Chemotherapy Review

Daniel A. Nikcevich, MD, PhD

Duluth Clinic Cancer Center

March 31, 2009

Chemotherapy Review

• What should we talk about in 1 hour?

• Ad nauseum review of drugs?

• Real patient stories?

Chemotherapy Review

• Who is this patient?• Stage of disease

– Molecular profile– Genetic profile– Immunophenotype

• What are the goals of therapy?– Curative– Palliative

• When to start/stop therapy• Follow-up

– Role of the primary-care physician

Chemotherapy Review

• Who is this patient?

• Performance status

• Comorbidities– Ability to tolerate side-effects

• Social/cultural/religious issues

• The patient’s wishes and desires

Mackler NJ and Pienta KJ (2005) Drug Insight: use of docetaxel in prostate and urothelial cancers. Nat Clin Pract Urol 2: 92–100 doi:10.1038/ncpuro0099

Table 2 Eastern Cooperative Oncology Group (ECOG) performance status

Mackler NJ and Pienta KJ (2005) Drug Insight: use of docetaxel in prostate and urothelial cancers. Nat Clin Pract Urol 2: 92–100 doi:10.1038/ncpuro0099

Table 3 Karnofsky performance status

Chemotherapy Review

• Breast cancer

• Colon cancer

• Chronic lymphocytic leukemia

Chemotherapy Review

• 60 yo female in excellent health presents to your office with a left breast mass.

• Mammogram shows 2 cm spiculated lesion in UOQ.

• What’s the next step?• Biopsy• Grade 1 infiltrating ductal carcinoma• She’s now s/p lumpectomy and sentinel

lymph-node biopsy

Chemotherapy Review

• Stage 1 (T1N0M0) infiltrating ductal carcinoma.• ER+/PR+, her-2-neu negative, grade 1.• How should she be treated?• Hormonal/endocrine therapy

– Tamoxifen– Aromatase inhibitor

• Chemotherapy– Doxorubicin/cyclophosphamide– Cyclophosphamide/methotrexate/flurouracil– Cyclophosphamide/docetaxel

Chemotherapy Review

• 5 years of adjuvant hormonal therapy = risk of recurrence of approximately 7% in 10 years.

• 5 years of adjuvant hormonal therapy plus chemotherapy = risk of recurrence of approximately 6% in 10 years.

• Absolute benefit of chemotherapy ~ 1%• So how should your patient be treated?• Hormonal therapy

– Tamoxifen– Aromatase inhibitor– Consider bisphosphonate (zoledronic acid)

Chemotherapy Review

• 38 yo female with a strong family history of breast cancer presents with mastalgia that developed shortly after the birth of her daughter.

• The breast exam is unremarkable and the mammogram reveals a vague density in the right breast which cannot be identified on ultrasound.

• What is the next step?• MRI• 3 cm mass in the central breast with enlarged

right axillary lymph nodes.• Grade 3 infiltrating lobular carcinoma

Chemotherapy Review

• Your patient undergoes a right modified radical mastectomy and axillary lymph node dissection.

• Stage IIIA (T2N1M0) infiltrating lobular carcinoma.– ER+/PR- and her-2-neu 3+ (positive)

• How should she be treated?

Chemotherapy Review

• Hormonal/endocrine therapy– Tamoxifen– Aromatase inhibitor

• Chemotherapy– Doxorubicin/cyclophosphamide/paclitaxel– Cyclophosphamide/methotrexate/fluorouracil– Cyclophosphamide/docetaxel

• Trastuzumab

Chemotherapy Review

• Estimate of recurrence in 10 years with no therapy = 70%

• Estimate recurrence with tamoxifen = 40%• Estimate recurrence with tamoxifen plus

chemotherapy = 30%• Estimate recurrence with tamoxifen,

chemotherapy, and trastuzumab = 15%• What therapy would you recommend for

your patient?

Chemotherapy Review

• She enrolled into a clinical trial and received chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel.

• Also received trastuzumab and lapatinib (an oral drug similar to trastuzumab).

• Now on tamoxifen and doing well 2 years out from her surgery.

Chemotherapy Review

• 58 yo retired nurse comes to your clinic with a c/o persistent right shoulder pain.

• Plain films show a lytic lesion in proximal right humerus, and bone scan indicates other sites of suspected disease.

• Biopsy of right humerus shows moderately-differentiated adenocarcinoma– ER+/PR+, her-2-neu negative

• Mammogram shows 1 cm lesion in left breast– Biopsy shows similar findings to bone biopsy

Chemotherapy Review

• What is the stage of disease?

