1.4.1 General treatment principles during the study period
In Norway, management of TC is centralized to four university Hospitals. The study participants have been treated in line with the recommendations by the SWENOTECA collaboration,15,65-67 or according to protocols by the European Organization for Research and Treatment of Cancer and Medical Research Council.68-76 SWENOTECA treatment protocols have been available for nonseminoma patients from 1980 and for seminoma patients from 2000.15
The initial treatment for most participants was an orchiectomy. For stage I nonseminoma, a post-orchiectomy retroperitoneal lymph node dissection (RPLND) was routinely performed as a staging procedure until the early 1990s,77 when 1-3 cycles of adjuvant cisplatin-based
chemotherapy (CBCT) or the surveillance strategy (orchiectomy followed by close monitoring with clinical examinations, diagnostic imaging and measurement of serum tumor markers) were
introduced as treatment options (Table 3).47,65,67,70,75 Abdominal radiotherapy (RT), with gradually reduced target dose from 36-40 Gy to 25.2-27 Gy,78,79 was the standard treatment for stage I seminoma until the early 2000s,76 when surveillance or 1 cycle of adjuvant carboplatin became the recommended treatment strategies.47,80-82
In case of metastatic disease, CBCT has been the standard treatment for both nonseminoma and seminoma during the entire study period, as it still is today (Table 3).6,66,83,84 In line with expanding insights regarding treatment efficacy and side effects, the number of CBCT cycles were reduced from ≥4 cycles to 3 cycles for patients with good prognosis (the majority) and 4 cycles for patients with intermediate and poor prognosis from the early 2000s.7,15,74 For small volume
metastatic seminoma, abdominal RT continued to be a treatment option during the entire study period, but the target dose was gradually reduced as described above.
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Table 3. General initial treatment principles for TC patients in Norway by decade of diagnosis
Decade Stage I-IIA Stage IIB-IV
1980 to 1989 Nonseminomas: staging RPLND (unilateral RPLND only if stage I) followed by CBCT if metastases were histologically verified.77
Seminomas: adjuvant RT towards paraaortal and ipsilateral iliacal lymph nodes by the L-field technique.78 The target dose was gradually reduced from 36-40 Gy to 25.2-27 Gy.78,79 One institution offered RT restricted to the para-aortic area only from 1989.76
Cisplatin in combination with bleomycin and vinblastine (CVB), and from 1987 etoposide (BEP), has since the late 1970s been the standard treatment of metastatic nonseminoma and seminoma.6,66,83,84 Generally ≥4 cycles administered. Some treated according to experimental regimens within research protocols.68,69,71-74
Nonseminomas: Post-chemotherapy RPLND and surgical removal of additional residual tumors if present in all patients with initial metastatic disease.66 Further CT if malignant cells present upon histological examination. RT was a treatment option if residual masses persisted after CBCT and/or surgery. Nerve-sparing RPLND from 1989.77
Seminomas: post-chemotherapy RT of residual masses (until 1986) or surgical removal.84 1990 to 1999 Nonseminomas: Primary staging
RPLND was abandoned for all patients. Stage I: offered surveillance or 1-3 cycles of adjuvant
CBCT.47,65,67,70,75 Stage Mk+ and IIA:
BEP x 3-4 followed by RPLND if residual masses.85
Seminomas: adjuvant abdominal RT continued as above, target dose usually <30 Gy.
The BEP-regimen remained standard first-line therapy in metastatic disease. From 1995, high-dose chemotherapy with autologous stem cell support was available. Some treated according to experimental regimens within research
protocols.68,69,71-74
Nonseminomas: From 1995 post-chemotherapy RPLND was performed if abdominal metastases >2 cm at diagnosis or in case of residual masses.85 Seminomas: Surgical removal of residual masses often performed.84,86-88
2000 to 2009 Nonseminomas: Stage I: surveillance or one adjuvant BEP cycle.47,89 Stage Mk+ and IIA: continued as above.
Seminomas: Stage I: RT was gradually abandoned. Patients increasingly offered surveillance or 1 cycle of adjuvant carboplatin monotherapy.47,80-82 Stage IIA: RT still a treatment option.78
The number of CBCT cycles was reduced to 3 cycles for patients with good prognosis (the majority of patients) and 4 cycles for patients with intermediate and poor prognosis.7,74 Seminoma patients offered EP instead of BEP.78,82,90 Nonseminomas: Post-chemotherapy RPLND continued as above.
