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Second primary cancer as late effect of cancer treatment

Second primary cancer as late effect of cancer treatment . Enrico Mini Department of Pharmacology University of Florence. Introduction (I).

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Second primary cancer as late effect of cancer treatment

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  1. Secondprimarycanceras late effectofcancer treatment Enrico Mini DepartmentofPharmacology UniversityofFlorence

  2. Introduction (I) • Of the many late complications of treatment, second cancers are generally considered to be the most serious, not only for substantial morbidity but also for considerable mortality. • Increased risks of second cancers have been observed after radiotherapy, chemotherapy, and combined modality treatment. • Not all second cancers are due to therapy.

  3. Schematic illustration of risk factors for second primary cancers Travis LB, Acta Oncologica 41:323-333, 2002

  4. Introduction (II) • In view of the high prevalence of cancer in the general population and the increasing incidence of most cancers with age, it is important to exclude the role of chance in the development of second cancers. • To this end, comparison with cancer incidence statistics derived from the general population is crucial. • If a second malignancy is demonstrated to occur in excess, the contributions of other risk factors need to be ruled out convincingly before the increased risk can be attributed to treatment. • The evaluation of the carcinogenic effects of therapy, however, is complicated by the fact that therapeutic agents are frequently given in combination. • Appropriate epidemiologic and statistical methods are required to quantify the excess risk and to unravel the role of treatment and other factors.

  5. Data sources to assess second cancer risk • Population-based cancer registries • Hospital-based cancer registries • Clinical trial series • Epidemiologic study designs: • cohort studies • case-control studies.

  6. Carcinogenicityofantineoplasticagents and theircombinations Group 2B – Drugswhich are possiblycarcinogenictohumans (generally, limitedhumanevidence, butabsenceofanimalevidence) Bleomycin Dacarbazine Daunorubicin Medroxyprogesteroneacetate Mitomycin Mitoxantrone Streptozocin Group 3 – Drugswhich are notclassifiableastoitscarcinogenicitytohumans Actinomycin D 5-Fluorouracil Metotrexate Prednisone Vinca alkaloids Group 1 – Drugswhich are carcinogenic (sufficienthumanevidenceofcarcinogenesis) • Busulfan • Chlorambucil • Cyclophosphamide • Melphalan • Semustine (Methyl-CCNU) • Thiotepa • Treosulphan • MOPP-combinationtherapy • Etoposide in combinationwithcisplatin and bleomycin • Etoposide • Azathioprine • Methoxsalen, plus UV radiation • Tamoxifen • Diethylstilbestrol Group 2A – Drugswhich are probablycarcinogenictohumans (generally, limitedhumanevidence, butsufficientanimalevidence) • Carmustine (BCNU) • Cisplatin • Doxorubicin • Lomustine (CCNU) • Mechlorethamine • Procarbazine • Teniposide IARC, 2011

  7. Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group (I) Grosse Y et al., LancetOncol 10:13-14, 2009

  8. Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group (II) Grosse Y et al., LancetOncol 10:13-14, 2009

  9. Hormonal treatments assessed by the IARC Monograph Working Group Grosse Y et al., LancetOncol 10:13-14, 2009

  10. Therapy-relatedneoplasms • Acute myeloid leukemia(up to 10-20% of all AML cases) • Other treatment-related leukemias: • ALL (5-10% of all secondary acute leukemia) • chronic granulocytic leukemia (a small percentage of secondary leukemia) • Solid tumors: • bladder cancer (induced by cyclophosphamide) • bone sarcomas (linked to alkylating agents) • lung cancer (linked to alkylating agents) • endometrial cancer (associated to tamoxifen) • contribution of chemotherapy to radiation-induced solid tumors to be investigated (e.g. doxorubicin potentiates the development of second solid tumors after radiation for Wilms’ tumor)

