymph node(s) larger than 5 cm in greatest dimension

• Distant metastatic staging

  • M0 - No distant metastases

  • M1a - Nonregional nodal or pulmonary metastasis

  • M1b - Distant metastases other than M1a

• Serum tumor marker staging

  • S0 - Marker studies within normal limits

  • S1 - LDH level less than 1.5 times the reference range, beta-hCG level less than 5000 mIU/mL, and AFP level less than 1000 ng/mL

  • S2 - LDH level 1.5-10 times the reference range, beta-hCG level 5,000-50,000 mIU/mL, or AFP level 1,000-10,000 ng/mL

  • S3 - LDH level more than 10 times the reference range, beta-hCG level more than 50,000 mIU/mL, or AFP level more than 10,000 ng/mL

Children’s Oncology Group Staging System for Testicular Germ Cell Tumors

STAGE I:  Limited to testis Completely resected by high inguinal orchiectomy Tumor markers negative Unknown tumor markers at                           diagnosis -> Need negative ipsilateral retroperitoneal lymph node biopsy if > 2cm on CT

STAGE II:  Microscopic residual disease Tumor markers remain elevated Tumor rupture or scrotal biopsy prior to complete orchiectomy

STAGE III:  Retroperitoneal lymph node involvement (> 4 cm on CT) RPLN < 4 cm, but > 2 cm need biopsy

STAGE IV:  Distant Metastasis

                             

Fertility evaluation/sperm banking

As a group, patients with testicular cancer are more likely to have subfertility characteristics (eg, lower motile sperm count, decreased sperm mobility, suboptimal motility characteristics) than a healthy, age-matched cohort.[18]

Modern adjuvant therapies for seminoma have a limited propensity to further negatively affect semen quality.[19]

All male cancer patients of reproductive age who have treatment that may affect testicular function and who may desire children in the future should cryopreserve sperm before initiation of therapy.[20, 21, 22]

Adjuvant radiation therapy

Most men with seminoma present with clinical stage I disease (confined to the testis); only 15-20% of patients are found to have pelvic or para-aortic lymphadenopathy during postoperative radiographic staging. However, in another 15-20% of patients, disease that is apparently confined locally ultimately relapses in subdiaphragmatic lymph nodes if treated with orchiectomy alone.[23]  Adjuvant postoperative radiotherapy remains the current standard method to significantly reduce the incidence of regional nodal failure, and its use is determined by disease stage.[24, 25]

Stage I

After radical orchiectomy, patients with stage I seminoma are treated with moderate-dose external beam radiotherapy to retroperitoneal and ipsilateral pelvic lymph nodes, typically 2500 cGy in 20 fractions (125 cGy per fraction). Using this approach, the in-field disease control rate approaches 100%.[26]  Contraindications to the use of adjuvant radiotherapy for these patients include the presence of a horseshoe kidney (more common among these patients than among the general population), previous abdominopelvic radiotherapy, and severe inflammatory bowel disease. Some reports have indicated that para-aortic lymph node irradiation may suffice without adverse impact on overall survival.[27, 28, 29, 30]

The recommended follow-up for patients receiving para-aortic and ipsilateral pelvic radiotherapy includes 2 examinations per year for the first 3 years after treatment, followed by yearly examinations in years 4-6 after treatment. Chest radiography is performed during each follow-up visit. For patients receiving para-aortic radiotherapy only, a CT scan of the pelvis is recommended during the follow-up schedule detailed above.[31]

Some patients with stage I disease prefer to avoid adjuvant radiation because their risk of relapse after orchiectomy is relatively low (15-20%) and because disease recurrences are usually treated with subsequent salvage radiation or chemotherapy.[32]  However, patients who choose this approach must understand that they will require frequent (and therefore expensive) follow-up evaluations with serum tumor markers and CT scanning of the abdomen and pelvis so that nodal recurrences may be identified early.[33]  For patients who undergo surveillance, follow-up includes 3 examinations per year for the first 2 years, 2 examinations in years 3 and 4, and 1 examination in years 5-10. At each follow-up examination, chest radiography and CT scanning of the abdomen and pelvis are recommended.[31]

An accumulating amount of literature states that 1 or 2 courses of carboplatin may give results similar to adjuvant radiotherapy without the carcinogenic risks of irradiation.[34, 2, 35, 36]  A recent randomized trial comparing radiotherapy versus carboplatin showed a reduction in risk for development of second germ cell tumor in patients receiving carboplatin.[35]  Patients should be examined 2 times during the first 3 years with chest radiography; thereafter, the follow-up schedule is unclear because limited data are available with regards to patterns of relapse.[31]  Note the image below.

