Different tumors should be selected for different chemotherapy. The selection is mainly based on the biological characteristics of the tumor and the sensitivity of antitumor drugs. For example, osteosarcoma is a chemotherapy based on high-dose methotrexate, cisplatin, adriamycin, and isocyclophosphamide. In contrast, Ewing sarcoma is a combination chemotherapy based on vincristine, adriamycin, actinomycin D, cyclophosphamide and Vp-16.
I. Chemotherapeutic drugs
(I) Related concepts
1, cell cycle: refers to the process of cell activity from the end of the previous division to the end of the next division, which can be divided into G1 phase (mainly for the increase in cell size, and for the preparation of DNA synthesis. Non-dividing cells stay in G1 phase, also known as G0 phase), S phase (DNA synthesis period), G2 phase (cell division preparation period, continue RNA and protein synthesis), M phase (cell division period).
The greater the GF value, the more rapidly the tumor grows and the more sensitive it is to drugs. The opposite is also true.
3. Quiescent cell population: i.e. G0 stage cells. It refers to the posterior cells that do not proliferate at the moment. G0 stage cells are the root cause of tumor recurrence.
4. Non-proliferative cells: The cells do not have the ability to proliferate and eventually die of aging.
(II) Mechanism of action
In chemotherapy of malignant bone tumors, chemotherapeutic drugs play the role of killing tumor cells by inhibiting DNA synthesis, destroying the structure and function of DNA, inhibiting protein synthesis and changing the balance of hormones in the body, so as to achieve the role of clinical treatment. Chemotherapeutic drugs usually kill proliferating cell populations, and the larger the GF value is, the shorter the cell proliferation cycle is, the more sensitive the tumor is to chemotherapy.
(III) Classification
Classification according to the principle of action
1.Inhibition of DNA synthesis
(1) Dihydrofolate reductase inhibitors: Dihydrofolate cannot be reduced to tetrahydrofolate and deoxycytidylate synthesis is blocked to inhibit DNA synthesis in tumor cells. Such as methotrexate, etc.
(2) Thymidylate synthase inhibitors: prevent the methylation of deoxyuridine to deoxythymidine and inhibit the synthesis of DNA in tumor cells, such as fluorouracil, etc.
(3) Purine nucleotide synthetase inhibitors: prevent the conversion of inosinic acid into adenosine and guanosine, interfere with purine metabolism, and thus inhibit the synthesis of DNA in tumor cells, such as mercaptopurine, etc.
(4) Nucleotide reductase inhibitors: prevent the conversion of cytidylic acid to deoxycytidylic acid and inhibit the synthesis of DNA in tumor cells, such as hydroxyurea, etc.
(5) DNA polymutase inhibitors: affect the synthesis of DNA and interfere with the replication of DNA, thus inhibiting the synthesis of DNA in tumor cells, such as cytarabine, etc.
2.Inhibit protein synthesis
(1) Affect microtubule protein assembly drugs: interfere with the formation of spindle body during mitosis of tumor cells, such as vincristine, etc.
(2) Interfere with nucleoprotein body function: inhibit the starting stage of protein synthesis in tumor cells, such as trichostatin, etc.
(3) Blocking amino acid supply drugs: they can degrade the menadione in blood and make tumor cells lack the supply of menadione acid, such as menadione enzyme.
3.Damage the structure and function of DNA
(1) Alkylating agents: Alkylating groups react with nucleophilic groups of tumor cells and cross-link with DNA to destroy DNA, such as cyclophosphamide.
(2) metal chemistry reactant: cisplatin produces divalent platinum can cross-link with the bases on DNA and destroy DNA.
(3) Embedded in DNA interferes with nucleic acid synthesis agent: the drug interferes with transcription by embedding between base pairs of DNA. For example, actinomycin D, etc.
(4) topoisomeric inhibitors: so that the damaged DNA is not repaired, such as hydroxycamptothecin.
(4) Altering hormone balance of the body: Tumors originating from hormone-dependent tissues can be treated by altering the hormone balance of the body, mostly used in bone metastatic cancer.
(1) Direct or feedback agents: such as the application of dexamethasone and methylhydroxyprogesterone ester for the treatment of bone metastases from lymphoma and breast cancer.
(2) Sex hormone receptor blocking agents: such as tamoxifen (triamcinolone) blocking estrogen receptors for the treatment of bone metastases from breast and ovarian cancer.
Classification by cell proliferation cycle
1.Cell cycle non-specific agents (CCNSA)
CCNSA can kill cells in all stages of proliferating cell populations, such as alkylating agents and anti-cancer antibiotics.