  11. Secondary acute myeloidleukemia • At least two major syndromes of treatment-related leukemia exist: • "classic" alkylating agent–induced AML • acute leukemia related to the topoisomerase II inhibitors

  12. Characteristics of therapy-related acute myelogenousleukemia(alkylator versus topoisomeraseinhibitorrelated) AHD—antecedenthematologicdisorder; MDS—myelodysplasticsyndrome FromBorthakur G & Estey EE, 2007, and Meadows AT, 2001, modified

  13. Occurrence of therapy-related acute myelogenous leukemia and myelodysplasticsyndrome followingcommon exposures ASCT—autologousstemcelltransplant. Borthakur G & Estey EE, CurrOncolRep 9:373-377, 2007

  14. Alkylatingagent-induced AML • Alkylatingagentswithknownleukemogeniceffects in humans include mechlorethamine, chlorambucil, cyclophosphamide, melphalan, semustine, lomustine (CCNU), carmustine (BCNU), prednimustine, busulfan, and dihydroxybusulfan. • Controversial findings have been reported with regard to procarbazine, which demonstrates an underlying mechanism of action similar to that of alkylating agents. • Few studies have addressed the relative leukemogenicity of the various alkylating drugs, but a strong body of evidence to date suggests that, at doses of equal therapeutic effect, cyclophosphamide is substantially less leukemogenic than melphalan, mechlorethamine, chlorambucil, CCNU, and thiotepa. • The risk of alkylating agent–related AML has been shown to increase with increasing cumulative dose, duration of therapy, and dose-intensity. • Few studies have attempted to separate the effects of cumulative dose, duration of treatment, and dose intensity, which tend to be highly correlated, and the results of such analyses have been controversial.

  15. Distribution and relative riskof acute or nonlymphocyticleukemiaaccordingtooverall treatment category Kaldor JM et al., N Engl J Med 322:7-13, 1990

  16. Distributionofcasesof acute nonlymphocyticleukemiaaccordingtotypeofchemotherapy* Kaldor JM et al., N Engl J Med 322:7-13, 1990

  17. Relative riskof acute nonlymphocyticleukemiaforpatientswithselectedchemotherapyhistories, regardlessofradiotherapyreceived Kaldor JM et al., N Engl J Med 322:7-13, 1990

  18. RiskfactorsforleukemiaafterHodgkin’s disease • Since the 1980s, MOPP-only chemotherapy has been gradually replaced by regimens containing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in many centers. • Patients treated with ABVD at the Milan Cancer Institute, where this regimen was designed, were shown to have a significantly lower risk of AML than MOPP-treated patients (15-year cumulative risks of 0.7% and 9.5%, respectively). • Another study showed that HD patients treated with MOPP- and ABVD-containing regimens in the 1980s had substantially lower risk of AML and MDS than patients treated in the 1970s with MOPP alone (10-year cumulative risks of 2.1% and 6.4%, respectively; P = .07). Valagussa P et al., 1982; Schellong G et al., 1997

  19. Smith RE et al., J ClinOncol 21:1195-1204, 2003

  20. Secondary AML in breastcancer (II) • There has been an increasing trend toward the use of dose-intensification strategies in chemotherapy protocols for breast cancer. • Typically, these regimens contain high-dose cyclophosphamide in combination with one of the anthracyclines (doxorubicin or 4-epidoxorubicin) and other active drugs. • The risk of AML associated with various AC regimens was quantified in six trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) (Smith RE et al, J ClinOncol, 2003)

  21. Cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome by cyclophosphamide intensity (mg/m2/cycle) AML/MDS, acute myeloidleukemia/myelodysplasticsyndrome; TX, treatment Smith RE et al., J ClinOncol 21:1195-1204, 2003

