How does cancer cause morbidity and mortality?
- Damages organs via local invasion and compression of vital structures
- Damages organs via metastasis (hallmark of cancer)
- Causes symptoms not related to mass effect (paraneoplastic syndromes)
----SIADH, hypercalcemia, neurological syndromes
----But more commonly, causes systemic symptoms via cytokines (cachexia, fatigue) -> wears patients down
What makes some cancers more lethal than others?
Absence of effective screening
- Do not cause symptoms until advanced
- Cause non-specific symptoms
- Hard to diagnose Inherently aggressive “biology”
- Early metastasis
- Relative resistance to available therapies
Example of tumor biology affecting behavior
Inherent qualities of tumor
- How much it grows before metastasis (e.g. GIST gets huge while GE jct cancer is small primary with large liver mets)
What does "tumor biology" mean?
- Process by which cancer develops from normal tissue (molecular biology, genetics, immunology)
- Pattern of spread
----Local vs distant
----“Preferred” distant sites (anatomy, “seed and soil”)
- Speed of growth (kinetics)
- Response to therapy
----Biological (targeted) therapy/immunotherapy
- 65 year old man presents with fatigue and shortness of breath. Laboratory evaluation reveals anemia (hemoglobin 9, ferritin 5). Colonoscopy shows a mass in the ascending colon, biopsy + for adenocarcinoma. CT imaging shows no evidence of metastases.
- The patient undergoes a right hemicolectomy. Pathological evaluation reveals adenocarcinoma invading the pericolonic fat and 4/15 resected lymph nodes, with negative surgical margins. The surgeon informs the patient that he “has gotten it all out” and that the patient does not recommend any further therapy.
- 15 months after his colon surgery, the patient presents to his primary doctor complaining of weight loss, abdominal pain, and fatigue. What happened? Did the surgeon perform an inadequate surgery?
- Not an inadquate surgery
- Stage IIIb colon cancer carries a 50% chance of relapse (micrometastases at time of resection)
- Chemotherapy (palliative)
What do localized treatments involve?
- Radiation (standard external beam, intensity-modulated, stereotactic, radioactive beads)
- Ablation (radiofrequency, microwave)
What does systemic treatment include?
- Cytotoxic chemotherapy
- Biological (targeted) therapy
- Hormonal therapy
- Immunotherapy (Vaccines, immune modulators, T cell therapy, infectious agents)
How do we choose localized vs. systemic treatment?
Anatomical extent of tumor
- Localized or spread
- Can it be safely resected or irradiated
- Potential morbidity of treatment
Biological behavior of tumor
- Chance of recurrence if resected
- Inherent responsiveness to systemic therapy and/or radiation
Increasingly combining modalities to maximize efficacy and optimize outcome
Resecting cancer is frequently feasible and can sometimes cure cancer by itself, but what are the problems?
- Bigger surgery = more morbid
- Cancer can recur locally
- Cancer frequently recurs systemically
What is TNM staging?
- T: extent of primary tumor (e.g. in GI wall; through wall; in nearby nodes)
- N: regional lymph nodes
- M: metastases
Can anything be done after surgery to lower chance recurrence (think back to adenocarcinoma case)?
Yes: adjuvant therapy
Potientially curable by itself; potentially curable
Administered after definitive treatment to improve the chance for cure; potentially curable
Given before definitive treatment to improve the chance for cure; potentially curable
Given to shrink tumor bulk, alleviate cancer-related symptoms, prolong life, and maintain QOL; incurable
Scenarios in which we use systemic therapy to treat cancer
- Advanced/metastatic and curable (definitive)
- Advanced/metastatic and incurable (palliative)
- Resected, likely to recur remotely (adjuvant)
- Potentially resectable but local therapy would be morbid and/or cancer likely to recur (neoadjuvant)
- Proven benefit (based on clinical trial data)
Processes for systemic therapies: inception -> approval
Step 1: Prove benefit in advanced, incurable cancer:
- Shrinking tumor
- Improving length of survival (by months or sometimes years)
Step 2: Apply this antitumor activity to improve cure rate for earlier stage disease (adjuvant, neoadjuvant, or definitive therapy)
More meaningful advances in cancer survival
Systemic therapy: lab -> clinic
- Preclinical: study cell lines, animal models to show in vitro benefit
- Phase I (human trial): establish maximum tolerated dose and safety
- Phase II trial: detect signal of efficacy (response), gather more safety data
- Phase III: randomized controlled trial to prove benefit (survival)
- FDA approval
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is partial response (PR)?
Shrinking of tumor(s) clinically and/or radiographically by >30%
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is complete response (CR)?
No tumor seen radiographically or clinically)
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is progression (PD)?
Growth of tumor(s) by >20% and/or new tumors
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is stable disease (SD)?
Does not meet criteria for PR or PD
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is response rate (RR)?
PR + CR
Endpoints of clinical trials: objective tumor response in the presence of measurable disease. What is disease control rate (DCR)?
PR + CR + SD
Endpoints of clinical trials: survival. What is progression-free survival (PFS)?
Time from starting therapy until cancer progression or death (in the presence of active, measurable disease)
Endpoints of clinical trials: survival. What is overall survival (OS)?
Time from starting therapy until death from any cause
Endpoints of clinical trials: survival. What is disease-free survival?
Time between definitive treatment until recurrence of cancer or death
Picture for survival endpoints (DFS, PFS, OS) over the course of cancer therapy
What does a phase III randomized controlled trial for palliative therapy in advanced cancer look like?
Primary endpoints? Secondary?
- Primary endpoint: PFS or OS
- Secondary endpoint: response rate, toxicity
What does a phase III randomized controlled trial for adjuvant therapy in advanced cancer look like?
Primary endpoints? Secondary?
- Primary endpoint: DFS or OS
- Secondary endpoints: toxicity