2.Cell cycle specific agents (CCSA)
CCSA is effective only in one phase of the proliferative cycle. The drugs that act in S phase include hydroxyurea, fluoroxypyrimidine, cytarabine, methotrexate and other antimetabolites. Drugs that act in the M phase include vincristine and vincristine. The drugs acting in the G2 and M phases include paclitaxel.
(iii) Common chemotherapy drugs
1.Anti-metabolic drugs: These drugs are similar to nucleic acid metabolism essential substances such as folic acid, purine, pyrimidine, etc. They interfere with the metabolism of nucleotides through competition and prevent the proliferation of tumor cells, and are cell cycle specific drugs, mainly sensitive to S phase. Methotrexate and fluorouracil are mainly used in bone tumors.
(1) Methotrexate (MTX): At present, this drug is mostly applied clinically in the mode of high-dose methotrexate with calcium formyl tetrahydrofolate (HD-MTX-CF) for relief. It was first reported and applied by Norman Jaffe in 1972 and is considered to be a turning point in the treatment of osteosarcoma. this chemotherapy approach has now become a fundamental step in the treatment of osteosarcoma. the single-drug efficiency of HD-MTX-CF is in the range of 20-30%. The so-called high-dose MTX refers to the use of more than 100 times larger than the conventional dose of MTX per drip, usually 4-6 hours of drip, so as to overcome the resistance of tumor and improve the necrosis rate of tumor tissue. After the drip is finished, relief measures must be taken to avoid life-threatening effects. Calcium formyl tetrahydrofolate is an analogue of tetrahydrofolate, which enters the body and transforms into methylenetetrahydrofolate and N10-methylenetetrahydrofolate, which can participate in the synthesis of deoxycytidylic acid and can go beyond the blocking site of MTX to provide relief. In the treatment of osteosarcoma, the dosage is 200 mg/kg or 8-12 g/m2 (12 g/m2 under 10 years of age and 8 g/m2 over 10 years of age).
2) Fluorouracil (5-Fu): This drug is more effective in combination chemotherapy for bone metastatic cancer, especially for tumors originating in the gastrointestinal tract and breast cancer. The general usage is 300mg/m2 ,each time for 5 days and repeated for 4 weeks.
2.Alkylating agents: They are the first drugs used in tumor chemotherapy. These drugs have active alkylating groups, which can produce cytotoxic effects by replacing hydrogen atoms in the corresponding groups of DNA through alkylation reaction. They are generally classified as cell cycle non-specific drugs. The main ones used clinically for bone tumors are cyclophosphamide, isocyclophosphamide and alanine nitrogen mustard.
(1) Cyclophosphamide (CTX): It has no direct anti-tumor effect and must be activated by hepatic cytochrome P450 oxidase into aldophosphamide, which then breaks down into phosphoramidite nitrogen mustard in tumor cells and takes effect. It is suitable for osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, malignant lymphoma, multiple myeloma, breast cancer, etc. It is administered as a single agent at 1g/m2 intravenously and repeated periodically, in combination with chemotherapy and discretion.
(2) Isocyclophosphamide (IFO): It is a tautomer of cyclophosphamide, with the same mechanism of action as CTX, but with stronger anti-tumor activity than CTX. it is suitable for soft tissue sarcoma, bone sarcoma and bone metastasis cancer. It is used at 2g/m2 intravenously for 3-5 days.
(3) Alanine nitrogen mustard (MEL): also known as levosarcoma solubilizing agent, with the same mechanism of action as nitrogen mustard, is suitable for Ewing sarcoma, multiple myeloma, breast cancer, etc. Dosage: Oral 0.25 (mg/kg/d) for 4 days, repeated for 3 weeks. Intravenous drip, 20-40mg each time, repeat regularly.
3.Antibiotics: These drugs are generally produced by actinomycetes or mycobacteria, and they have quinone-like aromatic structures in chemical structure, which interfere with mRNA synthesis by chimerizing in DNA and changing DNA template, and belong to cell cycle non-specific drugs.
1) Adriamycin (ADM): It is an aminoglycoside antibiotic extracted from the fermentation broth of Streptomyces strains, with a broad anti-tumor spectrum and most sensitive to S-phase cells. It is suitable for soft tissue sarcoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, etc. Dosage is 60mg/ m2 administered in 2 days. Toxic effects on the blood system and heart need to be noted.
2) Pyrantelamycin (THO-ADM): The mechanism of action and indications of this drug are similar to those of Adriamycin, and it is also effective against Adriamycin-resistant tumor cells. The main toxic side effects are in the hematological system, and the cardiotoxicity is less than that of adriamycin.
