# Presentation: 552830

## Survival Trends in Childhood Cancers

**Survival Trends in Childhood Cancers**

- 100

- 80

- 60

- 40

- 20

- 0

- 100

- 80

- 60

- 40

- 20

- 0

**5 Yr Survival [%]**

- 1989-91

- 1977-79

- 1974-76

- 1970-73

- 1960-63

**Diagnosis**

**Date of Diagnosis**

- 1980-82

- 1986-88

- 1983-85

- 1995-2001

**Notes:**
Cancer chemotherapy has had its greatest impact on the treatment of childhood cancers.
5 Year survival by diagnosis (all sites in red in the center) and by year of initial diagnosis.
Gradual improvement primary reflects the incorporation of chemotherapy into a multimodality approach to the treatment of childhood cancer, and an increase in our understanding of how to use these agents, including better supportive care to manage the side effects of treatment.

## Cancer Chemotherapy

| Mechanism | Cytotoxic |
| --- | --- |
| Dosing | Intermittent high dose
Toxicity-based |
| Drug Selection | Histology/stage/prognosis |
| Goal | Cure* |

## Principles of Cancer Treatment

- Multimodality approach
- Local therapy (surgery or radiation) for primary tumor
- Chemotherapy for systemic tumor spread
- Adjuvant setting - anticancer drugs are most effective against micrometastatic tumor
- Combination drug regimens - method to overcome drug resistance
- Dose intensity (highest dose/shortest interval) - more works better

**Notes:**
The principles of childhood cancer treatment that have been for the most part empirically derived (based on clinical observations) that have resulted in improved outcome are listed here.
The approach to treatment is a multimodality approach - combining local and systemic therapy.
Chemotherapy is administered in the adjuvant setting (in the absence of overt/detectable metastatic disease) rather than waiting for the tumor to relapse after local therapy for the primary tumor. All of the improvement on the previous slide has been in patients with localized disease - very little improvement in patients with solid tumors who present with metastatic disease.
Combination chemotherapy regimens are administered to overcome drug resistance.
Dose intensity, or administering drugs at the maximum tolerated dose rate, remains controversial and may not be applicable to all drugs and all types of cancer.
The goal is cure (at least in childhood cancers) - may be different than goal in adults of relieving “death and suffering”

## Ewing’s Sarcoma Survival (Pre-chemotherapy)

**Survival [%]**

**Time [months]**

- •	50 Pts. (36 localized/14 metastatic)
- •	Treatment
- 		Radiation (n=22)
- 		Surgery (n=10)
- 		Surgery + Radiation (n=4)
- •	Median survival 10 mo.

**Notes:**
The importance of multimodality therapy is illustrated by Ewing’s sarcoma.
This slide shows outcome in the prechemotherapy era. 
Cancer in children is a systemic disease.  If treatment only address the primary tumor, patients will develop metastatic disease (if they did not already have detectable metastases at diagnosis) and die.
The chance for long-term survival was less than 10%.
[click in data]
36 of the 50 pts. in this series had localized disease at presentation and 14 presented with metastatic disease
22 were treated with local XRT
10 had surgery alone and in 9/10 the surgery was an amputation.
4 had resections of tumor followed by XRT
Local control with XRT achieved in 15/19 (80%) patients with localized disease.
Most patients died from metastatic disease.

## Ewing’s Sarcoma Survival (Multimodality Rx)

**Ewing’s Sarcoma Survival (Multimodality Rx)**

**1.0**

**0.8**

**0.2**

**0.4**

**0.6**

**0**

**6**

**4**

**2**

**0**

**8**

**10**

**Year**

**Proportion Progression Free**

- Localized

- Metastatic

**Notes:**
Outcome with local therapy and the standard 5 drug chemotherapy regimen (cyt, vcr, dox, ifos, etop) in children with localized and metastatic Ewing’s sarcoma.
In the adjuvant setting survival is now 65% 
Although the addition of chemotherapy has not had as much impact in patients who present with overt metastatic disease

## Adjuvant Chemotherapy in Childhood Cancers

|  |  | Survival [%] |  |
| --- | --- | --- | --- |
| Cancer | Regimen | Without | With |
| Wilms tumor | Vcr, Act-D, ± Doxo | 40 | 90 |
| Ewing sarcoma | Vcr, Act-D, Cyclophos | 5 | 60 |
| Lymphoma | CHOP, COMP | <10 | 70-90 |
| Rhabdomyosarcoma | Vcr, Act-D, Cyclophos | 10-20 | 70 |
| Osteosarcoma | MTX, Doxo, CDDP, BCD | 15 | 65 |
| Astrocytoma | Pred, Vcr, CCNU | 20 | 45 |

**Notes:**
Although it may seem intuitive now, treating with highly toxic chemotherapy when a child was free of disease, rather than waiting until the tumor recurred after local therapy was a big step. 
The wait and treat with chemotherapy after the relapse approach produced responses but few long term survivors.
This table is a partial list of tumors in which adjuvant therapy has improved survival of patients with localized disease.
Survival has been increased by 2 to 10-fold. The last 3 represent result from randomized trials in which patients with localized disease were randomized to receive either adjuvant chemotherapy or no therapy.

