Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Nitrogen Mustards

      • Overview: Ifosfamide, a cyclophosphamide analog, exhibits clear structural similarity to cyclophosphamide (Cytoxan, Neosar and others.).

        • Adverse effects related to bladder toxicity represented an early impediment to ifosfamide use.²² 

          • Increasing patient hydration and coadministration of mesna (Mesnex) reduces ifosfamide (or cyclophosphamide) bladder toxicity.²²   

            • Mesna, an organosulfur compound, interacts with acrolein, a toxic ifosfamide metabolite, reduced toxicity.

              • Mesna (2-MercaptoEthane Sulfonate sodium (Na))

                Cystitis may be either prevented or mitigated by parenteral co-administration of an organosulfur compound, 2-mercaptoethane sulfonate (Mesna).4

         

        • Ifosphamide (left); Cyclophosphamide (right)

      • With cyclophosphamide, both chloroethyl groups are bound to the exocyclic nitrogen.⁴

        • By contrast, one of the two chloroethyl groups of ifosfamide is attached to the primary ring nitrogen.

      • Pharmacokinetics: 

        • The plasma elimination t_1/2 for ifosfamide is about 1.5 hours following doses of about 4-5 g/m² with a reduced half-life associated with lower doses.

          • Pharmacokinetic variability is expected based on a range of hepatic metabolic rates.²²

      • Metabolism:  As described earlier, cyclophosphamide is a "prodrug", requiring metabolic activation.⁴  

        • Ifosfamide is also prodrug, principally activated by the cytochrome P450 microsomal enzyme isoform CYP3A4.

          • With ifosfamide this activation is slower with increased dechlorinated metabolites and chloroacetaldehyde.

            • Most likely, these metabolic differences between cyclophosphamide and ifosfamide account for elevated ifosfamide doses needed for "equitoxic" effects.

              • Furthermore, metabolic differences may also result in greater neurotoxicity with ifosfamide.⁴

      • Adverse Effects:

        • Generally, ifosfamide exhibits a cyclophosphamide-like toxicity profile.

          • Ifosfamide administration causes increased platelet suppression.

          • Ifosfamide administration is associated with nephrotoxicity, urothelial pathology and neurotoxicity.

            • At the higher doses severe neurological toxicity may appear after 12 hours to about a week following initiation of ifosfamide IV administration.

              • The neurological toxicity may include hallucination, and even death.

                • The neurotoxicity may be due to an ifosfamide metabolite, chloroacetaldehyde.

          • More generally ifosfamide administration resulted nausea, vomiting, loss of appetite (anorexia), leukopenia and as noted earlier, nephrotoxicity.

            • Veno-occulsive disease (VOD) of the liver may also occur.

      • Example of Ifosphamide clinical use:

        • Ifosfamide is appropriate for treating patients exhibiting relapsed germ cell testicular cancer.

        • Ifosfamide is used with other drugs in high-dose chemotherapy protocols with bone marrow/stem cell rescue.

        • Soft Tissue Sarcoma:

          • Soft tissue sarcoma is a category of sarcoma developing in connective tissue.¹⁷

            • Soft tissue sarcoma (left lung)²⁰

              "Labelled CT image of undifferentiated soft tissue sarcoma in left lung of a child, showing involvement of pericardium and chest wall and mediastinal shift."20

            • Sarcoma itself refers to cancer rising from transformed mesenchymal cells.¹⁹  

              • Accordingly, malignant tumors of cancellous bone, fat, cartilage, muscle, vascular or hemopoietic tissues are sarcomas.

                • By contrast, malignant tumors originating from epithelial cells are described as "carcinoma."¹⁸

          • Metastatic soft tissue sarcoma is treated with conventional chemotherapy drugs.

            • Treatment with these agents has remained principally the same for over 20 years.

            • Chemosensitivity of tumor to these drugs very based on histologic subtype; furthermore, "higher-grade" tumors appear more responsive to chemotherapy.

              • Detailed algorithms have been developed that describe treatment approaches for specific sarcoma tumor types (e.g. myxoid liposarcoma, leiomyosarcoma, or angiosarcoma).

                • Angiosarcoma²¹

                  Epithelioid angiosarcoma-high magnification https://commons.wikimedia.org/wiki/File:Epithelioid_angiosarcoma_-_high_mag.jpg21 The image "shows abundant small blood vessels lined by large atypical endothelial cells. Mitoses, including some atypical forms, are present."21

              • These algorithms take into account both tumor subtype sensitivity to particular drugs as well as characteric molecular abnormalities.

          • Ifosfamide and doxorubicin are the two most active drugs for treating soft tissue sarcoma.¹⁶ 

            • The single-agent response rate for doxorubicin is about 20%-35%.

