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The optimal sequence of these agents remains uncertain. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Median overall survival was 22 months. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

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Testicular germ cell tumors TGCTs are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting.

Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting. Recently, this promise has been heightened by the realization that distinct and perhaps pharmacologically replicable epigenetic states, rather than fixed genetic alterations, may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies.

In this review, it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics. Metastatic TGCTs have been a model for transforming a once fatal metastatic solid tumor into one that is curable. Attempts to incorporate newer targeted therapies to treat refractory TGCTs have been unsuccessful. Further, TGCT patients successfully treated with cisplatin-based therapies suffer from acute and life-long toxicities including infertility, hypogonadism, androgen deficiency, decreased lung and kidney function and neurotoxicity and have a greater risk of developing cardiovascular disease and secondary malignancies [ 10 ].

Hence, there is a pressing clinical need to devise new strategies to treat cisplatin refractory TGCTs and a rationale to devise targeted, cisplatin-sparing therapies. TGCTs remain the only solid malignancy curable with chemotherapy.

A greater understanding of the hypersensitivity and resistance of TGCTs has the potential to not only impact refractory patients but also may inform strategies to sensitize other solid tumors to conventional chemotherapies [ 11 , 12 ]. TGCTs are classified based on histology into two distinct subtypes seminomas and nonseminomas. Both seminomas and nonseminomas likely arise from precursor cells called germ cell neoplasia in situ GCNIS [ 13 — 15 ]. Nonseminomas can be further classified as embryonal carcinoma EC , teratoma, yolk sac tumor and choriocarcinoma.

Pluripotent EC are the stem cell-like component of nonseminoma. The basis of this hypersensitivity and mechanisms to account for chemotherapy resistance remain elusive. TGCTs likely represent transformed germ cells and may have inherited unique mechanisms of sensitivity to DNA damage and other stress to prevent germline mutations.

Alterations in traditional mechanisms of cisplatin sensitivity and resistance in other solid tumors have generally not been accepted as the reasons for the hypersensitivity of TGCTs [ 3 , 12 , 18 ]. TGCTs have one of the lowest overall somatic mutation rates of all solid tumors and possess unique epigenetic states that are likely a reflection of the epigenetics of their primordial germ cell PGC origins [ 19 , 20 ].

Further EC and other pluripotent cells are known to undergo extensive plasticity in tumorigenicity depending on the environment [ 21 , 22 ]. These findings suggest that epigenetics may play a larger role in the chemotherapeutic hypersensitivity and resistance of TGCTs. Recently genetic susceptibility, biological signaling, and genetic and environmental factors have been examined to explain the mechanisms responsible for TGCTs curability, pathogenesis and development of treatment resistance.

This review will focus on potential mechanisms of cisplatin resistance in TGCTs that may relate to the exquisite sensitivity of this solid tumor to conventional chemotherapeutics that may provide strategies to overcome acquired cisplatin resistance.

The incidence of TGCTs has been steadily rising in young males [ 9 ]. According to the 2 01 8 WHO global cancer observatory, TGCTs are estimated to have the largest number of new cases among all cancers for males under the age of 34 years in the USA and second largest worldwide [ Figure 1 ] [ 23 ]. The incidence of TGCTs varies widely with geographic location with the highest incidence in northern European countries and the lowest in Africa nations [ Figure 2 ].

The reasons for these differences is not known but is hypothesized to be a combination of inheritable and environmental factors including exposure to endocrine disruptors in utero. Late age at puberty, male infertility and testicular dysgenesis syndrome are also associated with TGCTs [ 29 — 33 ]. Estimated new cancers in males aged 0—34 in the USA and worldwide for Pie charts represent the distribution of new cancer cases in the United States and worldwide for males 0—34 years of age.

Data source: World Health Organization global cancer observatory. Estimated number of new TGCT cases, deaths and prevalence worldwide for Data source: WHO global cancer observatory. TGCTs: testicular germ cell tumors. EC cells resemble embryonic stem ES cells [ 22 ]. Both cell types possess pluripotency and have close similarities in gene expression [ 34 , 35 ].

Interestingly, despite similarities, EC cells are malignant, while ES cells are not. GCNIS-derived TGCTs have cytogenetic and molecular anomalies that mainly include aneuploidy and gain and loss of distinct chromosomal regions coupled with somatic mutation rates that are low [ 19 , 20 ].