## Metastases in Osteosarcoma

| Metastases | No. of patients | 5-year EFS |
| --- | --- | --- |
| None | 1491 | 58% |
| All sites | 211 | 15% |
| Lung only | 155 | 18% |
| Other ± lung | 56 | 7% |

- Bielack SS *J Clin Oncol* 20:776-90, 2002

**Notes:**
Chemotherapy is not as effective in patients who present with metastatic disease, where chemotherapy has to eradicate bulk tumor rather than microscopic deposits.
1702 consecutive patients with high-grade OS of the trunk or limbs registered and treated by the COSS (Cooperative Osteosarcoma Study) Group before 7/98.
Other sites of mets mostly bone but also lymph node, skin, brain, liver, and  other soft tissues.
In multivariate analysis, primary mets were associated with a poor outcome.

## Combination Chemotherapy in ALL

| Treatment | CR [%] |
| --- | --- |
| Single agent treatment |  |
| Methotrexate | 20-40 |
| Mercaptopurine | 25 |
| Prednisone | 40-60 |
| Vincristine | 60-80 |
| Daunomycin | 5-40 |
| L-asparaginase | 45-70 |
| Combination regimens |  |
| Vcr, Pred, L-asp | 90-95 |
| POMP (Pred, Vcr, MTX, MP) | 90 |
| Pred, Vcr, L-asp, Dauno | 98 |

**Notes:**
Combining active agents improves the response rate and efficacy of chemotherapy.
In theoretical models of cancer which assume that drug resistance develops as a spontaneous, random genetic mutation, combination chemotherapy overcomes the drug resistant subpopulations, because cells are less likely to develop resistance to multiple drugs concurrently.
Combination chemotherapy is also more effective because of the additive or synergistic effect of the drugs on cancer cells.
The clinical observations that established the value of administering drugs in combination was first made in the treatment of ALL.
Initially single agents were used sequentially. At best 60% of patients achieved remission but all eventually relapsed despite continuation of therapy. 
With the use of combinations of agents, not only was the remission rate considerably higher but long term remissions and cures became a reality.

## Survival in Rhabdomyosarcoma (IRS-III)

|  | 5-Year Survival |  |
| --- | --- | --- |
|  | From Diagnosis | From
Relapse |
| Overall | 71%
(n=1062) | 17%
(n=605) |
| Embryonal |  | 26%
(n=313) |
| Alveolar |  | 5%
(n=273) |

**Notes:**
For most cancers we only have one chance to cure the patient.
Patients in first remission have a much better chance of being cured than patients with recurrent disease.  In RMS the 5-yr survival rate for newly diagnosed patients treated on IRS-III exceeded 70%.
Whereas in a population of patients with relapsed RMS only 17% survived for 5 years and with the alveolar subtype only 5% of patients survived for 5 years despite attempts at salvage therapy.

## Dose Intensity and Breast Cancer

- High CAF

- Moderate CAF

- Low CAF

**Years after Enrollment**

**DFS**
**%**

- High erbB-2 Expression

**Notes:**
High-dose arm (cyclophosphamide at 600 mg/m2, doxorubicin at 60 mg/m2, and 5-fluorouracil at 600 mg/m2); moderate-dose arm (cyclophosphamide at 400 mg/m2, doxorubicin at 40 mg/m2, and 5-fluorouracil at 400 mg/m2); or low-dose arm (cyclophosphamide at 300 mg/m2, doxorubicin at 30 mg/m2, and 5-fluorouracil at 300 mg/m2). All drugs were administered intravenously on day 1 of a 28-day cycle. Administration of 5-fluorouracil was repeated on day 8 independent of the hematologic values. Chemotherapy was repeated for 4 monthly cycles in the high-dose arm, for 6 monthly cycles in the dose moderate-dose arm, and for 4 monthly cycles in the low-dose arm.
Stage II (+Axillary nodes), adjuvant chemotherapy.  Overall DFS at 5 years 56% in Low CAF arm and 66% in high CAF group.
Low ErbB2 5 yr DFS was 60% for Low CAF and 65% for High CAF (p=0.058).
High ErbB2 (>50% cells expressing) 5 yr DFS was 50% for Low CAF and 71% for High CAF (p<0.001).

## Dose Compression in EWS

| Drug | Cycles | Total Dose [mg/m2] | Duration [wk] | Dose Intensity [mg/m2/wk] | RDI | 4 Year EFS [%] |
| --- | --- | --- | --- | --- | --- | --- |
| Regimen A |  |  |  |  |  |  |
| Cyclophosphamide | 7 | 8400 | 42 | 200 | 1 | 65 |
| Vincristine | 7 | 14 |  | 0.33 | 1 |  |
| Doxorubicin | 5 | 375 |  | 8.9 | 1 |  |
| Ifosfamide | 7 | 63000 |  | 1500 | 1 |  |
| Etoposide | 7 | 3500 |  | 83 | 1 |  |
| Regimen B |  |  |  |  |  |  |
| Cyclophosphamide | 7 | 8400 | 30 | 280 | 1.4 | 76 |
| Vincristine | 7 | 14 |  | 0.47 | 1.4 |  |
| Doxorubicin | 5 | 375 |  | 13 | 1.4 |  |
| Ifosfamide | 7 | 63000 |  | 2100 | 1.4 |  |
| Etoposide | 7 | 3500 |  | 117 | 1.4 |  |