Stage IIA-B

Patients with stage IIA or IIB seminoma are found to have regional nodal metastases no larger than 5 cm on postoperative imaging studies. Historically, these patients have been treated with external beam radiotherapy to the pelvic and paraaortic lymph nodes to a dose of 2500 cGy in 20 fractions (125 cGy per fraction) followed by a boost of 1000 cGy in 5-8 fractions (125-200 cGy per fraction); this has provided freedom from any relapse in approximately 90% of patients. As in patients with stage I disease, in-field control remains nearly universal.[37, 24]

Contraindications to the use of adjuvant radiotherapy for these patients include the presence of a horseshoe kidney (more common among these patients than among the general population), previous abdominopelvic radiotherapy, and severe inflammatory bowel disease. Adjuvant combination chemotherapy in lieu of radiotherapy has been used with increasing frequency over the past 2 decades, according to patterns of care studies;[38]  current randomized protocols are attempting to define which approach (adjuvant radiation versus adjuvant chemotherapy) carries the lowest morbidity while maximizing the cure rate. A study from the Spanish Germ Cell Cancer Group showed a 5-year progression-free survival of 100% and 87% for Stage IIA and IIB testicular seminoma treated with 4 cycles of cisplatin and etoposide or 3 cycles of cisplatin, etoposide, and bleomycin.[39]

Adjuvant carboplatin chemotherapy

Accumulating reports in the literature state that 1 or 2 courses of carboplatin may yield results similar to adjuvant radiotherapy without the carcinogenic risks of irradiation in stages IA and IB testicular seminoma.[34, 2, 35, 36]  A recent randomized trial comparing radiotherapy to carboplatin showed a reduction in risk for the development of a second germ cell tumor in patients receiving carboplatin.[35]  Patients should be examined 2 times during the first 3 years with chest radiography; thereafter, the follow-up schedule is unclear because limited data are available with regard to patterns of relapse.[31]

Adjuvant combination chemotherapy

In advanced seminoma (stage IIC or III), although local control with radiotherapy remains excellent, the risk of distant relapse is high. This risk mandates the use of systemic chemotherapy to achieve cure. Approximately 70-80% of these patients are curable with platinum-based chemotherapeutic regimens.

In selected stage IIB seminoma, where the location of nodal involvement and treatment with adjuvant radiotherapy is likely to cause renal dysfunction, combination chemotherapy should be considered.

Patients with bulky nodal disease or systemic metastases are best treated with combination chemotherapy using cisplatin-containing regimens; a representative regimen is 4 cycles of cisplatin/etoposide administered intravenously in an outpatient setting.

The appropriate surgical treatment for any patient with suspected testicular tumor is radical inguinal orchiectomy with high ligation of the spermatic cord. Transscrotal biopsy or transscrotal orchiectomy is inappropriate because the testis and scrotum have different lymphatic drainage patterns and these procedures can result in tumor recurrence in the scrotal skin or inguinal/pelvic lymph nodes.[40] In addition, an inguinal approach allows for more generous resection of the spermatic cord, improving surgical margins. Orchiectomy provides pathologic material for histologic diagnosis and primary pathologic staging information as well.

Consultation with the following specialists may be appropriate:

• Pediatric urologist

• Radiation oncologist

• Pediatric oncologist

• Reproductive endocrinologist or sperm banking specialist

Diet

No specific dietary concerns are associated with the care of these patients.

Activity

Any activity limitations are related to surgery (orchiectomy); for example, the patient's surgeon may recommend avoidance of heavy lifting or contact sports for a short time.

 

As discussed below, adjuvant moderate-dose pelvic and/or paraaortic radiotherapy remains the standard treatment for patients with early-stage seminoma (stage I, IIA, or IIB) after orchiectomy. However, patients who are found to have more advanced disease (stage IIC, III, IV) have a high risk of systemic relapse if treated with surgery and radiation alone, and the standard treatment for these patients is combination chemotherapy. These patients can be generally divided into good-risk and poor-risk categories. For patients with good risk, several combination chemotherapy regimens are available; one common schedule for adults includes 3 cycles of cisplatin/etoposide/bleomycin (detailed below). Patients with poor risk should be enrolled in clinical trials because the ideal chemotherapeutic strategy has not been determined.

Class Summary

Adjuvant chemotherapy regimens are for stages I to III disease.

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), then finally a mitotic cell division (phase M).

The rate of cell division varies for different tumors. Most common cancers increase very slowly in size compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy; it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measure in the management of several neoplasms.

Carboplatin (Paraplatin)

Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase. Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity.

Dose is based on the following formula: total dose (mg) = (target area under plasma concentration-time curve [AUC]) X (glomerular filtration rate [GFR]+25) where AUC is expressed in mg/mL/min and GFR is expressed in mL/min.