Pancreatic neuroendocrine tumors

NET classification

• foregut (bronchial, gastric, duodenal, pancreatic)

• midgut (ileal, jejunal, caecal)

• hindgut (distal colonic, rectal).3

Pancreatic NET

1. Typically are well differentiated

2. FDA approved treatment: somatostatin analogs, everolimus, sunitinib, and peptide receptor radionuclide therapy

3. Contrast enhanced EUS differentiates pan NETs from pancreatic adenocarcinoma

4.  68Ga-dotatate PET/CT had the highest detection rate for pancreatic lesions (95% CI, 89.4 to 98.1). Standard first line imaging.  68Ga-dotatate PET/CT has become the first-line modality of choice for detecting SSTR  ( somatostatin receptor) expression in PanNETs.

5. 5 types of F-Pan NET- insulinoma, glucagonoma, Gastrinoma, VIPoma, somatostatinoma

6. NF Pan NET < 2 cm observe, > 2 cm resect ( non functional)

7. F-Pan NET ( functional)- resect at any size if resection feasible.

8. In advanced pan-NET, resection is controversial.

9. Poorly differentiated pan-NET treated with chemo- temodar or streptozocin ( +5FU or doxorubicin, the latter preferred)

However temodar is preferred- CAPTEM 

CAPTEM resulted in median OS of 24 months (95% CI, 17.1% to 30.8%) as well as a 2-year OS of 42%

10. Everolimus in grade1/2 pan-NET- RADIANT III trial

median PFS with everolimus treatment (11 months v 4.6 months; HR, 0.35)

AE-stomatitis, rash, diarrhea, and fatigue

11. Sunitinib in advanced pan-NET-median PFS of 13.2 months and an overall response rate of 24.5% in patients given sunitinib treatment. AE  neutropenia, diarrhea, erythrodysesthesia, hypertension, and thrombocytopenia

12. PRRT- 2 trials ERASMUS ( GEP)  and NETTER ( mid gut NET).

177Lu had an overall response rate of 16% and a median duration of response of 35 months.40 However, approximately 1%-2% of patients reported acute leukemia and myelodysplastic syndrome.

13. Cabozantinib after sunitinib or everolimus in phase II:

A phase II study of cabozantinib demonstrated a 15% response rate and a median PFS of 21.8 months in patients with grade 1 and 2 PanNETs who had a treatment history of everolimus or sunitinib.44 An ongoing phase III CABINET trial 

Liver directed therapy

Liver mets are important in prognosis.

40% 5 yr survival in liver mets versus 100% OS in non liver mets

Liver debulking if > 70% hepatic mets resection or tumor clearance. Threshold lowered from previously used cut off of 90%.

Radiofrequency ablation- 5 yr OS 48%, median OS 4 yr. Improves survival for tumors < 3 cm ideally but can be done up to 5 cm.

HAE- transarterial embolization, TACE, Transarterial radioembolization ( TARE).

TARE has 89% disease control in the short term but concern for long term toxicity.

CLARINET Trial- metastatic foregut -lanreotide versus placebo

PROMID trial- metastatic mid gut- octreotide vs placebo

Reference: Understanding the management of Pancreatic NET

Toxicities of TKI

Dose Modification and Management – Non-Hematologic Toxicities ( CDK4/6)

      Grade 1 or 2                     No dose adjustment is required.
      Grade ≥3                          Withhold until symptoms resolve to: 

                                                    • Grade ≤1; 

                                                    • Grade ≤2  if not considered a safety risk for the patient. Resume at the       

                                                                  next lower dose

NHS UK Immunotherapy guidelines 

	Grade 1	Grade 2	Grade 3	Grade 4
Neutrophil count	< 1500	1000-1500	<1000	<500
Anemia	Less than 10 gm	8-10 gm	Hgb <8.0 g/dL; transfusion indicated	Life-threatening consequences; urgent intervention indicated
Thrombocytopenia	>75K	50-75K	25-50K	<25K

Skin toxicities

1. Hand-foot syndrome- ASCO resource
2. Mucositis
3. Skin rash- refer to ESMO EGFR toxicity and NHS IO toxicity guides

ESMO EGFR skin toxicities

GI toxicities

1. Diarrhea
2. Nausea/Vomiting
3. Elevated lipase/amylase
4. Mucositis: see above

GI system	Grade 1-mild or radiologic	Grade 2-limiting IADL	Grade 3-limiting self care ADL	Grade 4-Life threatening
Constipation	Occasional use of stool softeners	Regular use of stool softeners	manual evacuation	Admission, ICU etc
Diarrhea	Increased BM 1-3 above baseline	4-6 BM more than baseline	More than 7 above baseline
Dry mouth	Mild, thick saliva, flow of saliva > 0.2ml/mt, no change to diet	Moderate symptoms, diet modified, copious water, lubricants	Inability to adequately aliment orally; tube feeding or TPN indicated; unstimulated saliva <0.1 ml/min
Esophagitis
Mucositis/Stomatitis	Mild symptoms	Moderate pain, modified diet, able to maintain caloric intake	Severe pain, interfering with PO intake
Nausea	Mild, no change to oral intake	Reduced oral intake without wt loss	Poor fluid and caloric intake,wt loss, supplemental nutrition
Vomiting	Mild	Oupatient IV hydration	TPN, admission
General	Grade 1-mild or radiologic	Grade 2-limiting IADL	Grade 3-limiting self care ADL
Fatigue	Relieved by rest	Not relieved by rest affecting IADL	Not relieved by rest; affecting Self care ADL