| POG9354/CCG7942 | 17 |  | 48 |  | 0.97 | 70 |
| --- | --- | --- | --- | --- | --- | --- |

## Doxorubicin Dose Intensity in Osteosarcoma

**Dose Intensity**

**mg/m****2****/wk**

**% with >90% Necrosis**

**Notes:**
In this meta-analysis performed by Malcolm Smith and colleagues. The role of individual agents was assessed by relating the % of patients achieving >90% tumor necrosis after neoadjuvant therapy to the dose intensity of each agent administered in the neoadjuvantly.
This is a bubble plot - the difference between this plot and a scattergram is that the size of the bubble reflects the number of patients treated in the trial.
There appeared to be a strong relationship between doxorubicin dose-intensity and response. A similar, but less prominent relationship was also seen with cisplatin.
There was also no relationship between MTX dose-intensity and response, which is also not surprising since patients receive high-dose MTX infusions. MTX is an antimetabolite and its effect is more closely related to the duration of exposure to drug rather than the absolute dose. These dose-intensity analyses do not take this into account.
These dose intensity analyses are useful in defining the optimal dose of drugs when a relationship is seen, but they should be used to determine which drugs are active and which are inactive.

## Cisplatin Dose Intensity in Adults

**Poor-Risk Germ Cell Tumors**

|  | Treatment Arm |  |
| --- | --- | --- |
|  | Standard dose [%] | High-dose [%] |
| Complete response | 47 | 46 |
| Partial response | 18 | 26 |
| Disease-free (CCR) | 61 | 63 |
| Dead | 26 | 26 |
| Ototoxicity | 0 | 32 |
| Neurotoxicity | 1 | 26 |
| GI toxicity | 4 | 26 |

**Notes:**
Prospective randomized trial comparing the efficacy and toxicity of etoposide, bleomycin and two dose levels of cisplatin, the most active agent in germ cell tumors.
		Standard dose - 20 mg/m2 daily for 5 days
		High-dose - 40 mg/m2 daily for 5 days
153 patients (77 in the Std cisplatin arm and 76 in the high-dose arm)
Despite the greater oto-, neuro-, and GI toxicity on the high-dose arm, the dose intensity of the arms was maintained. 84% of patients in the high-dose arm and 90% of patients in the std dose arm received at least 80% of the protocol prescribed doses.

## Cisplatin Dose Intensity in Children

**Poor-Risk Germ Cell Tumors**

- Cushing et al. J Clin Oncol 22:2691, 2004

|  | Treatment Arm |  |
| --- | --- | --- |
|  | Standard dose [%] | High-dose [%] |
| Complete response | 51 | 58 |
| Partial response | 44 | 38 |
| 6 yr Event-free (CCR) | 81 | 90 |
| 6 yr Overall-free (CCR) | 86 | 92 |
| Ototoxicity | 0 | 17 |
| Creatinine clearance | 0 | 7 |
| Renal Mg loss | 0 | 13 |
| GI toxicity | 7 | 23 |
| Fatal infections | 0.7 | 4 |

- p=0.15

- p=0.03

- p=0.18

**Notes:**
Prospective randomized intergroup study for extracranial malignant germ cell tumor
Treatment
Bleomycin 15 units/m2 d1
Etoposide 100 mg/m2/d x 5 d (d1-5)
Cisplatin 40 mg/m2/d x5 vs. 20 mg/m2/d x5 (d1-5)
299 patients enrolled (149 on HD, 150 on StdD)

## Dose-Effect Curve

**Log Dose**

**% with Maximal Effect**

- Adverse Effects

- Desirable Dose Range

**Notes:**
Dose-effect relationship for the individual patient.
For most drugs the dose-response curve is not linear and at some point the dose-response curve approaches a plateau and there is a diminishing return for further increases in the dose
With this minimal added benefit, there may be significantly greater risk for toxicity.

## Dose and Effect

- The intensity of a drug’s effect (therapeutic or toxic) is a function of [Drug]effect site
- For an individual:	[Drug]effect site    Dose
- For a population:	[Drug]effect site    Dose
- Individualize the dose to reduce variability in [Drug]effect site from inter-patient differences in drug disposition
- Adaptive dosing based on patient characteristics
- Therapeutic drug monitoring

