1. Background
1.5 Treatment options
Orchiectomy is the surgical removal of the affected testicle. This procedure remains the cornerstone of local TC treatment, and is the first line of treatment in nearly all cases of TC. In addition to providing histological confirmation of the diagnosis, orchiectomy is curative in true CS1 TC (Figure 5).
Figure 5. Inguinal orchiectomy. This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International license. Cancer Research UK / Wikimedia Commons.
Retroperitoneal lymph node dissection
Retroperitonal lymph node dissection (RPLND) is the surgical removal of lymph nodes located in the retroperitoneum along the large vessels in the abdomen and pelvis (Figure 6).
Figure 6. Anatomic retroperitoneal nodal regions.47Used with permission.
RPLND is of value because the metastatic spread of TC usually follows a predictive anatomical route to these retroperitoneal lymph nodes.47 The procedure can be unilateral or bilateral (Figure 7).
Figure 7. Areas of retroperitoneal lymph node dissection.37 Numbers refer to lymph node regions.
RPLND has been used extensively in CS1 nonseminoma to establish an accurate pathological staging of the retroperitoneum. Moreover, the procedure can be curative in early-stage metastatic disease. After chemotherapy for metastatic nonseminoma, any remaining lesion (>1 cm) should be removed surgically. In rare cases, surgery is performed on seminoma patients with lesions >3 cm after chemotherapy.
The most common complications after an RPLND are lymphatic leakage and retrograde ejaculation, the latter leading to infertility.48
Radiotherapy
High-energy radiation has been used to treat cancer for more than a century.49 During this time, several methods of delivering external beam RT have been developed, some of which are no longer in use. At the Norwegian Radium Hospital in Oslo, Norway, RT was given by X-ray machines prior to 1955, from 1955 to 1969 by Betatron particle accelerator and since about 1970 by linear particle accelerators.50
Linear accelerators can deliver high-energy photons, or gamma radiation, which damages DNA mostly through indirect ionization of water.51 This forms free radicals which then react with DNA.
The resulting DNA damage leads to cell death or impaired cell division. Linear accelerators have also benefited from advances in technology, physics and biology, which has led to more accurate and safe treatment.
Seminomas are highly sensitive to radiation. RT has thus been commonly used to treat seminomas, with excellent rates of cure in CS1. Even in CS3, RT has the potential for cure, with reported survival of about 60%.52 Nonseminomas are less sensitive to radiation, and thus require higher radiation doses.
Typical infradiaphragmatic RT (IRT) fields were variants on L-fields, which included the lumbar and ipsilateral iliac lymph node regions (Figure 8). Until about 1980, the anterior field also included the inguinal region in selected patients and was then called a dog leg field (Figure 9). L-fields were gradually replaced by smaller para-aortic (PA) fields in the mid-2000s (Figure 9). Before 1980, supradiaphragmatic RT (SRT) was frequently given as prophylaxis to the mediastinum if lymph node metastases were detected.
Figure 8. L-field. Images used with permission from Olbjørn H. Klepp.
Figure 9. Para-aortic field (left) and dog leg field (right).53 Used with permission.
In most cancers, RT remains an important treatment modality.49 While fractionated external beam RT was commonly used to treat TGCT until 10-15 years ago, it has since been substituted by
adjuvant chemotherapy or surveillance, especially in CS1 seminoma. In Norway, adjuvant or curative RT was given to nonseminoma patients until 1980 and to seminoma patients until the early 2000s. Increasing evidence of serious RT late effects as well as effective adjuvant and salvage chemotherapy regimens led to this change of practice.
Acute and long-term RT side effects depend on radiation dose and irradiated volume. Acute effects are usually transient, predictable, and often caused by tissue inflammation. Long-term effects are largely related to tissue fibrosis.
Chemotherapy
In 1960, the first successful trial of combination chemotherapy for TC was published.54
Dactinomycin, chlorambucil and methotrexate had response rates of about 50-70%, including 10-20% complete responses.55, 56
In the early 1970s, vinblastine, bleomycin and mithramycin showed effect on TC.57-59 In the mid-1970s, bleomycin and vinblastine in combination was shown to induce complete responses in almost 40 % of cases.60 During 1974 to 1978, Norwegian TC patients received a combination of adriamycin, cyclophosphamide, actinomycin-D and medroxyprogesterone acetate (CAOS regimen, also called VACAM)61, 62 which led to partial responses in 73 % and complete responses in one third of patients.
In 1974, cisplatin monotherapy showed promising results in TC.63 Einhorn et al. published results of combined treatment with cisplatin, vinblastine and bleomycin (CVB) in 1977,7 with a 100 % response rate, including 74 % complete responses. CVB thus became the standard treatment of metastatic TC from the late 1970s.
In 1983, Peckham et al. reported encouraging results on the combination of bleomycin, etoposide and cisplatin (BEP) as first line treatment of metastatic TC.64 Four years later, a study comparing BEP and CVB showed that BEP had better efficacy and lower toxicity.65 BEP became the standard regimen in the treatment of metastatic TC in 1987.
Due to the chemo-sensitivity of TC, several studies were performed through the 1990s and 2000sto determine whether chemotherapy could be useful also in the adjuvant setting.66-71 The standard adjuvant regimen in the 2000s were two courses of BEP. Relapse rates after this regimen were low, although there was a lack of data on long-term toxicity.67 After reports on low relapse rates after one course of adjuvant BEP, this gradually became the new standard adjuvant regimen in
nonseminoma patients in the late 2000s.72 One course of adjuvant carboplatin became an option for seminoma patients.73
Different chemotherapy regimens are associated with varying degrees of short-term side effects such as nausea, diarrhea and hair loss, but also long-term effects. For cisplatin, these include peripheral neuropathy, ototoxicity, hypogonadism, infertility, renal toxicity, SC, CVD and pulmonary toxicity. 74