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Chemotherapy

Aim is to induce apoptosis by damaging DNA.

The average cancer drug approved has marginal benefit.

Of 71 consecutive for drugs approved for solid tumors between 2002 and 2014, the median improvement in overall survival was 2.1 months (Mailankody S).

Agents cause cell death by affecting processes that are frequently overactive or enhanced in tumors compared to normal tissues.

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific. 

 

Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific. 

 

The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective. 

 

This is why chemotherapy is typically given in cycles.

 

The “normal” cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss.

Delivery of full dose chemotherapy according to schedule is critical to successful tumor management and potentially curable malignancies.

A given percentage of cells may be killed with each dose, ultimately driving residual cell volumes down to zero.

Tumor cells increase in number between cycles of chemotherapy, and this occurs most rapidly when tumor cell burden is the lowest.

Chemotherapy is most effective at killing cells that are rapidly dividing. 

Relative dose intensity is calculated and takes into account the delivered dose of chemotherapy in the time it takes to complete such therapy compared with standard reference dose and schedule.

The actual chemotherapy dose intensity is calculated as the total dose delivered divided by the total time for completion of therapy, and the delivered dose intensity as a percentage of standard reference dose intensity, and the relative dose intensity is the result.

Doses of chemotherapy that are reduced or delayed results in a decrease relative dose intensity (RDI).

In chemotherapy dose delays reduce dose intensity and may allow tumor regrowth between cycles, possibly compromising survival rates for potentially curable cancers.

With delayed chemotherapy tumor cell counts at the end of each cycle may be higher than that achieved with doses delivered on schedule, increasing the potential for relapse, as the cells have an additional period of exponential growth before chemotherapy is re-administered.

Chemotherapy dose reductions decrease relative dose intensity with the potential of killing fewer tumor cells with the cycle and never reducing tumor burden enough to kill all viable cells: Reduced doses may fail to reduce tumor cell counts as much as full doses and potentially lead to higher counts at the end of each cycle of chemotherapy.

Survivors of chemotherapy treated with Hodgkin’s disease, testicular cancer and childhood leukemia have an excess of second cancers.

Not associated with secondary malignancies in breast cancer patients treated with chemotherapy.

Trials reveal that survival, toxicity and survival rates of elderly patients are similar to those of younger patients.

Poor performance status associated with lowered response rates and patients are more likely to experience toxic side effects than are more medically fit patients.

May be associated with more severe complications and they may be prolonged in elderly versus younger patients.

Most drugs used in the elderly have the same pharmacokinetics as in younger patients but differences that occur are usually due to physiologic changes associated with aging, such as changes in renal function.

Complications in elderly may have an increased effect on the quality of life including independence, disability, frailty and eventually death.

Age related comorbidities and physiologic changes such as declining renal and hepatic function and loss of total body protein increase toxicity in older patients.

Effects of age on the hematopoietic system becomes most pronounced after 65 years of age.

When dose reduction of ≤85% of standard dose intensity are made, to reduce toxicity, outcomes may be undermined related to disease control and overall survival (Bonadonna G et al).

In a retrospective analysis of 115 non-Hodgkin’s lymphoma patients survival was higher in patients receiving more than 75% of RDI compared to those receiving a lower RDI of doxorubicin (Kwak LW et al).

In breast cancer greater adiposity is associated with lower relative does intensity, and lower relative those intensity is associated with increased risk of death in breast cancer management.

In a retrospective analysis full dosing for a non-Hodgkin’s lymphoma patients with CHOP chemotherapy resulted in a greater overall five-year survival at five years for patients receiving gravy and 90% of RDI (Epelbaum R et al).

A retrospective analysis of 1056 patients with early breast cancer who completed chemotherapy and received 95% or more of RDI had significantly greater event free and overall survival at 10 years compared to those patients who completed and received less than 95% of RDI (Bosly A et al). will have him

Renal function must be factored into dosing of methotrexate, topotecan, capecitabine, cytabrine and carboplatin.

Induces lung toxicity in an estimated 10-20% of cases and may be responsible for up to 3% of deaths.

