Second+Primary+Cancers

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**Purpose** Traditional cancer therapies are typically focused on sending cancer into remission or expelling it from the body. This project will explore how traditional cancer therapies may give rise to rise to second independent tumors and the rates at which this occurs. =**Introduction**= After the remission of a first primary cancer, new tumors may arise to bring the patient out of remission and back into routines of hospitals and painful treatments. When a new tumor arises it can be as a result of metastasis, recurrence, or a new occurrence of the disease, and the origin of these tumors to classify them in one of these categories can be determined through histopathology (Ostrovnaya). According to the Gale Encyclopedia of Medicine, histopathology is the “study of diseased tissues at a minute level.” Through examination of the new tumors at a microscopic level, the tumor can be characterized by a distinct pattern of mutations which can be used to trace its clonal origins and determine if the new tumor arose as the progeny of a single (or multiple) cell left as a remnant of the primary cancer after the patient had completed treatment (Ostrovnaya). Cancer recurrence may appear as local, regional, or distant (metastasis), and is often influenced by the location and stage of the primary cancer. Recurrence refers to the original primary cancer returning after a period remission. In this discussion, we will focus minimally on cancer recurrence and instead focus on what is called a “Second Primary Cancer,” a cancer which occurs as completely new and independent of the first cancer (Mayo Clinic Staff). This project will explore how traditional cancer therapies may give rise to rise to second independant tumors and the rates at which this occurs. =**Why does cancer recurrence occur?**= There are many major factors that may increase cancer recurrence including genetics, environment, and treatment of previous cancers with traditional therapies such as chemotherapy and ionizing radiation. Genetic factors such as mutations and the presence or absence of a gene can cause multiple cancers. An example of this phenomenon is Retinoblastoma, which was discussed earlier in the quarter. This childhood disease, which causes tumor growth in the retina, is caused by a deletion of a certain region on chromosome 13 which contains the Rb gene.

Familial Retinoblastoma patients, who are usually affected in both eyes, inherited a defective copy of the Rb gene from one of their parents. These familial patients are predisposed to developing sarcomas, particularly osteosarcomas during adolescence or later in life (Weinberg 221). It is still unknown why sarcomas and not other types of cancers are the most common type of cancers that develop in these patients.

Environmental factors may also play a role in cancer recurrence. Traditional cancer therapies wreak havoc on the immune system, suppressing its normal capabilities. Consequently, cancer survivors who return to their lives at home may be more susceptible to environmental risks such as diet, tobacco and alcohol use, lack of exercise, and chemicals in the environment.

The bulk of our research will focus on the treatment of previous cancers and its effect on the development of second cancers in cancer survivors. The traditional therapies include radiation, chemotherapy, and surgery, but we will be focusing on the first two methods. We hypothesize that these treatments play a large role in secondary cancer development. In the next section, we will provide some background information on how chemotherapy and radiation damage the DNA and cause cell death.

=** Background: How do traditional cancer therapies work? **= Essentially, traditional cancer therapies like chemotherapy and ionizing radiation achieve their goal of killing cancer cells by damaging the DNA and disrupting the cell cycle, therefore preventing cell division. Many cancer cells have eliminated the checkpoint controls in the cell cycle process, like the checkpoint that blocks entrance into the M phase until DNA damage has been repaired. Therefore, these cancer cells will continue through the cell cycle, only to encounter "mitotic catastrophe" due to their damaged chromosomes (Weinberg 734). This catastrophe may result in aneuploidy, polyploidy, or formation of micronuclei. This overwhelming damage will then succeed in triggering apoptosis of the cells. Unfortunately, these therapies can cause damage to other quickly dividing cells in the body such as hair, gastrointestinal epithelium, skin, and bone marrow cells.

There are various ways by which chemotherapeutic agents can damage the DNA and/or sabotage proper mitosis events. For example, alkylating agents such as nitrogen mustard derivatives add methyl or other alkyl groups to guanines and can cause DNA strand cross-links, which prevent the separation of the two strands of a DNA double helix during replication and transcription 1 (Deans). Other chemicals prevent replication and transcription by binding to the DNA and also by causing DNA strand breaks. “Spindle poisons” such as paclitaxel and docetaxel disrupt microtubule function, thereby disrupting mitotic spindle configuration during mitosis. Table 1 below lists various chemotherapeutic agents, the cancers they are used to treat, and their mechanism of action.



Ionizing radiation therapy most frequently causes single and double strand DNA breaks, and less frequently base damage. Cancer cells may become resistant to these traditional therapies because of their altered pathways and response systems. For example, STATISTIC of tumor cells do not have a functioning p53 tumor suppressor protein. Therefore, they do not respond to signals which normally cause the cell to enter apoptosis. This resistance of cancer cells illustrates the incredible capability they have to constantly evolve and mutate to adapt to different environmental factors. As discussed in class, we may be “fighting a war with the wrong weapons” since traditional therapies are static, linear, and often crude (Islas). For this reason, we desperately need to develop targeted therapies to not only combat the dynamic nature of cancer but to also decrease the amount of damage caused to normal cells.

