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
Problems with current approach?
- Resources – process requires large numbers of subjects, lots of time, and lots of money
- Not individualized – therapy may show benefit over large populations, but we can’t tell if it will benefit the patient sitting in our clinic
—-Be mindful of statistical significance vs clinical significance (NNT = number needed to treat)
—-Develop biological markers (biomarkers) to predict who will benefit and who will not
- Pitfall of “median overall survival”
How does cytotoxic chemotherapy work?
“Cyto-toxic”- kills actively dividing cells by various mechanisms
How come chemo works well on cancer cells (more than our own)? Pitfall?
Tumors have high “growth fraction” (high percentage rapidly dividing cells)
- Benefit derived from “debulking”
- Response plateaus b/c chemo kills constant fraction of cells each course (rather than fixed number): log-kill hypothesis
How do we use cytotoxic agents?
- Combine drugs w/ different mechanisms and compatible toxicity profiles
- Administer in cycles
- Anti-emetics beforehand
- Generally outpatient
- Intermittent radiographic evaluation
Common chemo toxicities?
- Bone marrow suppression: pancytopenia
- GI toxicity – nausea, diarrhea (or constipation), oral mucositis
- General: fatigue, loss of appetite, dysgeusia
Specific chemo toxicities?
- Neuropathy: taxanes, platinum (oxaliplatin), vinca alkaloids
- Cardiac: anthracyclines (doxorubicin)
- Hand-foot syndrome: 5FU/capecitabine
- Nephrotoxicity: cisplatin
- Diarrhea: 5FU, irinotecan
What do pts fear most about chemo? What can be done?
Nausea, but now we have some great anti-emetics:
- 5HT antagonists (ondansetron)
- Steroids (dexamethasone)
- NK1 antagonists (aprepitant)
Fun Fact: With few exceptions, solid tumors with residual gross disease cannot be cured with chemotherapy alone (cancer stem cells)
Who is more likely to benefit from chemo?
- Patients with more chemoresponsive tumors
- Patients with fewer comorbidities
- Patients with good social support and understanding of their condition
- Patients with a good performance status
While these patients’ cancer cells don’t have a higher chance of being killed by chemotherapy, they have a higher chance of tolerating treatment and clinically deriving benefit
What is ECOG performance status?
Grades given to people…
- Associated highly with prognosis
- Validated score for determining who has an acceptable chance of benefiting from chemotherapy (ECOG PS 0-2)
- Good PS usually a criterion for clinical trials
Case 2) - An 18 year old male presents with a large testicular mass. Orchiectomy is performed, and pathology reveals choriocarcinoma (nonseminomatous germ cell tumor). He is in otherwise excellent health, and his only additional complaints are vague abdominal pain and shortness of breath with vigorous exertion (ECOG PS 1).
- What is the treatment recommendation? - What is the goal of treatment?
- What is the pt prognosis?
- Why is this pt’s disease potentially curable?
- Recommend: combo chemo -> resection of residual
- Goal = cure
- Prognosis: Excellent (75-80% complete response rate to chemotherapy, 85-90% 5 year progression-free survival)
- Dz is curable due to biology (exquisite chemoresponsiveness)
What can be done with stage III colorectal cancer to improve prognosis after surgery?
Adjuvant therapy with 5FU-based chemo
- Adjuvant chemotherapy for Stage III colon cancer improve DFS and OS
When is adjuvant chemo for Stage III colon rectal cancer recommended; what are the outcomes?
How can neoadjuvant chemo improve outcomes in locally advanced cancer?
- May improve resectability by shrinking tumor
- Increases the chance that patients actually receive adjuvant therapy (chemo better tolerated pre-op)
- Maximizes the benefit of surgery by weeding out those with occult aggressive disease and those who cannot tolerate surgery
- Tests chemosensitivity in vivo
- Facilitates research – tissue studies
- Makes sense for cancers that metastasize early
- Cancer is a heterogeneous group of diseases (highly variable tumor biology)
- Treatment (local vs systemic) is based on tumor stage and biology
- Cytotoxic chemotherapy can be used with palliative, definitive, adjuvant, and neoadjuvant intent (depends on disease)
- We still have far to go, especially with personalizing therapy (tomorrow’s lecture)