Chemotherapy is most effective at killing cells that are rapidly dividing. 

Alkylating agents including cyclophosphamide, busulfan and chlorambucil are associated with pulmonary adverse reactions.

Alkylating agents and an alkyl group to a DNA residue.

Alkylating agents damaged DNA and induce a number of signaling pathways involved in DNA damage repair.

Alkylating agents initiate programmed cell death through apoptosis.

Alkylating agents induce DNA damage by cross linking strands of DNA, creating inter-strand cross linking and intra-strand cross linking leading to DNA breaks that activate DNA repair mechanisms.

Two DNA bases are linked by and alkylating agent, which has 2 DNA binding sites.

DNA cross-linking prevents DNA synthesis and transcription.

Alkylating agents can induce mispairing of the nucleotides leading to mutations.

Alkylating agents attach alkyl groups to DNA bases and to replace the alkylating basis results in DNA fragmentation by repair enzymes.

Alkylating bases prevent RNA transcription and DNA synthesis.

Nitrogen mustard derivative alkylating agents, such as mechlorethamine, had more than one alkylating group per molecule and are di- or poly alkylating agents.

Melphalan is a phenylalanine derivative of mechlorethamine.

Ifosfamide is a nitrogen mustard derivative alkylating agent.

Cyclophosphamide is converted in the liver into acrolein and phosphoramide which interfere with cell growth by interfering with the action DNA.

Chelating agents have indirect effects on cell division, and cells that have undergone DNA damage exhibit impaired DNA replication and transcription.

Blood brain barrier prevents adequate delivery of chemotherapy to brain tumors and only small and lipophilic molecules are able to cross this barrier.

Preclinical and clinical data suggests that reductions in standard dose-intensity chemotherapy may compromise disease-free and overall survival.

Pharmacokinetic studies suggest that chemotherapy dosing should be based on actual rather than ideal body weight.

Chemotherapy associated neutropenia has been shown to result in improved disease-free or overall survival years later in some studies, and may be a marker for drug exposure.

The risk of hematological toxicity and obese cancer patients from chemotherapy at full or near full doses is no greater than that healthy weight patients receiving full dose therapy.

Chemotherapy can produce early menopause and infertility.

Chemotherapy induced ovarian failure is caused by apoptotic oocyte–in primordial follicles, damaging ovary reserve and interrupting the follicle recruitment and maturation.

Almost all premenopausal women develop chemotherapy induced amenorrhea.

Chemotherapy induced amenorrhea for women younger than 40 years of age with early breast cancer occurs in about 40% of cases, compared with 76% in older women.

Alkylating agents are associated with the highest risk of ovarian failure, reaching 90% of women older than 40 years.

Current chemotherapy regimens have less ovarian toxicity, with lower rates of permanent amenorrhea, with one report suggesting 85% of women 40 years and younger recovering their menses at 1 year (Fornier MN et al).

Fatigue can result from chemotherapy and a number of factors, including anemia, depression, and radiation therapy.

Alopecia affects many patients.

Sexual dysfunction resulting from chemotherapy can often result in loss of libido.

Affecting about 60% to 80% of patients receiving chemotherapy, cutaneous toxicities can include skin rash and mucositis.

Mucositis is also one of the common side effects.

Thromobocytopenia is caused by alkylating, antirheumatic, and antimetabolite agents.

Damage to the optic nerve and the ocular motor nerves can often occur when a patient is receiving antineoplastic chemotherapy.

Chemo-brain can be a side effect of cancer therapy that causes memory loss and other cognitive changes.

Nausea, vomiting, diarrhea, and constipation are among the most common experienced during chemotherapy.

Certain chemotherapy agents, such as antimetabolites, can cause hepatotoxicity and nephrotoxicity.

Alkylating agents can cause hemorrhagic cystitis, resulting in dysuria, frequency, urgency, nocturia, suprapubic pain, and microscopic or gross hematuria.

One of the most serious side effects of cancer treatment is cardiotoxicity, which can occur early or late in treatment.

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