  22. Secondary AML in breastcancer (I) • The low risk of AML after CMF-based chemotherapy was confirmed by the Milan Cancer Institute and the Eastern Cooperative Oncology Group, who found cumulative risks of AML of 0.23% at 15 years and 0.18% at 7 years, respectively. • The University of Texas M. D. Anderson Cancer Center reported a higher risk of leukemia after a standard dose-intensity FAC treatment. • Fourteen cases of leukemia were observed among 1474 patients for an estimated cumulative risk of 1.5% (95% CI, 0.7 to 2.9) at 10 years. • The risk of AML was significantly higher when chemotherapy was given in combination with radiotherapy (2.5% vs. 0.5%). Valagussa P, et al, Ann Oncol 1994; Tallman MS et al., J ClinOncol 1995; Diamandidou E et al., J ClinOncol 1996

  23. Platinatingagent-induced AML • The platinating agents cisplatin and carboplatin are among the most important cytotoxic drugs introduced in the last few decades and are widely used to treat many cancers. • The platinum compounds, however, demonstrate carcinogenicity in vitro and in laboratory animals, forming intrastrand and interstrand DNA cross-links as do bifunctionalalkylating agents. • In a population-based study of women with ovarian cancer,cisplatin-based combination chemotherapy was linked to significantly increased risks of leukemia (P trend for cumulative dose, <.001) in a multivariate model adjusted for other treatment parameters. • Future studies should evaluate whether other drug combinations that include platinum might also be linked to elevated risks of leukemia, because it is not clear whether cisplatin acts as a human leukemogen only in combination with selected cytotoxic agents

  24. Risk of Leukemia According to the Cumulative Dose of Platinum, Duration of Therapy, and Specific Druga aThe data are limited to 27 patients with leukemia and 103 controls who receive platinum-based chemotherapy without melphalan. bThe values shown are median cumulative doses of platinum and the median duration of therapy among controls. cThe reference group consisted of 6 patients with leukemia and 94 controls who were not exposed to platinum derivatives of other alkylating drugs. dCumulative amounts of carboplatin were divided by 4 to convert them to cisplatin-equivalent doses. e for trend <.001. f for trend = .001. (From Travis LB, et al. N Engl J Med 1999;340(5):351., with permission.) FromvanLeeuwen FE & Travis LB, 2005

  25. Plasma platinum concentrations of 61 cured testicular cancer patients 10–20 years after cisplatin combination chemotherapy and 20 cured testicular cancer patients 10–20 years after orchidectomy Horizontal line=limit of quantification of platinum (6 pg/g plasma). Gietema JA et al., Lancet 355:1075-6, 2000

  26. Concentration-time plot of plasma platinumconcentrations of 61 cured testicular-cancer patients 10–20years after cisplatin combination chemotherapy Gietema JA et al., Lancet 355:1075-6, 2000

  27. Topoisomerase II inhibitors-related AML • Ratain and coworkers (1987) were the first to recognize the potentially leukemogenic properties of etoposide-containing regimens in patients with non–small cell lung cancer, and this has also been documented for patients with other types of malignancies.

  28. Acute leukemiarelatedtoepipodophillotoxins • Use of etoposide and cisplatin to treat testicular cancer has been linked to increased risks of leukemia in relatively small studies, typically at large total amounts of etoposide (3000 mg/m2 or more). • Considerably lower total doses of etoposide were administered in the case-control investigation reported by Travis et al., (2000) similar to the dose of less than 2000 mg/m2 used in current regimens. • The IARC concluded that there is sufficient evidence that etoposide in combination with cisplatin and bleomycin is carcinogenic to humans. • The overall level of risk, however, appears relatively low. • Based on a review of selected U.S. clinical trials, Smith et al. (1999) estimated that the 6-year cumulative risk of secondary leukemia is 0.7% after cumulative etoposide doses of 1500 to 2999 mg/m2. • Kollmannsberger et al. (1999) concluded that the cumulative incidence of leukemia among testicular cancer patients given etoposide at cumulative doses of 2000 mg/m2 or less and more than 2000 mg/m2 was 0.5% and 2.0%, respectively, at a median of 5 years of follow-up.