(3) Epi-Adriamycin (EADM): The difference with Adriamycin is only that the hydroxyl group at position 4 of the amino sugar part is changed from cis to trans, the efficacy is not much different from Adriamycin, and its toxicity to heart and bone marrow is obviously reduced. The mechanism of action and indications are similar to those of Adriamycin. The dosage is 60-90mg/m2 as a single dose or 40-50mg/m2 as a 2-day drip.
4) Mitoxantrone (MIT): Its chemical structure is similar to that of Adriamycin, with strong antitumor activity, synergistic effect with many anticancer drugs, and no cross-resistance. It is suitable for malignant lymphoma, breast cancer, various acute leukemias, etc. Dosage: 8-14 mg/ m2 , repeated over 3 weeks, with a restricted dose at 160 mg/ m2 . The drug also has hematologic and cardiac toxic effects.
(5) Actinomycin (ACTD): also known as actinomycin D, is extracted from the fermentation broth of an actinomycete. It is suitable for Ewing sarcoma and rhabdomyosarcoma. Dosage: 10-15ug/kg for 5 days as a course of treatment. May have blood and digestive system side effects.
(6) Bleomycin (BLM): It is a complex with iron embedded in DNA, causing DNA single and double strand breaks. After entering the body, the drug is rapidly and widely distributed, especially in the skin and lung, because the amidase activity in the cells there is low and bleomycin hydrolysis inactivation is low. It is mainly used for esophageal cancer, squamous lung cancer, skin cancer, malignant lymphoma, etc. The dosing is 15mg/ m2 ,2 times/week, 4-6 weeks as a course of treatment. This drug can cause side effects such as pulmonary fibrosis and hyperthermia.
4.Botanicals: They are a class of drugs extracted from plants containing alkaloids and other antitumor components, which are cell cycle specific drugs. Most of them act on microtubules, preventing the formation of spindle and stopping mitosis at mid-stage; another small part acts on DNA topoisomerase, stopping cell division at late S or early G2 stage.
(1) Vincristine (VCR): It is an alkaloid extracted from the periwinkle plant of the family Oleaceae, which acts by inhibiting the polymerization of microtubulin. It also synchronizes cell proliferation, and other chemotherapeutic drugs used in the following hours can improve the efficacy. It is indicated for Ewing sarcoma, soft tissue sarcoma, lymphoma, and myeloma. It is administered as 0.03 mg/kg/dose intravenously. The drug has neurological toxicity.
2) Etoposide (VP-16): also known as onychomycin. It exerts cytotoxic effects by acting on DNA topoisomerase II so that DNA cannot be rejoined after breakage. It can be used for the treatment of Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, malignant tumor bacillary tumor, breast cancer, etc. The dosage is 60-100 mg/ m2 for 3-5 days.
3) Teniposide (VM-26): also known as onychomycin and majestic. It can inhibit thymidine nucleoside synthesis on one hand, and act on DNA topoisomerase II on the other hand, thus inhibiting DNA synthesis and mitosis. It is mainly used for the treatment of malignant lymphoma, intracranial malignancy, small cell lung cancer, neuroblastoma, acute leukemia, etc. The dosage is 100 mg/ m2 for 3 days. It can have toxic side effects such as digestive system, hematological system, and allergic reactions.
(4) Paclitaxel (PTX): also known as Tysol, is a novel anti-microtubule drug that promotes the assembly of microtubule dimers into microtubules and later stabilizes them by preventing the process of depolymerization, which is necessary for cell life cycle and division function. It is mainly used in ovarian cancer, breast cancer, lung cancer, and gastrointestinal tumors, etc. The usage is 135-200 mg/m2 IV for 3 hours, repeated for 3 weeks. Allergic reactions can occur and should be prevented before chemotherapy.
(5) Tysodi (TAT): It is an anticancer drug obtained by extracting and semi-synthesizing from the needles of European yew. Its mechanism of action and indications are similar to those of Tysol, but its effect is slightly stronger. It is administered as 75 mg/ m2 , 1 hour intravenous drip and repeated for 3 weeks.
5.Hormones: Clinically, they are mostly used for tumors of hematological system and bone metastases, and can also be used to control the toxic side effects of chemotherapy.
(1) Adrenocorticotropic hormones: In the aspect of tumor treatment, they are mainly used for: (1) treatment of breast cancer, lymphocytic leukemia, malignant lymphoma and multiple myeloma. (2) Complications of malignant tumors, such as hypercalcemia, increased intracranial pressure, superior vena cava compression syndrome, spinal cord compression syndrome and cancer hyperthermia. (3) Protection of bone marrow hematopoietic function in chemotherapy and control of vomiting and other discomforts.