• Stage IV (T1NXM1)

• Metastatic breast cancer is incurable

• What are the goals of therapy?

• Palliation– Symptom relief– QOL

• Prolong survival

Chemotherapy Review• How should your patient be treated?• Hormonal/endocrine therapy

– Tamoxifen– Aromatase inhibitor– Fulvestrant

• Chemotherapy– Doxorubicin/cyclophosphamide– Cyclophosphamide/methotrexate/fluorouracil– Epirubicin– Paclitaxel– nab-paclitaxel– Docetaxel– Carboplatin– Gemcitabine– Vinorelbine– Capecitabine– Ibexapilone– Bevacizumab– Trastuzumab

Chemotherapy Review

• Bone-only breast cancer is often an indolent disease.

• Does she have a clinical trial option?• This patient has been treated on study with

anatrozole, an aromatase-inhibitor.• She is pain-free and with excellent QOL, four

years from diagnosis.• I use chemotherapy for metastatic breast cancer

in setting of visceral crisis and/or rapidly progressive disease.

Chemotherapy Review

• Breast cancer

• Colon cancer

• Chronic lymphocytic leukemia

Chemotherapy Review

• 60 yo male who is in good health presents for a screening colonoscopy.

• He is found to have a mass at 30 cm.

• Biopsy shows moderately differentiated adenocarcinoma.

• He goes to surgery for a sigmoid colectomy.

• Stage 3B (T3N1M0) colon cancer.

Chemotherapy Review

• How should your patient be treated?• Chemotherapy is standard of care for stage 3

colon cancer.• Chemotherapy options

– 5-FU/leucovorin– 5-FU/leucovorin/oxaliplatin (FOLFOX)– Clinical trial

• Estimate of recurrence within 5 years if no chemotherapy = 60%.

• Estimate of reurrence within 5 years with FOLFOX = 30%.

Chemotherapy Review• How should your patient be treated?• He opted for participation in a clinical trial

– NCCTG trial N0147 (FOLFOX +/- cetuximab)– He is KRAS wild-type– Only KRAS wild-type predict response to EGFR

inhibitors

• He completed chemotherapy (FOLFOX), but incurred a persistent, mild peripheral neuropathy.

• Disease-free 4 years from diagnosis.

Chemotherapy Review

• 64 yo retired nurse in excellent health presents to your office with a c/o of constipation.

• Fecal occult blood test is positive.

• Colonoscopy shows 2 cm cecal mass; a well-differentiated adenocarcinoma.

• She has a right hemicolectomy.

• Stage 2 (T3N0M0) colon cancer.

Chemotherapy Review

• How should your patient with stage 2 colon cancer be treated?

• Does he need chemotherapy?– 5-FU/leucovorin– 5-FU/leucovorin/oxaliplatin (FOLFOX)– Chemotherapy not necessarily standard of care for

stage 2 disease– Clinical trial

• Can we distinguish between “high-risk” and “low-risk” stage 2 colon cancer?

Chemotherapy Review

• Average risk of recurrence at 5 years for stage 2 colon cancer = 15% (w/o chemo)

• Range of risk recurrence = <10% - 40%.• Patients with tumors that exhibit 18q LOH and

MSI with much higher risk.– Subject of current clinical trial (ECOG 5202)

• This patient enrolled into the study.• Has low-risk disease (<10% recurrence).• Did not receive chemotherapy and is followed

with observation alone.

Chemotherapy Review

• 78 yo male presents to the ER with increasing abdominal pain.

• He is found to have a bowel obstruction.

• Surgical exploration reveals large cecal mass with multiple liver metastases.

• Stage 4 (T3N2M1) colon cancer.

Chemotherapy Review

• How should your patient with stage 4 colon cancer be treated?

• Does he need chemotherapy?– Yes.– 5-FU/leucovorin/oxaliplatin (FOLFOX)– FOLFOX plus bevacizumab– Capecitabine plus oxaliplatin (XELOX)– FOLFIRI– FOLFIRI plus cetuximab (k-ras wild-type predicts

response to cetuximab)– Clinical trial

Chemotherapy Review

• What are the goals of therapy?– Palliation– QOL– Prolong life– Cure?

• What are the patient’s goals?– QOL– Wishes to live at his retirement cabin and cut

wood, fish, ski, and spoil his grandchildren.

Chemotherapy Review

• How should your patient with stage 4 colon cancer be treated?

