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Cancer Chemotherapy

Cytotoxic drugs, hormones, antihormones, and biologic agents have become increasingly effective means of cancer chemotherapy. Many patients are treated on protocols to provide optimal therapy for refractory or poorly responsive malignancies. Treatment may be inadequate or ineffective because of drug resistance of the tumor cells. This has been attributed to spontaneous genetic mutations in

Molecular mechanisms of drug resistance to chemotherapy are now the subject of intense study. In many instances, specific drug resistance results from an amplification in the number of gene copies for an enzyme inhibited by a specific chemotherapeutic agent. A more general form of "multidrug resistance" (MDR) has been described in association with expression of a gene (MDR1) encoding a transmembrane glycoprotein of MW 170 (P-glycoprotein) on tumor cells. This protein is an energy-dependent transport pump that facilitates drug efflux from tumor cells and promotes resistance to a broad spectrum of unrelated cancer drugs. Acquired multidrug resistance in multiple myeloma and lymphoma. Unfortunately, the doses of verapamil required to. The use of cyclosporine to enhance the effect of etoposide in purging resistant tumor cells in vitro from autologous bone marrow is under investigation. Cyclosporine has also been shown to enhance the cytotoxic effect of multiagent chemotherapy against resistant multiple myeloma. Verapamil and cyclosporine increase the accumulation and cytotoxicity of daunorubicin in myeloid leukemia cells, enhancing cell kill. MDR modulators will need

High-dose chemotherapy followed by bone marrow transplantation is curative therapy for various types of leukemia, multiple myeloma, and high-risk lymphoma and testicular cancer. Allogeneic or autologous bone marrow or peripheral blood stem cells with or without ex vivo purging is used depending on the disease. The use of growth factors and blood stem cells has decreased the toxicity and cost of bone marrow transplantation. Autologous transplantation may now be used with low morbidity and mortality on selected patients up to age 70. In addition, dose-intense chemotherapy regimens with autologous bone marrow or peripheral blood

While most anticancer drugs are used systemically, there are selected indications for local or regional administration. Regional administration involves direct infusion of active chemotherapeutic agents into the tumor site (eg, intravesical therapy, intraperitoneal therapy, hepatic artery infusion with or without embolization of the main blood supply of the tumor). These treatments can result in

A summary of the types of cancer responsive to chemotherapy and the current treatments of choice is offered in Table 4B3. In some instances (eg, Hodgkin's disease), optimal therapy may require a combination of therapeutic resources, eg, radiation plus chemotherapy rather than either modality alone. Patients with stages I, II, and IIIA Hodgkin's disease are often treated with radiation alone, avoiding the potential toxicity of systemic chemotherapy. A small percentage of these patients may require chemotherapy later for.

Treatment choices for cancers responsive to systemic agents.

Diagnosis Current Chemotherapy of Choice and Procedures

Acute lymphocytic leukemia Induction: Combination chemotherapy. Adults: Doxorubicin, cytarabine,

Vincristine, prednisone, daunorubicin, and asparaginase. cyclophosphamide, etoposide, teniposide (VM-26),1

Children: Vincristine, prednisone with or without allopurinol,2 autologous bone marrow transplantation


Consolidation: Multiagent alternating chemotherapy.

Allogeneic bone marrow transplant for young adults or

high-risk disease or second remission. CNS prophylaxis

with intrathecal methotrexate with or without whole brain


Remission maintenance: Methotrexate, thioguanine.

Acute myelocytic and Induction: Combination chemotherapy with cytarabine Mitoxantrone, idarubicin, etoposide,

myelomonocytic and an anthracycline (daunorubicin, idarubicin). mercaptopurine, thioguanine,

leukemia Tretinoin for acute promyelocytic leukemia. azacitidine,1 amsacrine,1

Consolidation: High-dose cytarabine. Autologous methotrexate, doxorubicin, tretinoin,

(with or without purging) or allogeneic bone marrow allopurinol,2 leukapheresis, prednisone

transplantation for high-risk disease or second remission.

Chronic myelocytic Hydroxyurea, alpha interferon. Allogeneic bone marrow Busulfan, mercaptopurine,

leukemia transplantation for young patients. thioguanine, cytarabine, plicamycin, melphalan,

autologous bone marrow transplantation, allopurinol2

Chronic lymphocytic Chlorambucil and prednisone or fludarabine (if treatment Vincristine, cyclophosphamide, doxorubicin,

leukemia is indicated). Cladribine (2-chlorodeoxyadenosine; CdA),

androgens,2 allopurinol2

Hairy cell leukemia Cladribine (2-chlorodeoxyadenosine; CdA). Pentostatin (deoxycoformycin), alpha interferon

Hodgkin=s disease Combination chemotherapy: doxorubicin (Adriamycin), Carmustine, lomustine, etoposide,

(stages III and IV) bleomycin, vinblastine, dacarbazine (ABVD) or thiotepa, autologous bone marrow transplantation

mechlorethamine, vincristine, prednisone, procarbazine

(MOPP) or alternating MOPP/ABVD or MOPP/ABV,

autologous bone marrow transplant for high-risk patients

or relapsed disease.

Non-Hodgkin=s lymphoma Combination therapy depending on histologic classification Bleomycin, methotrexate, etoposide,

but usually including cyclophosphamide, vincristine, chlorambucil, fludarabine, lomustine, carmustine,

doxorubicin, and prednisone (CHOP) with or without cytarabine, thiotepa, amsacrine, mitoxantrone,

other agents. Autologous bone marrow transplantation in autologous or allogeneic bone marrow transplantation

high-risk first remission or first relapse.