  29. Secondaryleukemiasfollowingchemotherapyoftesticularcancercontaning cumulative etoposidedoses <2 g/m2 Bokemeyer C & Kollmannsberger C, “SecondaryMalignances” in Lipp HP ed, 1999

  30. Secondaryleukemiasfollowingchemotherapyfortesticularcancercontaning cumulative etoposidedoses ≥2 g/m2 Bokemeyer C & Kollmannsberger C, “SecondaryMalignances” in Lipp HP ed, 1999

  31. AML-relatedtoanthracyclines • Evidence has accumulated that the anthracyclines doxorubicin and 4-epidoxorubicin may induce a similar type of AML as the one related to epipodophyllotoxin treatment. • According to the IARC, doxorobicin is probably carcinogenic to humans. • An evaluation of the carcinogenic potential of doxorubicin is complicated, because it is typically given in combination with other chemotherapeutic agents, including alkylators. • Curtis et al. (1992)found no increase in the risk of leukemia associated with doxorubicin therapy for breast cancer after adjustment for the effects of alkylating agents and radiotherapy. • Although an increase in the dose of doxorubicin given to treat childhood cancer seemed weakly associated with an increased risk of leukemia after adjustment for use of alkylating agents, the investigators concluded that the excess risk was almost completely attributable to alkylators (Tucker MA, 1987). • In a study of children with Wilms' tumor, the RR of leukemia (six cases) after doxorubicin-containing regimens was approximately 14; however, because a relatively constant dose of doxorubicin (300 mg/m2) was used and data on treatment of relapse were incomplete, evaluation of a dose-response relation was not possible (Breslow NE, 1995).

  32. Antimetabolites and carcinogenicrisk • The antimetabolites have generally not been regarded as carcinogenic. • Cheson et al. (1999) observed that nucleoside analogue therapy (fludarabine, deoxycoformycin, cladribine) for chronic lymphocytic leukemia did not appear to confer a significantly increased risk of second cancer. • However, in a report from St. Jude Children's Research Hospital (Relling et al., 1999), it was shown that children with ALL who received cranial irradiation and who had a wild-type thiopurinemethyltransferase phenotype had an 8.3% cumulative risk of brain cancer, whereas children with ALL who received irradiation and had a defective phenotype had a 42% risk (P = .0077). • Patients also received concurrent systemic chemotherapy with high-dose 6-mercaptopurine (75 mg/m2) plus high-dose methotrexate. • It was hypothesized that the defective thiopurinemethyltransferase activity resulted in higher exposures to thioguanine nucleotide metabolites of 6-mercaptopurine during the period of irradiation.

  33. ChronicHealthConditions in AdultSurvivorsofChildhoodCancer Roughly 40% ofcancersurvivorswilldeveloplife-threateninghealthproblemswithin 30 yearsoftheirinitialcancerdiagnosis Oeffinger KC et al., N Engl J Med 355:1572-82, 2006 Marder J, Science 328:1474-5, 2010

  34. Risk of Bladder Cancer According to Cumulative Dose and Duration of Cyclophosphamide Therapy aMedian cumulative dose of cyclophosphamide or median duration of therapy among all patients within the specified category. bThe referent group consists of 6 case subjects and 42 control subjects who were not treated with cyclophosphamide and who received a radiation dose to the bladder of 0.5 Gy or less. The multivariate model also included terms for patients who received radiotherapy without cyclophosphamide (6 case subjects and 16 control subjects). cThe minimum cumulative dose of cyclophosphamide in this group was 2.1 g. d <.05. e for trend <.005. (From Travis LB, et al. J NatlCancerInst1995;87:524, with permission.) FromvanLeeuwen FE & Travis LB, 2005

  35. Riskofbladdercanceraccordingto cumulative dose and durationofcyclophosphamide and administrationofradiotherapy Travis LB et al., J National CancerInst 87:524-530, 1995