**Notes:**
The intensity of a drug’s pharmacologic effect (therapeutic or toxic) is a function of the drug concentration at the effect site.
For drugs that interact reversibly with a receptor, this relationship is described by this sigmoidal shaped dose-response curve, which asymptotically approaches a maximum effect (the effect achieved when all receptors are occupied with drug). The optimal drug concentration at the effect site is one that achieves the maximum therapeutic effect, while minimizing toxics effects.
Within a single individual, the drug concentration at the effect site is in turn proportional to the dose of the drug administered.
We cannot easily measure the drug concentration at the effect site, so dose becomes a surrogate for this concentration. However, we can get one step closer to the effect site concentration by measuring the drug concentration in plasma.
Presumably the drug concentration at the effect site is more closely related to the plasma concentration than the dose of drug administered, so we can
Identify patient characteristics that account for variability in the plasma concentration and adjust the dose based on this characteristic (adaptive dosing)
Adjust the dose the achieve a plasma concentration within a therapeutic range (therapeutic drug monitoring) or
Within a heterogeneous population, such as children of different ages and developmental status, the concentration achieved at the effect site is proportional to the dose and to a variety of factors, such as body size and composition and excretory organ function, that affect the disposition of the drug before it reaches the effect site. In addition, for most cancers the sensitivity of tumors to individual agents is also variable. These interpatient differences obscure the dose effect relationship in a population.
Adaptive dosing and TDM are attempts to overcome variability resulting from interpatient differences and achieve a uniform therapeutic drug concentration at the effect site.

## Inter-Patient Variability

**Inter-Patient Variability**

**[Drug]****effect site**

**Uniform Dose**

**Toxic level**

**Therapeutic range**

**Individualized Dose**

## Anticancer Drugs

| altretamine | daunomycin | imatinib | pentostatin |
| --- | --- | --- | --- |
| arsenic trioxide | dexamethasone | irinotecan | pipobroman |
| asparaginase | docetaxel | levamisole | plicamycin |
| bexarotene | doxorubicin | liposomal daunomycin | prednisone |
| bleomycin | epirubicin | liposomal doxorubicin | procarbazine |
| busulfan | erlotinib | lomustine | streptozocin |
| capecitabine | estramustine | mechlorethamine | sorafenib |
| carboplatin | etoposide | melphalan | temozolomide |
| carmustine | etopophos | mercaptopurine | teniposide |
| chlorambucil | floxuridine | methotrexate | thioguanine |
| cisplatin | fludarabine | methoxsalen | thiotepa |
| cladribine | fluorouracil | mitomycin | topotecan |
| clofarabine | gefitinib | mitotane | tretinoin |
| cyclophosphamide | gemcitabine | mitoxantrone | uracil mustard |
| cytarabine | hydroxyurea | paclitaxel | vinblastine |
| dacarbazine | idarubicin | pamidronate | vincristine |
| dactinomycin | ifosfamide | PEG-asparaginase | vinorelbine |

|  | daunomycin | imatinib |  |
| --- | --- | --- | --- |
| arsenic trioxide | dexamethasone | irinotecan |  |
| asparaginase | docetaxel |  |  |
|  | doxorubicin | liposomal daunomycin | prednisone |
| bleomycin |  | liposomal doxorubicin | procarbazine |
| busulfan |  | lomustine |  |
|  |  | mechlorethamine |  |
| carboplatin | etoposide | melphalan | temozolomide |
| carmustine | etopophos | mercaptopurine | teniposide |
|  |  | methotrexate | thioguanine |
| cisplatin | fludarabine |  | thiotepa |
|  |  |  | topotecan |
| clofarabine |  | mitotane | tretinoin |
| cyclophosphamide | gemcitabine | mitoxantrone |  |
| cytarabine | hydroxyurea |  | vinblastine |
| dacarbazine | idarubicin |  | vincristine |
| dactinomycin | ifosfamide | PEG-asparaginase | vinorelbine |

**Anticancer Drugs**

**Notes:**
This is a list of approved anticancer drugs, not including hormonal agents used to treat adult cancers, cytokines like IL-2 and interferon, and newer immunotherapy agents like rituxan.
There are over 60 drugs on this list
 [CLICK] If we narrow it down to drugs that are used to treat childhood cancer and drugs that are still under evaluation for childhood cancers there are still over 40 drugs left on the list.  

## Mechanism of Action

**DNA**

**RNA**

**Protein**
**tubulin**

**Purines and**
**Pyrimidines**

**Notes:**
Most anticancer drugs produce their effect by interfering with the synthesis or function of DNA and RNA [click]
The alkylating agents for example are chemically reactive compounds that damage DNA by forming convalent bonds to and crosslinking nucleobases [click on “Alkylating agents”]
The topoisomerases are the site action for a number of agents, including the antitumor antibiotics (anthracyclines, actinomycin) and the epipodophyllotoxins (etoposide and teniposide) [click on “Topoisomerase inh”]
The antimetabolites are close structural analogs of the nucleoside precursors of DNA and RNA or analogs of cofactors involved in the synthesis of these building blocks, and they deplete the precursors or are incorporated into DNA or RNA resulting in a defective product. [click on “Antimetabolites”]
Tubulin is the precursor of microtubules which are important in the cells cytoskeleton, excretory functions and most importantly, form the spindles in mitosis. Several agents specifically target tubulin and as a result interfere with mitosis.

