Dosing by body surface area
Most cytotoxics are not dosed by simple weight. Their posology uses body surface area (BSA) in square metres, because BSA tracks metabolic rate and organ size better than weight alone. With such a narrow therapeutic index, a more careful size estimate matters. The dose then sits close to the maximum tolerated dose — the most the patient can endure before unacceptable harm — because pushing the dose up is one of the few levers that increases tumor kill.
Worked BSA dose (Du Bois formula)
BSA (m^2) = 0.007184 x height(cm)^0.725 x weight(kg)^0.425
Patient: 170 cm, 70 kg
BSA = 0.007184 x 170^0.725 x 70^0.425
~ 1.81 m^2
Drug ordered at 75 mg/m^2:
Dose = 75 mg/m^2 x 1.81 m^2
~ 136 mg per cycle
Note: many regimens then CAP or reduce the dose for organ
impairment, low blood counts, or prior toxicity (dose titration).Why we combine drugs
Single agents rarely cure. The modern standard is combination chemotherapy, and the design rules are elegant. Pick drugs that each work on their own. Pick drugs with different mechanisms, so a tumor cell resistant to one is still vulnerable to another. And — crucially — pick drugs whose worst toxicities do not overlap, so you can give each near its full dose without stacking the same organ damage. A drug that hits the heart can pair with one that hits nerves; you cannot easily pair two marrow-crushers at full strength.
- Each drug must be active alone against the tumor — never add a passenger.
- Choose non-overlapping mechanisms so resistance to one does not mean resistance to all.
- Choose non-overlapping toxicities so each can be given near full dose.
- Give in intermittent cycles so healthy marrow recovers between hits.
The resistance arms race
Tumors fight back, and chemotherapy resistance is the main reason treatment fails. A tumor is a population of cells with random mutations; when chemotherapy kills the sensitive ones, any rare resistant cell survives and repopulates. Resistance can arise many ways: the cell pumps the drug back out, repairs DNA faster, mutates the target, or finds a detour around the blocked pathway.
One mechanism deserves a name because it confers resistance to many drugs at once: a pump called P-glycoprotein, an efflux transporter that sits in the cell membrane and throws a wide variety of cytotoxic drugs back out before they can act. When a tumor over-expresses it, several unrelated chemotherapies stop working together — so-called multidrug resistance. This is one more reason combinations and full doses given early, before resistant clones expand, give the best shot at cure.