• He received FOLFOX plus bevacizumab.– Standard of care for stage 4 colon cancer

• Responded well with reduction in liver metastases.

• Surgical excision of liver disease.

• Remains well 3 years from liver resection.

Chemotherapy Review

• Breast cancer

• Colon cancer

• Chronic lymphocytic leukemia

Chemotherapy Review

• 44 yo male in excellent health is noted to have WBC 40K (HgB and platelets normal) during routine life-insurance examination

• What is the first step?

• What is the second step?

• What is the third step?

• Look at the blood film.

Chemotherapy Review

• Flow cytometry confirms clinical suspicion of CLL (CD5+CD19+CD20+CD23+CD38-)

• FISH shows 13q-

• He is asymptomatic and has no lymphadenopathy or splenomegaly.

• He has Rai stage 0 disease with favorable prognostic features (CD38- and 13q-)

Chemotherapy Review

• How should this patient be treated?

• Does he need any treatment?

• What is the natural history of CLL?

• What is the significance of staging?

• What is the significance of the molecular markers documented at diagnosis?

Clinical Features of CLL

• Often an incidental diagnosis in an asymptomatic patient.

• Indolent disease common• Progressive adenopathy often correlates with

symptoms: fatigue, malaise, weight loss, fevers• Progressive bone marrow involvement leads to

severe cytopenias, increase risk infection• Autoimmune sequelae and Richter’s

transformation are long-term complications

Staging

• Rai system• Rai 0: lymphocytosis• Rai 1: lymphadenopathy• Rai 2: splenomegaly• Rai 3: HgB < 11 g/dL• Rai 4: platelets < 100K

• Binet system• A: lymphocytosis +/- 1-3

sites lymphadenopathy• B: lymphocytosis with > 3

sites lymphadenopathy• C: lymphocytosis +

anemia and/or thrombocytosis

Why is staging important?

• Rai staging• Rai 0: lymphocytosis

• Rai 1: lymphadenopathy• Rai 2: splenomegaly• Rai 3: HgB < 11 g/dL• Rai 4: platelets < 100K

• Median survival• > 10 years• 7 years

• 2-5 years

Fig 1. Kaplan-Meier survival curve comparing CLL patients with mutated and unmutated VH genes. Median survival for unmutated CLL: 117 months; median survival for mutated CLL: 293 months. The difference is significant at the P = .001 level (log-rank test).

Chemotherapy Review• So how should this patient be treated?• Corticosteroids• Alkylating agents

– Chlorambucil– Cyclophosphamide

• Nucleoside analogs– Fludarabine– Pentostatin

• Monoclonal antibodies– Rituximab (anti-CD20)– Alemtuzumab (anti-CD52)

• Combination chemotherapy– PCR– FCR

• Allogeneic stem cell transplantationcell

Chemotherapy Review

• Mutual decision reached to not treat, but to observe and monitor with serial exams and blood tests.

• 6 years later, he remains asymptomatic with WBC 44K, HgB 14 g/dL, and plts 150K.

Chemotherapy Review

• 57 yo accountant comes to your office at the insistence of his wife.

• He describes fatigue, night sweats, and a 10 lb weight loss.

• Exam shows multiple enlarged (2 cm) cervical and axillary lymph nodes.

• WBC 102K, HgB 10 g/dL, plts 95K

• What to do next?

Chemotherapy Review

• Diagnosis of CLL established.

• Rai stage 4 (plts < 100K)

• CD38+ and FISH shows trisomy 12

• A symptomatic patient with unfavorable molecular markers and immunophenotype

• How should this patient be treated?

Chemotherapy Review• Corticosteroids• Alkylating agents

– Chlorambucil– Cyclophosphamide

• Nucleoside analogs– Fludarabine– Pentostatin

• Monoclonal antibodies– Rituximab (anti-CD20)– Alemtuzumab (anti-CD52)

• Combination chemotherapy– PCR– FCR

• Allogeneic stem cell transplantationcell

Chemotherapy Review

• Clinical trial option?– Nothing available

• I treated him with PCR– Pentostatin, cyclophosphamide, rituximab– Well-tolerated, but leads to marked

immunosuppression

• Entered into complete remission with resolution of trisomy 12

Chemotherapy Review

• Who is the patient?

• What is the disease?

• What are the treatment goals?– Of the patient?– Of the physician?

• What are the treatment options?

• What will the treatment do?

• What will the treatment not do?

Chemotherapy Review

• Questions?

• dnikcevich@smdc.org