## Anticancer Drugs

| Alkylating agents | Topoisomerase inhibitors | Antimetabolites | Molecularly targeted |
| --- | --- | --- | --- |
| busulfan | dactinomycin | cytarabine | erlotinib |
| carboplatin | daunomycin | clofarabine | imatinib |
| carmustine | doxorubicin | fludarabine | sorafenib |
| cisplatin | etoposide | gemcitabine | sunitinib |
| cyclophosphamide | etoposide phosphate | mercaptopurine | tretinoin |
| dacarbazine | idarubicin | methotrexate |  |
| ifosfamide | irinotecan | nelarabine | Miscellaneous |
| lomustine | liposomal daunomycin | thioguanine | arsenic trioxide |
| mechlorethamine | liposomal doxorubicin | Tubulin binders | asparaginase |
| melphalan | mitoxantrone | docetaxel | bleomycin |
| oxaliplatin | teniposide | ixabepilone | dexamethasone |
| procarbazine | topotecan | vinblastine | hydroxyurea |
| temozolomide |  | vincristine | mitotane |
| thiotepa |  | vinorelbine | PEG-asparaginase |
|  |  | paclitaxel | prednisone |
|  |  |  |  |

**Notes:**
The drugs can be grouped based on their mechanism of action and most fall into 4 main categories - alkylating agents, topoisomerase inhibitors, antimetabolites, and tubulin binding agents.
Within these categories there are groups of chemically related agents (analogs), such as:
The nitrogen mustards
The platinum analogs
The anthracyclines
The epipodophyllotoxins
The vinca alkaloids
With new initiatives to target molecules and pathways in cancer cells that are responsible for the development of the malignant phenotype, we are likely to see considerably more diversity in the drug mechanism of action over the next decade.

## Source of Anticancer Drugs

| Synthetic |  |
| --- | --- |
| Lead compound | Analogs |
| mechlorethamine | melphalan
cyclophosphamide
ifosfamide |
| cisplatin | carboplatin |
| Carmustine (BCNU) | lomustine (CCNU) |
| dacarbazine | temozolomide |
| busulfan
procarbazine
thiotepa |  |
| cytarabine | gemcitabine |
| mercaptopurine
thioguanine
methotrexate
fludarabine | 

clofarabine |

| Natural Products |  |
| --- | --- |
| Lead compound | Analogs |
| daunomycin | doxorubicin
idarubicin
liposomal forms |
| podophyllotoxin | etoposide
etopophos
teniposide |
| dactinomycin |  |
| camptothecin | topotecan
irinotecan |
| mitoxantrone |  |
| vincristine
vinblastine | vinorelbine |
| paclitaxel | docetaxel |

**Notes:**
The source of the various anticancer drugs is also quite diverse.  Nitrogen mustard, for example was first synthesized as a chemical warfare agent.
Drugs can be divided into those that were synthesized by humans and those that were discovered in nature (in plants or micro-organisms).
The human creations are alkylating agents and antimetabolites, where as the natural products are topoisomerase inhibitors and tubulin binding agents.
Analogs share many characteristics, but also have distinct pharmacological properties that make them distinct from their chemically similar relatives.  For example the chemical reactivity of the various nitrogen mustard analogs varies considerably and the toxicity profile of the three vinca alkaloids differ significantly.

## Natural Products

**Notes:**
The natural products have complex chemical structures and even retrospectively it is hard to conceive how these compounds could have been rationally designed and synthesized.
In most cases the function of the compounds in organism that synthesized them is unknown and in some cases the agents can make up as much as 5% of the dry weight of the plant or microbe.
The compounds were created through millions of years of evolution.

## Synthetic Drugs

- Nitrogen mustards

- Thiotepa

- Cytarabine

- Imatinib

**Notes:**
The synthetic drugs have much simpler chemical structures
In the case of the antimetabolites, the a usually analogs of naturally occurring compounds involved directly or indirectly in the synthesis of nucleic acids.

## Clinical Pharmacology of Anticancer Drugs

- Toxicity*
- the treatment is worse than the disease
- determines dose, schedule, dose adjustments
- Drug resistance*
- primary reason for treatment failure
- principles of chemotherapy use are designed to overcome resistance
- Pharmacokinetics
- drug disposition is highly variable
- dosing methods do not account for variability

**Notes:**
In addition to their mechanism of action, there are other pharmacological properties of these agents that impact on their efficacy.
The Mechanism of action is non-selective (pathways effected are not unique to cancer cells).  As a result most anticancer drugs are toxic.