  36. Relative risk and absolute excess risk of second malignant disease in 32,591 patients treated for Hodgkin’s lymphoma Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  37. Published studies of a second lung cancer in patients previously treated for Hodgkin’s disease (I) Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  38. Published studies of a second lung cancer in patients previously treated for Hodgkin’s disease (II) Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  39. Relative risk and absolute excess risk of a second lung cancer by age at first treatment (years) in 5519 patients treated for Hodgkin’s lymphoma Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  40. Relative risk and absolute excess risk of subsequent lung cancer by time since treatment (years) in 5519 patients treated for Hodgkin’s lymphoma Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  41. Relation between radiation dose, treatment with alkylating drugs, and cigarette smoking on relative risk of lung cancer in 222 patients with lung cancer after treatment for Hodgkin’s disease Lorigan P et al., Lancet Oncol 6: 773–79, 2005

  42. Effects of SERMs and Aromatase Inhibitors on Nonbreast Tissue Hayes DF, New Engl J Med, 2007

  43. Actuarial endometrial cancer-specific survival according to duration of tamoxifenuse Survivalprobability (%) Tamoxifen No (n=198) <2 yr (n=56) 2-5 yr (n=39) ≥5 yr (n=15) months From Bergman L et al., Lancet 356: 881–87, 2000

  44. Risk of Endometrial Cancer after Tamoxifen Therapy in Women with Breast Cancer EBCTCG, Early Breast Cancer Trialists' Collaborative Group; NA, not available; SEER, Surveillance, Epidemiology, and End Results program. aSeveral early reports are not presented because the dates are included in larger or updated studies presented here.bBecause the incidence of endometrial cancer appeared to be unexpectedly low among placebo-treated women, the investigators reestimated the risk associated with tamoxifen, using population-based rates and information from another trial. However, the resulting risk estimates of 2.2 and 2.3, respectively, are less valid than the estimate based on the endometrial cancer rate in placebo-allocated controls (relative risk, 7.5) because (a) regardless of treatment, a population of breast cancer patients entered into a clinical trial may have different endometrial cancer rates than the general population; and (b) the rates used were from a different geographic area, a different period, or both.183 (Adapted from ref. 137.) FromvanLeeuwen FE & Travis LB, 2005

  45. Forest plots of odds ratios for adverse events in endometrial carcinoma ATAC = Anastrozole, Tamoxifen alone or in combination (5); BIG 1-98 = Breast International Group 01-98 (3); ABCSG8 = Austrian Breast Cancer Study Group VIII (4); ITA = Italian TamoxifenAnastrozole Trial (2); TEAM = TamoxifenExemestane Adjuvant Multinational Trial (15); AI = aromatase inhibitor; CI = confidence interval; OR = odds ratio. Amir E et al., J NatlCancerInst 103:1299-1309, 2011

  46. Conclusions • Knowledge of risk factors for second malignancy has made it possible to identify patient groups at high risk of developing second cancers due to treatments that they received in the past. • Whenever effective screening methods are available, these should be implemented in the patients' follow-up program to improve their survival after diagnosis of second malignancy. • The issue of treatment-induced second cancers must always be viewed in relation to the sometimes dramatic improvement in survival rates for patients with various malignancies. • Clinical research should focus on the development of therapeutic regimens with less carcinogenic potential. • It is of the utmost importance that changes in therapy to reduce the risk of late complications be made only in the context of carefully designed clinical trials that evaluate whether the overall efficacy of treatment is maintained. • For many cancer treatments, the long-term effects on second malignancy risk are not yet known. • In addition, new therapies are being introduced continuously, and the associated risks of late sequelae need to be evaluated. • Results of investigations at the molecular levelmay clarify the influence of genetic susceptibility on treatment-related risk and contribute importantly to the elucidation of mechanisms underlying drug- and radiation-induced carcinogenesis.

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