(2) Androgen: It can counteract the effect of estrogen and is mainly used to control advanced breast cancer, ovarian cancer and multiple myeloma. It is used as testosterone propionate 50mg, deep intramuscular injection, 2 times/week for 3 months.
3) Estrogen: Suppress the level of androgens in the body, change the balance of hormones in the body and destroy the growth conditions of tumors. It can be used to treat prostate cancer. It is used as bromoacetyl estradiol, 10mg/time, orally, 3 times/day.
4) Anti-androgen: By competitively binding to androgen receptors, it blocks the uptake of androgens by tumors. Such as flutamide, which is suitable for prostate cancer.
5) Anti-estrogen: Triamcinolone, also known as tamoxifen, is a non-steroidal anti-estrogen drug. It inhibits the proliferation of tumor cells by competing with estrogen for receptors. It is used for the treatment of breast cancer. The dosage is 20mg/day.
6.Other
1) Cisplatin (CDP): also known as cis-chloroplatinum. The platinum atom in cisplatin molecule is important in the anti-tumor effect, it forms cross-linkage with DNA and inhibits the proliferation of cancer cells, which is a cell cycle non-specific drug. Only the cis-form has an effect, the trans-form is ineffective. Cisplatin is gradually converted to trans and hydrolyzed in aqueous solution. It is indicated for osteosarcoma, soft tissue sarcoma, malignant lymphoma, ovarian cancer, breast cancer and lung cancer. It is administered as 80-120 mg/ m2 , intravenous or arterial drip, repeated periodically. Be aware of hydration diuresis. Cisplatin can have toxic side effects such as urinary and nervous system and allergic reactions.
2) Azelenimine (DTIC): It acts by converting into alkylation-active products under the action of hepatic microsomal mixed function oxidase, which inhibits the synthesis of DNA and RNA. It is suitable for soft tissue sarcoma and malignant lymphoma. The dosing is: 400 mg/ m2 for 5 days. Toxic side effects such as digestive system, hematological system, liver and kidney function damage may occur, but are mild. Local irritation is more obvious and care should be taken not to leak out.
II. Dose intensity
Hryniuk et al. proposed the concept of dose intensity in the 1980s, and what they mean by “dose intensity” is the dose of the drug given per unit time and per unit body surface area during the course of treatment, regardless of the route of administration and drug regimen, expressed in mg/m2 /week. “Relative Dose Intensity (RDI) refers to the ratio of the actual dose intensity to the artificial standard dose intensity. In the case of combination chemotherapy, the dose intensity of several drugs and the average relative dose intensity can be calculated. The dose intensity is the average weekly dose received over the course of the treatment, so in clinical chemotherapy, the dose intensity decreases whether the dose is reduced per dose or the interval between doses is extended. Atsumasa et al. in 1996 conducted a retrospective study of two groups of patients with osteosarcoma who did not differ significantly in terms of gender, age, tumor site, and histological staging. All used HD-MTX, DDP, and ADM chemotherapy regimens (OOS-B), only with different dose intensities. The dose intensity was found to be positively correlated with 5-year survival. plasma concentration levels of MTX varied from patient to patient, and even in the same patient, from one treatment course to another. This may be related to factors such as age and renal capacity to excrete MTX, and also influenced by some therapeutic factors, such as the timing of MTX administration and the degree of hydration. By studying the plasma concentration levels of MTX, several data sets showed a significant positive relationship between the plasma concentration of MTX and the tumor response rate and survival. the dose intensity of ADM was also significantly associated with the tumor response rate and survival.
In the clinical chemotherapy of human tumors, there is also a lot of information that demonstrates a significant correlation between the dose intensity of chemotherapy and the therapeutic effect. In clinical treatment, for patients with curative potential, the maximum tolerable dose intensity of chemotherapy should be used as much as possible to ensure the efficacy. Of course, we should not blindly pursue efficacy without regard to the side effects of high-dose chemotherapy. In order to obtain the maximum dose intensity, the following measures are often taken: 1) Pre-assess the patient’s tolerance, including physical and economic conditions. 2) Reduce the variety of combination drugs to ensure the main intensity. 3) Granulocyte colony-stimulating factor (G-CSF), auto-bone marrow transplantation (ABMT) and peripheral blood hematopoietic stem cell transplantation (PBSCT) can be applied appropriately to reduce the drug on the hematological system.