## Cancer Chemotherapy

- Administered with curative intent
- Agents selected based on tumor histology, stage, prognostic factors, outcome in previously treated patients
- Non-selective mechanism of action (low therapeutic index)
- Toxicity-based dosing
- Drug resistance = treatment failure
- Anticancer drug dosing does not account for individual differences in drug disposition
- New molecularly-targeted drugs may radically change our approach to cancer treatment

## Molecular View of Cancer

- Enter and traverse the cell cycle in the absence of normal mitogenic signals
- Silence programmed cell death (apoptotic) signals
- Reactivate telomerase
- Invade surrounding tissues and induce angiogenesis

## Molecularly-Targeted Anticancer Agents

- Inhibit molecular lesions (mutations) responsible for the malignant phenotype
- Tretinoin, targeting the PML/RAR fusion protein in PML, and imatinib, targeting the BCR/ABL fusion protein in CML, are clinical validation for this approach
- The molecular bases (pathogenesis) of many forms of cancer have been elucidated - providing new therapeutic targets
- Proteins (receptors or enzymes) in cell signaling pathways can be inhibited by small molecules
- Signal transduction
- Regulation of apoptosis

**Notes:**
Many of the proteins involved in cell cycle regulation, signal transduction, and the regulation of apoptosis are enzymes or receptors and are, therefore, potentially amenable to inhibition by small molecules

## MAP Kinase Signaling Pathway

**Notes:**
The Mitogen-activated Protein Kinase (MAPK) Cascades
Several MAPK cascades have been identified in mammalian cells, including the extracellular signal-related kinase pathways (ERK1/2, ERK5) and the stress activated kinase pathways (JNK/SAPK, p38 MAPK). These pathways are linked to many G protein-linked cell surface receptors and receptor tyrosine kinases. Thus, most cytokines, growth factors, hormones, and neurotransmitters can selectively activate these cascades via receptor activation of intracellular second messengers. All MAPK pathways operate through sequential phosphorylation events to phosphorylate transcription factors and regulate gene expression. They can also phosphorylate cytosolic targets to regulate intracellular events. These cascades are implicated in the regulation of cellular proliferation, differentiation, development, cell cycle, and transmission of oncogenic signals.

## The List

- Conventional chemotherapy
- Cytotoxic (irreversible)
- Non-selective
- Toxic (dose-limiting)
- Pulse/cyclical (IV)
- Toxicity-based dose adjustments
- Selected by histology
- Cure

- Molecularly-targeted drugs
- Cytostatic (reversible)
- Selective
- Non-toxic
- Continuous (PO)
- Therapeutic drug monitoring
- Selected by biology
- Control

**“****Out”**

**“****In”**

- (dose based on therapeutic endpoint)

## Slide 30

## Cure Vs. Control

**Cure** is not the goal of most pharmacological interventions

**Curative Intent**
- Antimicrobial agents
- Anticancer drugs

**Control Disease or Symptoms**
- Antihypertensives
- Antiarrhythmic agents
- Anxiolytics
- Antidepressants
- Antacids
- Antiinflammatory agents
- Analgesics
- Immunosuppressive agents
- Hormonal replacement

**Notes:**
Cure is usually not the goal of a pharmacological intervention.
With the exception of the antimicrobial agents and anticancer drugs, most drugs are designed to control disease or symptoms caused by a disease rather than to cure the underlying disease.
If a patient with hypertension normalizes his or her blood pressure on antihypertensive therapy, but the blood pressure goes back up after the drug therapy is stopped, we would consider the treatment to be effective.
If a child with ALL achieves a complete remission on chemotherapy, but relapses 6 months after completion of that therapy, we would consider the therapy a failure.
We have much higher expectations for cancer chemotherapy than we do for other classes of drugs.  

## Infection vs. Cancer

- Many types with predilection for different sites
- Can be localized or disseminated
- Treated with chemotherapy with curative intent
- Drug resistance limits efficacy of treatment
- Combinations of agents more effective

***Similarities***

## Infection and Cancer

- Efficacy of chemotherapy (especially with disseminated disease)
- Tolerance to chemotherapy
- Selectivity of chemotherapy
- Selection of agents (empirical vs. sensitivities)
- Dose adjustments (toxicity vs. plasma levels)

***Differences***

## Alkylation of DNA

- Bifunctional Nitrogen Mustard

- Reactive Intermediate

- Alkylated Guanosine

- Guanosine

- Alkylated Guanosine

- Busulfan

**7**

- SN1

- SN2

**Notes:**
This shows the chemical reactions involved in alkylation of DNA. These reactions are very nonspecific and the alkylating agents can attack any nucleophilic group in comes in contact with, but it is the reactions with DNA that produce the cytotoxic effect.
The bifunctional nitrogen mustards illustrate the SN1 type of alkylation:
A reactive intermediate is spontaneously formed which then
Rapidly reacts with a nucleophilic group (the N7 position of guanine)
Formation of the reactive intermediate is the rate limiting step, thus the reaction exhibits first order kinetics
The second bischlorethyl group can react with another nucleobase or protein and a crosslink is formed
Busulfan exemplifies an SN2 reaction, characterized by a bimolecular displacement
The methyl sulfonate group on either end is displaced by the nucleophilic group on guanine
The reaction follows second order kinetics because it is dependent on the concentration of alkylating agent and the nucleophile.