=**Risk of Recurrence in Relation to Previous Diagnosis**=

According to an [|article] in //The Oncologist// on “Second Malignancies in Elderly Survivors of Cancer,” second independent primary cancers account for nearly 14% of incident malignancies in the United states, and these second malignancies may be “related to prior chemotherapy, radiation therapy, hormonal therapy, or a combination of effects” (VanderWalde 2). These treatment-related second malignancies are important because they are often less responsive to traditional therapies and more aggressive. The median survival of therapy related leukemia has a 5-year survival rate of less than 10% compared with the 5-year survival rate of 23% seen in the same type of acute myeloid leukemia in patients experiencing it as their first cancer (VanderWalde).

In a longitudinal study conducted for the //Journal of Clinical Oncology//, the health records of 14,358 people who had been diagnosed with childhood cancer (predominantly acute lymphoblastic leukemia, Hodgkin’s disease, or kidney cancer) between 1970 and 1986 were followed. The average age of the primary cancer diagnosis was 8 years, and the subjects were, on average, followed for 18 years after the initial diagnosis. Overall, 9.6% of the subject pool was diagnosed with second primary independent cancers later in adulthood. Each subsequent cancer resulted in a greater risk of diagnosis with an additional primary independent cancer as evidenced by findings in the study that approximately 30% of the childhood cancer survivors who had been diagnosed with a second independent primary cancer were later diagnosed with a third independent cancer, and approximately 40% of these survivors of the third cancer were diagnosed with an additional cancer. Of the initial population of childhood cancer survivors, 66% were treated with radiation, and in this study, researchers concluded that cancer survivors who received radiation therapy were “more likely to be diagnosed with a new cancer…later in life compared with childhood cancer survivors who [did not receive] radiation therapy.” (“[|Childhood Cancer Treatment]”) In another study conducted by CANCER RESEARCH UK, the relative risk of developing a second primary independent cancer was four times greater in childhood cancer survivors relative to the general population. In this study, researchers at the University of Birmingham followed the health records of 18,000 childhood cancer survivors for an average of 25 years. Among the survivors of childhood cancer, 837 new instances of cancer where recorded, significantly higher than the 216 new instances expected in a population for which there was no prior diagnosis (“[|Childhood Cancer Survivors]”). In similar research study complied by St. Jude’s children’s hospital, this risk was even higher, with cancer risk for childhood leukemia survivors at nearly 13 times that of the general population when examining high-grade tumors (this study included 2,169 patients who had achieved complete remission from acute lymphoblastic leukemia and had an average 19 year follow-up period) (“[|Childhood Leukemia Increases Cancer]”). The researchers concluded that the increased risk of developing second cancers could be connected to the treatment therapies used for the original cancer as survivors treated with radiotherapy were three times more likely to develop a new cancer, particularly in areas localized around the site of treatment. “Survivors treated with radiotherapy to the abdomen and pelvis…were three times more likely to develop a new cancer of the digestive system.”(“[|Childhood Cancer Survivors]”) The figure below shows the trends of relative risk over time, based on patients involved in the Surveillance, Epidemiology, and End Results (SEER) Program from 1973 to 2000, conducted by the National Cancer Institute Division of Epidemiology and Genetics. The figure shows the increase in risk of a second primary independent cancer and its increase each year after initial diagnosis and remission. The table below shows common primary cancers and their associated secondary cancers as well as probable causes for the second cancers (VanderWalde 3). Many second primary independant cancers are shown to relate to genetic factors, but at he same time, many can be associated to treatments used to combat the initial primary cancer. For example, the second cancers following Hodgkin's lymphoma are primarily connected to irradiation and alkylating agents in chemotherapy.



=**Retinoblastoma & Radiation Therapy**= This article discusses the increased incidence of secondary cancers in familial retinoblastoma survivors who received radiotherapy. The researchers followed retinoblastoma patients diagnosed from 1914 to 1984 in two medical centers in New York and Boston. They excluded from their cohort those that died within 12 months of diagnosis, died outside of the United States, or had an unknown birth year. Of the 963 patients they studied, 60% had familial retinoblastoma with one or both eyes affected, while 40% had sporadic retinoblastoma with one eye affected. The median year of diagnosis was 1966, therefore some of the patients had already died by the time they conducted their study. 80% of familial patients were treated with radiation for Rb, compared to only 18% of the sporadic patients. The table below summarizes the characteristics of the researchers' cohort for this study.