Chromosome 1 2 p amplification, such as isochromosome 1 2 p and chromosome 1 2 p overrepresentation are nearly universally present and pathognomonic for TGCTs [ 36 , 37 ]. Other chromosomal anomalies associated with TGCTs include gain of genetic material on chromosome 1, 2 p, 7, 8 , 1 2 , 14q, 15q, 17q, 2 1q, and X and the deletion of genetic material from chromosome 4, 5, 11q, 13q, and 1 8 q 2 [ 38 ].

Similarly, multiple passaging of ES cells has been shown to result in acquired alterations similar to those found in TGCTs and EC, including chromosome 1 2 , 17, and X gain [ 39 ]. Genetic alteration in TGCTs. Top genetic alterations are arranged by frequency.

Data source: TCGA. Further, abnormalities of germ cell development are associated with TGCT incidence [ 46 ]. Taken together the data support that TGCTs come from arrested PGCs or gonocytes that lie dormant but further progress with gonadal hormones during sexual maturation [ 41 ].

Genetic drivers of TGCTs are poorly understood compared to other cancers. Several genes have been implicated in the pathogenesis of TGCTs, but their exact roles are still uncertain and underscore that TGCT etiology is likely widely polygenic in nature. Genome-wide association studies have been useful in identifying variants that contribute to risk of TGCTs. Allelic variation within the kit-ligand gene 1 2 q 22 is the strongest genetic risk factor for TGCTs [ 49 ].

Several other allelic variants have been identified that correlate with TGCTs susceptibility [ 45 ]. There is considerable evidence that epigenetics may play a role in TGCT biology. As stated above, environmental exposures in utero and testicular dysgenesis syndromes are major risk factors for TGCTs.

Further, normal ES cells are very similar in gene expression and biology to EC cells. Transformation of both of these pluripotent cell types are influenced by environmental factors exemplified by findings that ES cells form teratoma and teratocarcinomas when implanted ectopically in mice, while EC cells in certain situations can participate in normal development when placed in the early embryo [ 21 , 50 ].

It is important to remember that PGCs normally undergo erasure of imprinting during development [ 51 ]. Thus, TGCTs may have arisen from a germ cell lacking imprinting. Evidence to support this comes from the finding that IGF 2 and H19 are expressed from both alleles in TGCTs but are otherwise exclusively expressed from one parental allele in adult tissues [ 52 ]. Seminomas possess very little DNA methylation while EC have an intermediate level of DNA methylation compared to somatic cancers and EC-derived teratoma are hypermethylated [ 20 , 52 — 55 ].

Teratoma is resistant to cisplatin treatment. Also, mCpH does not occur in the mature components of nonseminoma or in seminoma, suggesting mCpH is closely associated with the pluripotent and reprogrammed state of EC [ 52 ]. The role of non-CpG methylation in EC is currently unclear. Histone modifications are well-established epigenetic regulators. Polycomb complexes modify chromatin to repress homeotic genes which have an important role in stem cell dynamics [ 57 , 58 ].

Gene repression is initiated by polycomb repression complex 2 wh ich contains histone methyltransferase activity resulting in histone H3 trimethylation on lysine 2 7 H3K 2 7me3. Little is known concerning alterations in histone modifiers in TGCTs [ 61 , 62 ]. Voorhoeve et al. For example, miRa-3p was reported to have high sensitivity and specificity for detecting TGCT disease burden and was not elevated in control patients or patients with other cancer types [ 66 , 67 ].

Since TGCTs appear to have distinct epigenetics compared to normal tissues and other cancers, the use of epigenetic biomarkers may be particularly useful for disease management of TGCT patients.

Several principles of solid tumor chemotherapy were validated during the optimization of curative TGCTs regimens. For advanced TGCTs, bleomycin, etoposide and cisplatin or etoposide, ifosfamide and cisplatin VIP are the first line standards of care. Currently there are no predictive biomarkers to identify which poor-risk patients will die from disease. There is a clinical need to better identify which high risk patients will fail conventional therapy.

Targeted approaches including tyrosine-kinase inhibitors and immunotherapy have failed to demonstrate activity in these refractory cases.

Mechanisms of hypersensitivity and acquired resistance in TGCTs are likely multi-factorial and could include cellular detoxification, altered platinum accumulation, DNA repair, and alterations in apoptotic pathways [ 12 , 18 , 70 ]. However, these mechanisms are shared by many solid tumors that are not curable. Further TGCTs are highly sensitive to a variety of agents that do not share common import and export pathways and mediate different forms of DNA damage repaired by distinct mechanisms.