## DNA Crosslinks

## Topoisomerases

- Topoisomerases orchestrate the topology of DNA
- Required for replication, transcription, recombination, repair
- Create and religate single- (topo I) and double- (topo II) stranded breaks to allow uncoiling or strand passage
- Inhibitors block religation leading to strand breaks

**Notes:**
Topoisomerases orchestrate the topology of DNA - untangle the mess
They create and religate single- (topoI) or double- (topoII) stranded breaks in the DNA which allow for uncoiling and strand passage
Inhibitors convert topoisomerases into physiologic poisons by blocking religation resulting in protein associated stand breaks
DNA breaks occur after traversal of replication complexes or helicase
The effect of inhibitors on topoisomerase I & II is shown graphically on the next slide

## Topoisomerase Inhibitors

## Microtubules

**Notes:**
Cell transport
Cell motility
Mitosis
Signal transduction

## Tubulin Binding Agents

- 

- 

- Polymerization

- tubulin

- Depolymerization

**Notes:**
Microtubules are made up of repeating alpha-beta tubulin heterodimers that join end to end into protofilaments. 13 parallel protofilaments form the microtubule.
Microtubules are cytoskeletal polymers essential for survival of all eukaryotic cells
Microtubule dynamics are regulated by signal transduction pathways and also provide spatial organization for signal transduction pathways.

## Methotrexate

**Methotrexate**

**FH****4**

**5,10-CH****2****-FH****4**

** ****Serine**

** ****Glycine**

**FH****2**

**10-CHO-FH****4**

**DHFR**

**5-CH****3****-FH****4**

** ****Homocysteine**

** ****Methionine**

**Purines**

**dUMP**

**dTMP**

**Notes:**
Methotrexate is an example of an antimetabolite.  It is a structural analog of folic acid, which is a cofactor for the synthesis of thymidine and purines.
MTX inhibits DHFR which chemically reduces folates to their active tetrahydrofolate form
When thymidine is synthesized from dUMP, 5,10-methylene THF donates a single carbon fragment and is oxidized to the inactive dihydrofolate.
In the presence of MTX, FH2 accumulates and inhibits purine synthesis, and the depletion of tetrahydrofolate pools blocks the synthesis of thymidine and purines

## Methotrexate

**FH****4**

**5,10-CH****2****-FH****4**

** ****Serine**

** ****Glycine**

**FH****2**

**10-CHO-FH****4**

**DHFR**

**5-CH****3****-FH****4**

** ****Homocysteine**

** ****Methionine**

**Purines**

**dUMP**

**dTMP**

**Notes:**
In the presence of MTX, FH2 accumulates and inhibits purine synthesis, and the depletion of tetrahydrofolate pools blocks the synthesis of thymidine and purines

## Purine/Pyrimidine Analogs

- Cytarabine (Ara-C)

- Ara-CTP

- Mercaptopurine

- Deoxythioguanine triphophate

- Inhibits DNA polymerase
- Incorporated into DNA

- Incorporated into DNA

## Toxicity in IRS-IV

- Worst Degree of Any Toxicity (n=1062)

**No. of Patients**

**Severity of Toxicity**

- (n = 32)

**Notes:**
This graph shows the number of patients from a recent front line treatment protocol for rhabdomyosarcoma that experienced one of these toxicity grades as their worst toxicity on the trial.  A total of 1062 patients were treated on one of seven regimens.
Over 80% of patients had at least one toxicity that was severe, life-threatening or fatal.
22 of the 32 deaths were from sepsis during neutropenia. Other drug-related causes of death include ADRS (1), cardiac toxicity (2), radiation toxicity (3), metabolic complications (2), CNS toxicity (1), and hemorrhage during thrombocytopenia (1).
This is standard therapy for childhood cancer cancer.

## Toxicity of Anticancer Drugs

| Common Toxicities | Unique Toxicities |
| --- | --- |
| Myelosuppression
Nausea and vomiting
Alopecia
Oro-intestinal mucositis
Hepatotoxicity
Allergic reactions
Cutaneous reactions
Local tissue damage | Cardiotoxicity (anthracyclines)
Hemorrhagic cystitis (oxazaphosphorines)
Peripheral neuropathy (alkaloids, cisplatin)
Coagulopathy (asparaginase)
Ototoxicity (cisplatin)
Nephrotoxicity (methotrexate, cisplatin)
Leucoencephalopathy (methotrexate) |

**Notes:**
The table lists some of the more common and significant toxicities that are common to many of the anticancer drugs as well as those that are unique to certain agents.
Myelosuppression is the most common dose-limiting toxicity
The common toxicities are acute (hrs to weeks) and reversible, whereas many of the unique toxic effects are cumulative effects which are seen after multiple doses.
Many of the common, acute toxicities occur in most or all of the patients that receive the treatment.  The unique toxicities are fortunately more uncommon.