Multiple myeloma Combination chemotherapy: melphalan and prednisone Etoposide, cytarabine, alpha interferon,

or melphalan, cyclophosphamide, carmustine, dexamethasone, autologous bone marrow

vincristine, doxorubicin, and prednisone. Autologous transplantation

bone marrow transplantation in first complete or partial

remission. Allogeneic bone marrow transplantation for

young patients with poor prognosis disease.

Waldenström=s Chlorambucil versus combination chemotherapy: Etoposide, alpha interferon, doxorubicin,

macroglobulinemia cyclophosphamide, vincristine, prednisone. Allogeneic dexamethasone, plasmapheresis, autologous bone

bone marrow transplantation for high-risk young patients. marrow transplantation

Polycythemia vera Hydroxyurea, phlebotomy Busulfan, chlorambucil, cyclophosphamide, alpha

interferon, radiophosphorus 32P

Carcinoma of lung Combination chemotherapy: cisplatin and etoposide. Cyclophosphamide, doxorubicin, vincristine

Small cell Palliative radiation therapy.

Non-small cell3 Advanced disease: cisplatin, vinorelbine Doxorubicin, etoposide, mitomycin

Localized disease: cisplatin, vinblastine

Carcinoma of the head and Combination chemotherapy: cisplatin and fluorouracil Methotrexate, bleomycin,

neck3 hydroxyurea, doxorubicin, vinblastine

Carcinoma of the Combination chemotherapy: fluorouracil, cisplatin, Methotrexate, bleomycin,

esophagus3 mitomycin doxorubicin, mitomycin

Carcinoma of the stomach Stomach: etoposide, leucovorin,2 fluorouracil (ELF) Carmustine, mitomycin, lomustine,

and pancreas3 Pancreas: fluorouracil or ELF, gemcitabine doxorubicin, gemcytidine.

Doxorubicin, methotrexate, cisplatin, combinations

for stomach

Carcinoma of the colon and Colon: fluorouracil plus levamisole (adjuvant) or with Methotrexate, mitomycin, carmustine,

rectum3 leucovorin.2 cisplatin, floxuridine

Rectum: fluorouracil with radiation therapy (adjuvant)

Carcinoma of the kidney3 Floxuridine, vinblastine, IL-2, alpha interferon Alpha interferon, progestins, infusional FUDR,


Carcinoma of the bladder3 Intravesical BCG or thiotepa. Combination Cyclophosphamide, fluorouracil

chemotherapy: methotrexate, vinblastine, doxorubicin

(Adriamycin), cisplatin (M-VAC) or CMV alone

Carcinoma of the testis3 Combination chemotherapy: etoposide and cisplatin Bleomycin, vinblastine, ifosfamide,

Autologous bone marrow transplantation for high-risk or mesna,2 carmustine, carboplatin

relapsed disease.

Carcinoma of the prostate3 Estrogens or LHRH analog (leuprolide) plus an Ketoconazole, doxorubicin,

antiandrogen (flutamide) aminoglutethimide, progestins, cyclophosphamide,

cisplatin, estramustine, vinblastine, etoposide,


Carcinoma of the uterus3 Progestins or tamoxifen Doxorubicin, cisplatin, fluorouracil, ifosfamide

Carcinoma of the ovary3 Combination chemotherapy: cyclophosphamide and Docetaxel, topotecan

cisplatin (or carboplatin) or paclitaxel and cisplatin/


Carcinoma of the cervix3 Combination chemotherapy: methotrexate, Carboplatin, ifosfamide, lomustine

doxorubicin, cisplatin, and vinblastine; or mitomycin,

bleomycin, vincristine, and cisplatin

Carcinoma of the breast3 Combination chemotherapy: cyclophosphamide, Mitoxantrone, vinblastine, paclitaxel,

doxorubicin, fluorouracil, or cyclophosphamide, docetaxel, topotecan, thiotepa, vincristine,

methotrexate, fluorouracil. Tamoxifen for estrogen/ carboplatin, cisplatin/carboplatin, mitomycin,

progesterone receptor-positive tumors. Adjuvant therapy vinorelbine, progestins, androgens, aminoglutethimide

for high-risk patients and for limited metastatic disease:

Dose intensification or autologous bone marrow


Choriocarcinoma Methotrexate or dactinomycin (or both) plus Vinblastine, cisplatin, mercaptopurine,

(trophoblastic neoplasms)3 chlorambucil doxorubicin, bleomycin, etoposide

Carcinoma of the thyroid Radioiodine (131I) Doxorubicin, cisplatin, bleomycin,

gland3 melphalan

Carcinoma of the adrenal Mitotane Doxorubicin, suramin1


Carcinoid3 Fluorouracil plus streptozocin with or without alpha Doxorubicin, cyclophosphamide,


Toxicity and Dose Modification of Chemotherapeutic Agents

A number of cancer chemotherapeutic agents have cytotoxic effects on rapidly proliferating normal cells in bone marrow, mucosa, and skin. Still other drugs such as the vinca alkaloids produce neuropathy, and hormones often have psychologic effects. Acute and chronic toxicities of the various drugs are summarized in Table 4B4. Appropriate dose modification usually minimizes these side effects, so that therapy can be continued with relative safety.

Bone Marrow Toxicity

Depression of bone marrow is usually the most serious limiting toxicity of cancer chemotherapy. Autologous bone marrow or

Table 4B5. A common scheme for dose modification of cancer chemotherapeutic agents.1

Granulocyte Suggested Drug

Count Platelet Count (/mL) Dosage (% of full dose)

> 2000/mL > 100,000/mL 100%

1000B2000/mL 75,000B100,000/mL 50%

< 1000/mL < 50,000/mL 0%