Hence, mechanisms responsible for TGCT sensitivity and resistance may be related to how these tumors respond to damaged DNA mediated in part by their unique cellular context [ 3 , 71 ].

In the next section, we will review suggested mechanisms of therapy resistance in TGCTs. Cisplatin resistance mechanisms can be classified as pre-target, on-target, and post-target [ 70 ]. Pre-target involve alterations preceding the binding of cisplatin to DNA, on-target resistance involves alterations directly relate to DNA-cisplatin adducts, post-target resistance involves mechanisms downstream of cisplatin-mediated DNA damage [ Figure 4 ].

In this section we will discuss these cisplatin resistance mechanisms. Proposed mechanisms mediating cisplatin sensitivity and resistance in TGCTs. Cisplatin resistance mechanisms are classified as pre-target, on-target, post-target and epigenetic mechanisms. Cellular uptake of cisplatin is typically mediated by passive diffusion or facilitated transport, although the copper transporter SLC31A1 has also been implicated as a cisplatin transport mechanism [ 72 ]. Cisplatin uptake rates in TGCT and other cancer cells have been reported to be similar [ 73 ].

However, no cisplatin resistance mechanism related to drug transporters has been reported for TGCTs. Resistance to cisplatin is often associated with increased levels of thiol-containing proteins such as glutathione and metallothionein which detoxify cisplatin through conjugation. In general it appears that the level of these detoxifiers are low in TGCTs compared to some other tumor types [ 74 ]. Interestingly, one study showed high levels of a glutathione-S-transferase, an enzyme that conjugates GSH in resistant teratoma [ 75 ].

These finding suggest that low levels of exporters and detoxifiers may play at least a contributory role in TGCT sensitivity to cisplatin. However, in general pre-target mechanisms have not been widely recognized as significant sources of cisplatin resistance in TGCTs. TGCTs have been shown to have similar rates of cisplatin DNA adduct formation upon initial exposure compared to other tumor types [ 71 , 74 , 76 ].

However, other reports have implied that TGCTs possess a diminished capacity to repair cisplatin adducts [ 77 , 78 ]. Correspondingly, cisplatin-resistant cells may have acquired the ability to repair adducts at an enhanced rate or gained the ability to tolerate unrepaired lesions. We refer the reader to an excellent recent review on this topic [ 86 ].

However, the precise molecular mechanisms are unclear. Post-target resistance to cisplatin can result from alterations in signal transduction pathways that mediate apoptosis in response to DNA damage. Non-repairable cisplatin-induced DNA damage leads to the activation of a multi-branched signaling cascade with proapoptotic outcomes.

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The optimal sequence of these agents remains uncertain. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test.

Median overall survival was 22 months. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months. Renal cell carcinoma RCC accounted for nearly 64, new cases and over 13, deaths in the United States in The safety and efficacy of TKIs after prior cytokine therapy have been previously demonstrated in large prospective trials of these agents in the second-line setting.

In a retrospective analysis of 23 patients who received salvage HD-IL2 therapy after prior VEGF-targeted therapy, there were no responses, and the incidence of severe cardiovascular toxicity was high, including 1 sudden cardiac death during HD-IL2 therapy. Thus, this collaborative effort was mounted to evaluate the safety and efficacy of HD-IL2 therapy in an expanded cohort of such patients, and to explore the potential patient-related, disease-related, and drug-related factors that may predict safety and efficacy.

A patient may have a recent diagnosis of mRCC and be anxious to initiate any therapy. Once on medical therapy, the disease may stabilize. IRB approval or exemption was obtained at all of the participating institutions.

Patient-related variables included age, sex, performance status, cardiac risk factors, personal history of CAD, and baseline cardiac evaluation if available. Disease-related variables included histology, number and sites of metastatic disease, Memorial Sloan Kettering Cancer Center MSKCC prognostic stratification, 21 , 22 and prior treatments. Primary data were too sparse to stratify by the Heng criteria.

In this retrospective analysis, we used descriptive statistics including estimates of proportions, as well as, means, medians, and interquartile range, and range. Relationships between 2 factors were explored using the Fisher exact test.

Quantitative outcomes such as the number of cardiac risk factors were explored, especially in relation to incidence of severe cardiac toxicity, and analyzed using the Wilcoxon rank-sum tests.

However, given the sample size limitations, any formal comparisons were truly exploratory and hypothesis generating. A Kaplan-Meier survival curve was used to display the OS function.

