This is an introduction to a fourth P2T project, a study in patients with a favorable stage of Breast cancer, stage 1 and 2, after complete local regional control with surgery and radiotherapy, but a high chance of fatal, metastatic disease within with a year. (1) These patients are called ‘triple negatives’ because their tumors lack receptors for estrogens, progesterone and epidermal growth factor receptors.
In 1987 Vriesendorp, H.M., Vriesendorp, R., and Vriesendorp, F.J. published a serious paper entitled Prediction of Normal Tissue Damage Induced by Cancer Chemotherapy. Cancer Chemotherapy and Pharmacology, 19:273-276; 1987, in honor of the death of their father/father in law from colon cancer. Due to its unusual authorship it got honorary mention on a Canadian website ‘Improbable Results’ as their first entry of ‘Vriesendorpiana’.
The Vriesendorps recommend to prescribe chemotherapy in a 3 dimensional unit, per kg bodyweight, rather than the then current and still prevailing to this day 2D prescription unit for cancer chemotherapy per square meter body surface area, promoted by Dr. Freireich from MDAnderson Cancer Center in Houston Texas. Freireich E.J., Gehan E.A, Rall D.P, Schmidt, L.H, Skipper H.E. Quantitative comparision of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemotherapy Rep, 50: 219-44, 1966.
Freireich et al. document that the same dose of chemotherapy can be given in all species investigated if the dose is prescribed per meter square body surface area. Convenient, but rational? No. A priori: all drugs are ‘systemic’ drugs with a 3D volume of distribution. Drugs have dose effect curves. Dose cannot be measured in a 2D parameter. Freireich et al. acknowledge this anomaly and go as far as stating, correctly that skin surface has never been a dose limiting normal tissue to cancer chemotherapy but must be positively correlated to some other target that is dose limiting to cancer chemotherapy. In 1966 and still in 2014 most cancer chemotherapy drugs have dose limiting side effects on the hemopoeietic system: they induce bone marrow aplasia.
In the Vriesendorp x 3 paper we discuss the results of bone marrow transplantation after lethal total body irradiation (TBI) in all the species investigated by Freireich et al except the hamster. We find a negative correlation between the LD50 for TBI, the dose that kills 50% of the animals – we extrapolated this for man on radiation accident experiences- and the minimal number of bone marrow cells needed per kg body weight to prevent TBI induced death. Smaller species need less bone marrow cells per kg for rescue. Mice appear to have a 10 times higher concentration of hemopoietic stem cells in their marrow, than men! If you dose smaller animals per BSA, their serum concentration of a drug will be higher, because smaller animals have a higher surface to volume ratio than larger animals. The smaller animals can handle higher drug doses of hematotoxic drugs because they have more hemopoietic stem cells!
The universal and persistent use of the BSA prescription unit leads to overdosing in pediatric patients and small men and women and under dosing in large men and large women. The most dramatic effect was noted in neonates with neuroblastoma. Quickly the recommendation was issued to decrease the chemotherapy drug dose per BSA in half.
The BSA prescription was continued for young and old adults. The determination of BSA of human beings is made with the help of a nomogram developed by DuBois in the 1920s based on length, 1D, and Bodyweight, 2D. His database consisted of 20 adult cadavers, rolled in thin paper till their whole body was covered with one sheet of this paper. The paper was peeled off, weighed and divided by the thickness of the paper and presto!: there we have the BSA. Myself at 75Kg body weight and 181cm body length have a BSA of 2. If I ever develop a malignancy requiring chemotherapy, I will insist on being treated per kg body weight, as I do not want to be under dosed.
The target population is women with Stage 1 or 2 breast cancer after state of the art surgery and radiation therapy that are free of cancer by all imaginable diagnostic tests, but have a high chance of developing fatal hematogenous metastases within one to two years, because they are so-called triple negative, see for example Farr D, Khan S.A. Local Therapy for Breast Cancer in the Molecular Era: Relevant or Relic? Oncology, 2014; 28: 918-928
These women are treated by high dose adjuvant chemotherapy, not hormonal therapy or anti-Her-2 neu drugs, because their tumor cells lack the necessary cell membrane targets.
The table illustrates what would happen to women receiving dose intense chemotherapy for small, average or large women. The body average BWs and Body lengths are culled from the Internet and therefore rough approximations. The trends are clear: small women will receive approximately 20% less drug on a kg BW prescription and large women will receive approximately 20% more drug on a kg BW prescription. The dose effect curves for tumor control and normal tissue side effects are known to be steep.
The hypothesis to be tested in the project is whether the change to a BW prescription would decrease chemotherapy side effects in smaller women and increase tumor control in larger women. P2T has a preference for a so-called staged pair analysis to be performed in a single academic institution, but remains flexible in terms of study design. Like all P2T studies, this study will have 2PIs, one from P2T, and one from the Academic institution in which the study will be performed. All the regular approval pathways and rules and regulation requirements will be adhered to. Week 1 and 2 after chemotherapy administration serum levels of chemotherapy and its metabolites will be determined.
All chemotherapy is administered intravenously. After each cycle of chemotherapy patient will be checked for CBC, serum chemistry, interim anamnesis, and vital signs. Tumor restaging will be performed after 2, 4 and 6 cycle of chemotherapy. The stepped wedge trial design will be used, e.g. Brown CA, Lilford RJ. The stepped wedge design trial design. BMC Medical Research Methodology, 2006, 6:254. The first group of patients –60 in total- will start their adjuvant chemotherapy patients on Monday with a kg BW prescription. Concurrently patients initiating treatment of Wednesday will receive a meter2 BSA prescription. After 60 patients have been treated in total. BSA and Kg BW prescription will be compared. If only insignificant differences in side effects and pharmacokinetics are observed the study will be closed. If significant differences in side effects are observed the study will be repeated with a new set of 60 patients with one difference: now the Monday patients will receive a BSA prescription and the Wednesday patients will receive a Kg BW prescription. The first set of patients will continue in monthly follow up.
The overall purpose of the study is to decrease tumor recurrence, decrease side effect and explore whether adjuvant chemotherapy can be delivered in 3 to 6 months rather then 12 months.
Table. BW and BSA of a small, average, large woman (30-60 years of age)*
|Small women||Average woman||Large woman|
|Length in cm||154||162||180|
|Weight in kg||48||63||78|
|Surface area in m2||1.43||1.67||1.98|
|Epi dose in mg/m2||250||250||250|
|Epi dose in mg/kg||5.2||4.0||3.2|
|Pax dose in mg/m2||2400||2400||2400|
|Pax dose in mg/kg||50||38||31|
|Cyclo dose in g/m2||2.5||2.5||2.5|
|Cyclo dose in g/kg||0.077||0.066||0.063|
Epi = Epirubicin, an anthracycline
Pax = Paclitaxel, a cis-platinum derivative
Cyclo = Cyclophosphamide
- All drugs induce hair loss, nausea and vomiting, mouth sores, infertility. All drugs lower blood counts.
- Epi causes pain on extravasation, cardiotoxicty, and red urine,
- Pax causes neurotoxicity, nephrotoxicity, arthralgias and myalgias., liver function test abnormalities.
- Cyclo causes discoloration of skin and nails and hemorhagic cystitis.