From 1993 to 2000, the researchers identified 78 new primary cancers affecting these patients. The most common secondary primary cancers were sarcomas (which comprised one half of the total), brain cancer, and melanomas.The familial patients had a significantly higher incidence of secondary cancers, which was expected. What is novel about this study is that they found that the risk of secondary cancer was elevated almost seven-fold in nonirradiated familial patients and radiotherapy further increased this risk by 3.1-fold. This meant that the radiotherapy increased the high risk the familial patients already had of developing a new cancer later in life. Furthermore, the highly irradiated sites had the highest incidence of new cancer (Table 4). For example, since most familial patients treated with radiotherapy received it near their face and neck, cancer in the brain, nasal cavities, and eye were more common than moderately or lightly irradiated sites. Figure 1 below illustrates the cummulative incidence of secondary cancers in the years after Retinoblastoma diagnosis for hereditary patients treated with radiotherapy and hereditary patients treated without chemotherapy.

Figure 2. Cumulative incidence and 95% Cls of new cancers by time since diagnosis of hereditary retinoblastoma by radiotherapy  This study confirms the urgency to develop targeted drug therapy treatments to replace traditional treatments such as radiotherapy and chemotherapy, which can cause damage to normal cells, thereby increasing the risk of a new cancer. An article written by Howard B. Lieberman describes how these therapies damage the DNA and what response systems are in place inside a cell to combat this damage. At the end of his article, he proposes that DNA damage repair and response proteins can be used as targets for cancer therapy. He theorizes that if drug therapies can target these DNA damage repair systems of the cancer cells, it will prevent the cancer cells from repairing their DNA and therefore become more likely to be eradicated. Researchers could avoid the drug therapies from affecting normal cells by only targeting defective proteins or pathways that are utilized in cancer cells only. For example, cancer cells are genetically unstable and consequently may have a deficiency in DNA repair systems. Therefore, the cancer cells may rely on backup repair processes that normal cells do not have to resort to since their primary process is still intact. If these backup pathways could be pinpointed, they could also be targeted for inactivation so the cancer cells cannot repair DNA. A therapy like this would make chemotherapy and radiation more effective against cancer while protecting normal cells from damage. Many cancer cells are mutated in the BRCA1 or BRCA2 genes; this makes the cell rely on other pathways such as NHEJ or BER to fix certain types of DNA damage. In this example, the NHEJ or BER pathways would be targeted.

= = **Second Malignancies and Chemotherapy** According to an [|article] in “Second Malignancies in Elderly Survivors of Cancer,” published in //The Oncologist in// 2011, the risk for survivors of breast cancer contracting contralateral breast cancer was five-fold greater than relative risk expected in the general population. New solid malignancies are more likely following radiation treatment for breast cancer, particularly in areas localized around the site of treatment. For example, in a population based study mentioned in the article, the relative risk for a woman developing lung cancer after radiation treatment for breast cancer was 1.62 fold that of the general population, and the risk for developing esophageal cancer was 2.19 fold that of the general population after a period of 10-15 years. The use of alkylating agents in chemotherapy, however, showed an even greater increase in the relative risk for contraction of a second primary independent cancer. In one study cited by the article, “those who received alkylating agents had a 10-fold higher risk for subsequent [acute myeloid leukemia] than those who received neither chemotherapy nor radiation” (VanderWalde 2).

The increased risk for the development of second cancer is shown in all age groups, even amongst elderly survivors of cancer older than 70 years of age at the time of their initial diagnosis. In elderly women diagnosed with ovarian cancer, chemotherapy is linked to the development of both acute myeloid leukemia and acute lymphocytic leukemia, even in populations of patients that did not undergo radiation treatment. Alkylating agents (ex: melphalan and chlorambucil) showed the greatest increased relative risk, but these therapies are becoming more infrequent in the treatment of ovarian cancer in favor of platinum-based chemotherapy, a therapy which the article suggested may also be associated with a higher late risk rate for leukemia. In survivors of breast cancer and Hodgkin’s lymphoma as well, the risk for developing leukemia as a second independent cancer was greatly aggravated by alkylating agents in chemotherapeutic treatment (VanderWalde 4).

=**Conclusion**=

In conclusion, we believe that the traditional therapies discussed throughout this investigation play a large role in the high rate of cancer recurrence among cancer survivors. It is clearly evident from our research that new cancer therapies should be developed to avoid this discouraging problem. These new therapies could target oncoproteins, transcription factors, and other specific proteins inside the cancer cell. As discussed in the Retinoblastoma and Radiation section above, another option is to develop targeted therapies to be taken in combination with traditional therapies to increase their efficacy against cancer cells without the harmful side effects and damage. As always, follow up is paramount especially in those who have already survived a first primary cancer, not only for their own health but so we can better understand the effects of chemotherapy and radiation.

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