Cox proportional hazards regression models were used to estimate the hazard ratios of potential prognostic factors. A total of 28 men and 12 women were treated. The median age was All but 1 patient had clear cell histology subclassification data not available. Twenty-two patients had primary metastatic disease, and 18 patients had recurrent metastatic disease.

Three, 25, and 2 patients had MSKCC good-risk, intermediate-risk, and poor-risk disease, respectively. Data were not available to categorize 10 patients using this model.

Two patients had personal history of CAD. Left ventricular LV hypertrophy and valvular abnormalities were seen in 2 patients each.

Wall motion abnormality and ischemic changes were seen in 1 patient. Grade 1 creatine kinase or troponin elevations were reported in 3 patients. Two patients had reversible noncardiac respiratory failure. Two patients died within 1 month of receiving HD-IL2 therapy. Twenty-seven, 12, and 1 patient s received 1, 2, and 3 courses of HD-IL2, respectively. The median number of doses of HD-IL2 received was 17 range, 2— Twenty patients had disease progression PD and 2 patients were not evaluable.

The median duration of SD was 12 months range, 1. The duration of response was 6, 11, and 24 months for the 3 patients with PR. Median overall survival mo from time of starting HD-IL2 therapy. Although patient numbers were small and it is difficult to compare findings of small studies years apart, our observed median OS was 22 months, compared with There were 2 deaths due to CHF thought to be treatment related.

This retrospective study design has several limitations. Second, the reliance on chart review may underestimate cardiac-related AEs if they were not noted formally as in prospective therapeutic trials.

Other small studies in the post-TKI setting have now been reported. To the best of our knowledge, our study is the first series to examine potential associations between number of cardiac risk factors and incidence of severe cardiac toxicities. Multiple traditional cardiovascular risk factors are used for risk assessment of CAD.

On the basis of our findings, and the assumption that the low overall incidence of cardiac toxicity is the result of a careful patient selection process already in place at major HD-IL2 institutions, we recommend risk-adapted cardiac evaluation before HD-IL2 therapy, similar to standard preoperative cardiac risk evaluation.

The half-life of sunitinib is 2. With repeated daily administration, sunitinib accumulates 3- to 4-fold, whereas the primary active metabolite accumulates 7- to fold, with a metabolite half-life of 96 hours [Sunitinib Sutent prescribing information, Pfizer Labs, ]. The cardiotoxicity, in particular CHF, associated with sunitinib and sorafenib, has been previously reported. The reported time to improvement of LV EF was between 1 and 9.

On the basis of the pharmacologic half-lives of sunitinib and its active metabolites, complete clearance of the drug may require at least 3—4 weeks off therapy. However, the time to complete resolution of other clinical drug effects is not known.

On the basis of these considerations, we would recommend an interval of at least 2 months between completion of a TKI and initiation of HD-IL2. Sorafenib and sunitinib were the dominant TKIs in use during the time period encompassed by this study. With the approval of pazopanib and axitinib, we now have TKIs that are associated with a lower incidence of cardiomyopathy overall. Their effect on subsequent salvage IL2 therapy is unknown and requires further investigation. In the meantime, it would be prudent to exercise the same degree of caution in the selection of patients for HD-IL2 therapy after prior treatment with these agents.

Although limited by its retrospective nature and limited patient numbers, the strength of this study is that it incorporates data from multiple experienced investigators and HD-IL2 centers and reflects a diverse cross section of this patient population.

We conclude that administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. All authors have declared that there are no financial conflicts of interest with regard to this work. National Center for Biotechnology Information , U. Journal of Immunotherapy Hagerstown, Md. J Immunother. Published online Aug Elaine T.

Michael K. Bruce G. Thomas W. Timothy M. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Reprints: Elaine T. Received Feb 7; Accepted May 5. The work cannot be changed in any way or used commercially. This article has been corrected. This article has been cited by other articles in PMC. Key Words: high-dose interleukin-2, tyrosine kinase inhibitor TKI , renal cell carcinoma, sunitinib, sorafenib.

Open in a separate window. Cancer statistics, CA Cancer J Clin. Current algorithms and prognostic factors in the treatment of metastatic renal cell carcinoma. Clin Genitourin Cancer. J Clin Oncol.

Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between and Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.

N Engl J Med. Sorafenib in advanced clear-cell renal-cell carcinoma. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma AXIS : a randomised phase 3 trial.

Lancet Oncol. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.

Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. Expert Panel Recommendations.

J Am Coll Cardiol. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma.

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