## Vinca Alkaloid* Toxicity

| Toxicity | Vincristine | Vinblastine | Vinorelbine |
| --- | --- | --- | --- |
| Neurotoxicity* | DLT | +/- | + |
| Constipation | +++ | + | +++ |
| Alopecia | +++ | +++ | +++ |
| Myelosuppression | - | DLT | DLT |
| Nausea & vomiting | - | +/- | +/- |
| Mucositis | - | ++ | + |

## Platinum Analog Toxicity

| Toxicity | Cisplatin | Carboplatin | Oxaliplatin |
| --- | --- | --- | --- |
| Peripheral neuropathy | DLT | +/- | DLT* |
| Nausea & vomiting | +++ | + | +++ |
| Nephrotoxicity | +++ | +/- | +/- |
| Ototoxicity | +++ | - | - |
| Myelosuppression | +/- | DLT (plt) | ++ |
| Hepatotoxicity | +/- | +/- | ++ |
| Hypersensitivity | + | ++ | + |

- * Pharyngolaryngeal dysesthesia

## Rescue (Attenuating Toxicity)

| Toxicity | Rescue |
| --- | --- |
| Myelosuppression

Nausea and vomiting
Hemorrhagic cystitis
	(cyclophosphamide, ifosfamide)
Nephrotoxicity (cisplatin)
Cardiotoxicity (anthracyclines)
Myelosuppression/mucositis
	(methotrexate) | Cytokines (G-CSF)
BM/stem cell reinfusion
Anti-emetics
Mesna

Amifostine, chloruresis
Dexrazoxane (ICRF-187)
Leucovorin |

**Notes:**
Oncologist spend most of their time managing the toxicity of anticancer drugs
Toxicity is such a problem with anticancer drugs that considerable effort has been devoted to developing rescue agents that can attenuate toxicity.
These rescue agents have improved the safety of the therapy and alleviated the drug-related symptoms suffered by patients, but they have also been used to further intensify the doing of anticancer drugs.
These are examples of some successful methods to alleviate toxicity without interfering with the anticancer effects of the drugs.

## Toxicity-Based Dosing of Anticancer Drugs

- Endpoint of dose-finding studies is dose-limiting toxicity
- Optimal dose = Maximum tolerated dose
- Treatment interval based on recovery from toxicity (q21 to 28 days)
- Dose modifications based on toxicity from prior cycle

**Notes:**
Toxicity is such an integral part of cancer chemotherapy that it is the primary determinant of how we dose these drugs.
The dosing of cytotoxic anticancer drugs is toxicity-based.
The endpoint of the dose-finding (phase I) trials is dose-limiting or unacceptable toxicity
The optimal dose is the maximum tolerated dose, not the most efficacious dose
The treatment interval is determined by the duration of recovery from toxicity of the prior treatment cycle
Dose modifications are based on the severity of toxicities in the prior treatment cycle

## Balancing Toxicity vs. Inadequate Therapy

- Exceeds cancer-related symptoms
- Acute and easily quantifiable
- Dose is toxicity-based

- Relapse determines long-term survival
- Therapeutic effect may takes years to assess
- Lower doses associated with poor outcome

- Risks
- Drug toxicity

- Benefit
- Cure

- Short term pain for long term gain

**Notes:**
As oncologist we are faced daily with balancing the short term risk from toxicity with the long term risks from disease recurrence when making therapeutic decisions.
Decisions that impact on the therapeutic effect of the drug, such as dose, treatment interval and dose modifications are based on the drug’s toxic effects rather than their therapeutic effect.
Drug toxicity is usually worse than the symptoms produced by the underlying disease, especially in the adjuvant setting, so we are more likely to react to the toxicity - BUT long-term outcome is determined by whether we control the disease.  For most childhood cancers a recurrence of disease will eventually lead to the child’s death.
Drug toxicity is easy to quantify and grade - WBC nadir, duration of neutropenia, severity of mucositis - in part because it occurs over a short interval (weeks).  It is easier to use criteria based on toxicity to determine dose modifications.
If the ultimate goal of treatment is cure, it takes years to measure the therapeutic effect.
If the probability of cure is higher then we accept more risks from the treatment, but if the chance of curing a patient is small, we don’t want them to suffer from severe toxicity from the therapy.

## Vincristine Neurotoxicity

- Peripheral neuropathy
- Sensory (numbness, paresthesias, pain)
- Motor (fine motor, loss of DTR)
- Cranial nerve involvement
- Diplopia, ptosis, hoarseness
- Autonomic neuropathy
- Constipation, abdominal pain, paralytic ileus
- Orthostatic hypotension
- Urinary retention
- SIADH

## Anticancer Drug Resistance

- Drug resistance has a genetic basis
- Through random mutations, drug resistant cells may be present prior to drug exposure
- Mechanism of drug resistance can be agent specific or affect other agents (multidrug resistance)

## Mechanisms of Drug Resistance

| Mechanism | Examples | Drug Affected |
| --- | --- | --- |
| Drug-specific mechanisms |  |  |
|  drug uptake into cells | f | methotrexate |
|  drug activation |  deoxycytidine kinase | cytarabine |
|  drug catabolism |  aldehyde oxidase | cyclophosphamide |
|  or altered affinity of target | tubulin alterations | vincristine/taxanes |
|  competitive substrates |  asparagine synthase | L-asparaginase |
| Multidrug resistance mechanisms |  |  |
|  drug accumulation |  P-glycoprotein (mdr) | natural products |
|  drug detoxification |  glutathione transferase | alkylating agents |
|  or altered affinity of target | topoisomerases | topo I & II inhibitors |
|  DNA repair |  AGT | alkylating agents |
|  apoptosis |  Bcl-2 expression | all classes of agents |