Seminomas: Post-chemotherapy surgery not recommended.78,82,8788
Note: Clinical stage as described by Peckham et al.62 Abbreviations: TC, testicular cancer; RPLND, retroperitoneal lymph node dissection; CBCT, cisplatin-based chemotherapy; RT, radiotherapy; Gy, Gray.
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1.4.2 Platinum compounds and the retention of platinum
The metal platinum is the most fundamental component of the cytotoxic drugs cisplatin and carboplatin.91 For 40 years, cisplatin and its analogs have had a considerable impact on the treatment of a number of solid cancers, and it made TC a model of a curable malignancy.6,91
Genomic features that can explain the chemosensitivity of TC have been identified. Through whole-genome sequencing and functional measurement of apoptotic signaling, primary TCs have been found to have high mitochondrial priming, a trait that facilitates chemotherapy-induced apoptosis.42
Cisplatin is a highly-potent cancer drug that interacts with and modifies DNA through intrastrand (>90%) crosslinks in addition to interstrand crosslinks, DNA-protein crosslinks and DNA monoadducts, ultimately leading to apoptosis of cancer cells. 92-94 Germ cell TC is highly sensitive for cisplatin, presumably because of an overexpression of some crucial proteins, decreased repair of DNA-crosslinks and a hypersensitive apoptotic response.93,95 However, multiple dose-limiting acute side effects are related to cisplatin, such as nephrotoxicity, ototoxicity, neurotoxicity, and nausea.91 To reduce the risk of renal damage, high fluid intake and sufficient diuresis during treatment is important. Modern antiemetic treatment is effectively minimizing cisplatin-induced nausea. The elimination of cisplatin compounds is mainly renal.96 Although 50% of cisplatin is eliminated within the first 5 days after infusion, the elimination of cisplatin requires several half-lives that increases with follow-up time.97,98
The cytotoxic mechanism of carboplatin is similar to that of cisplatin, although carboplatin requires a much higher drug concentration and longer incubation time to induce the same amount of DNA changes.99 Carboplatin is considered 4-fold less potent than cisplain.100,101 The acute toxicity following carboplatin is less frequent and milder than that of cisplatin, except for a larger degree of myelosuppression.92 Carboplatin is generally excreted as an unchanged drug in the urine.92
Traces of platinum have been detected in several organs months after administration,102,103 and in 2000, Gietema et al. discovered that platinum metabolites could be detected in plasma for up to 20 years after treatment with CBCT.104 Moreover, serum concentrations up to a 1000 times higher than in unexposed controls have been detected in TCS >5 years after treatment,96 and up to 10% of the long-term circulating platinum remains reactive.105 Likewise, adducts have been detected in urine up to 16.8 years after treatment.96 The retention of platinum is highly relevant for
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the development of adverse health outcomes after treatment with platinum-based chemotherapy (PBCT).
1.4.3 Other important cytotoxic drugs in the treatment of TC
Cisplatin has been used in combination with other cytotoxic drugs during the study period. From the late 1970s to 1987, cisplatin in combination with bleomycin and vinblastine (CVB) was the standard treatment.6,66 Because of less acute neurotoxicity when cisplatin and bleomycin was combined with etoposide (BEP), this has been the standard treatment combination from 1987.83 From the early 2000s, metastatic seminoma patients were offered cisplatin and etoposide (EP) instead of BEP.90
Bleomycin, a glycopeptide antibiotic, acts by forming free radicals that induces DNA cleavage.91 The elimination of bleomycin is renal. Pulmonary toxicity is the most important dose-limiting toxicity.91
Vinblastine is a vinca alkaloid that exerts its anticancer effect by acting upon microtubules, leading to cell cycle arrest in metaphase.91 The elimination is hepatobiliary, and the most important dose-limiting toxicity is neutropenia.91 Peripheral neurotoxicity may occur, but milder than for some other vinca alkaloids.91
Etoposide is a DNA topoisomerase II inhibitor.91 DNA topoisomerases are enzymes
involved in the transient DNA breaks essential for fundamental biological processes. By poisoning this process, etoposide inhibits the re-ligation of DNA ultimately leading to apoptosis.91,106 The elimination of etoposide is renal, and myelosuppression is the most important dose-limiting toxicity.91