            • Ifosfamide exhibits a comparable single-agent response rate. ¹⁶

              • Optimal responses for ifosfamide may also depend on the infusion duration i.e. 2-3-hour vs. 24-hour infusion.

              • Combination treatment with high-dose doxorubicin + ifosfamide improves both response rates in progression-free survival with the possibility of improved overall survival.¹⁶ 

          • Depending on soft tissue sarcoma subtypes a variety of drug and drug combinations may be used including:¹⁶ 

            • doxorubicin + ifosfamide

            • doxorubicin + dacarbazine

            • cyclophosphamide + dacarbazine + dacarbazine,

            • gemcitabine + docetaxel

    • Nitrogen Mustards

      • Overview:   Melphalan (L-phenylalanine mustard)^13,22

        • Melphalan (Evomela)

           

        • Melphalan (Evomela) is a nitrogen mustard alkylating agent which has clinical uses in both multiple myeloma and in high-dose treatment prior to bone marrow transplantation.

        • This agent is an aromatic mustard incorporating the l-isomer of phenylalanine since that the l-amino acids are preferentially transported by specific amino acid carriers.

          • However, melphalan may enter cells by facilitated diffusion as opposed to active transport.

          • Melphalan is associated with a lone electron pair which is less reactive compared to the lone electron pair found on aliphatic mustards.

            • The reduced reactivity was thought to confer both greater likelihood of drug distribution reaching cancer cells and reduction in severity of side effects.

            • A reduced incidence of nausea and vomiting with melphalan has been noted, compared to that observed with mechlorethamine.

              • Patients receiving melphalan however can experience myelosuppression.

                • Melphalan is considered mutagenic in itself and leukemogenic.

                  • Melphalan in Treating Myleloma:  Mutagenic Effects

                    Attribution: Landgren O The Mutagenic Impact of Melphalan in Myeloma https://www.youtube.com/watch?v=oyth9VZRv3w (9/2021) VJHemOnc-Video Journal of Hematological Oncology Youtube Channel https://www.youtube.com/channel/UCsQXL4_zTA-FoG9RA1tEGiw

      • Absorption, Distribution, Metabolism, Excretion:

        • Oral melphalan can be absorbed orally but by this route of administration the absorption appears inconsistent.

          • Absorption is reduced with food but protocols do not require an empty stomach.

          • Usually, melphalan (as the hydrochloride salt) is administered by IV infusion; however, this route of administration appears associated with a higher incidence of serious adverse effects.

          • Melphalan distributes readily in the body water.

            • Therefore toxicity may be more noted in patients were dehydrated or in patients experiencing renal dysfunction.

              • In patients with renal disease, dosage adjustments may be made, thus possibly avoiding severe myelosuppression.

          • Melphalan following oral dosing exhibits variable absorption ranging from about 25% to about 90%.²⁴ 

          • Melphalan volume of distribution is estimated at 0.5 L/kg.

          • This agent exhibits protein binding mainly to albumin (60%-90%, described as moderate to high) and secondarily to α1-acid glycoprotein.

          • Melphalan is not metabolized actively; rather, the agent spontaneously degrades to mono- and dihydroxy products.  

            • Renal clearance therefore is not a notable route of elimination of the parent agent, accounting for about 10% in the 24 hours following administration.

            • Melphalan half-life is estimated to be about two hours.²⁴ 

      • Clinical Uses:^22,23

        • Melphalan has clinical uses in both multiple myeloma and in high-dose treatment prior to bone marrow transplantation.

          • "Treating Newly Diagnosed Myeloma"²⁵

            Source material attribution:  Mateos MV et al:  Daratumumab and Standard Therapy for Myeloma.  The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa1714678) Attribution:  NEJMvideo Treating Newly Diagnosed Myeloma (2018); https://www.youtube.com/watch?v=yHrJC11-hro NEJM Youtube Channel:  https://www.youtube.com/channel/UCqO3GxVYutcugyknCWdAcUA

           

          • In high-dose treatment (myeloablative) prior to hemopoietic cell transplantation, melphalan administration is associated with liver enzyme elevation and acute hepatic injury secondary to sinusoidal obstruction syndrome.

          • Melphalan may also be used in the palliative setting both in multiple myeloma and in cases of non-resectable epithelial ovarian carcinoma.

          • Melphalan has also found use in adjuvant treatment of  breast cancer.

          • Melphalan has also been used in palliative treatment of locally recurring or "nonresectable in-transit" metastatic melanoma of the extremities.

          • Along with prednisone, melphalan may be used in treatment of amyloidosis