CV toxicities

1. Hypertension
2. LV dysfunction
3. QTc prolongation
4. Arterial thromboembolism

Lung toxicities

1. Pneumonitis

2. Dysphonia

Other known toxicities

1. Proteinuria

2. Cytopenias

3. Fatigue

4. Hypothyroidism

5. Wound healing

6. Hyperglycemia

TKI toxicity

General approach to toxicities

Step 1- grade the toxicity;  affecting self care or IADL?

Step 2- decide if the patient needs to be evaluated right away ( i.e ER) or within 24 hr or within a week. 

Step 3- holding the drug, supportive care, guidelines for restarting the drug

Skin Toxicities

Grade 1- no impact on ADL, localized, no superinfection

Grade 2- generalized, some impact on IADL, no superinfection--> within 24 hr--> cultures, pain control, antibiotic, hold the drug

Grade 3- Generalized, superinfection, impact on self-care ADL-->urgent evaluation esp if fever.

Management of grade 3:

- requires hospital admission. 

- focused exam, CBC, blood cultures, cultures of the affected area, viral culture,

-antibiotic, antiviral or antifungal

1. Hand-foot syndrome: Differentiate from PATEO syndrome, allergic eczema, bleomycin acral toxicity

2. Oral mucositis

3. Skin rash

GI toxicities:

Diarrhea- abemaciclib

Grade 1 no dose change needed

Grade 2- maximal supportive measures, hold for 24 hr or longer until less than grade 1. If needing to hold for > 24 hr, dose reduce when resuming

Grade 3/4- Suspend until Grade 1 or less. resume at next lower dose

Cytopenias

Neutropenia with CDK4/6 inhibitor: 

-Monitor CBC beginning of each cycle, day 15 of cycles 1 and 2

-patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated.

Grade 1 no dose change needed

Grade 2- no dose change

Grade 3 with fever or grade 4 without fever: hold until grade 2 or less. Reduce the dose to next lower level; 2 level reduction if recurrent or recovery > 7 days

Grade 3/4- Hold until Grade 2 or less. Resume at next lower dose if ANC recovery takes 7 days or more. Recheck ANC weekly.

Thrombocytopenia with CDK4/6 inhibitor:

Hold for grade 3/4, resume at one lower dose. Resume at 2 doses lower if recurrent grade 3. Plt count has to recover to grade2  or less.

Anemia in cancer

Role of ESA

Other known toxicities

1. Proteinuria

2. Cytopenias

3. Fatigue

4. Hypothyroidism

5. Wound healing

6. Hyperglycemia

Hyperglycemia

Abnormal glucose above baseline with no medical intervention

Change in daily management from baseline for a diabetic; oral antiglycemic agent initiated; workup for diabetes

Insulin therapy initiated; hospitalization indicated

Life-threatening consequences; urgent intervention indicated

Hyperglycemia with PIK3 kinase inhibitor

Anticipatory /preventative monitoring for toxicities

1. BP controlled for 1 week prior to starting VEGF Ab or TKI

2. EGFR skin toxicity prevention: Before initiating EGFR inhibitor therapy, several preventive measures can reduce the risk of skin rash. Areas of dry skin should be moisturized twice daily, because good hydration can prevent TKI-associated rash. Patients should minimize sun exposure and use sunscreen with a protection factor of at least 15 to prevent photosensitivity rash. Patients should also avoid products that dry out or irritate the skin, such as soaps or alcohol-based perfume products.

3. Hyperglycemia

4. Cardiac monitoring- echo, EKG

Ibrutinib- concurrent antiplatelets and anticoagulants

Antiplatelet management with ibrutinib

 1. Patients should be cautioned against the use of NSAIDs, fish oils, vitamin E, and inadvertent use of aspirin-containing products. 

2. Consider stopping aspirin in patients on ibrutinib who have low or moderate cardiovascular risk. 

3. For patients at high cardiovascular risk that may compromise their survival, including those with recent myocardial infarction (MI) or stroke, consider ibrutinib plus 81 mg of aspirin. We recommend against higher doses of aspirin in light of data suggesting increased bleeding with no benefit [50]. 

4. For patients with recent bare metal cardiac stent placement, consider delaying or withholding ibrutinib while on DAPT. After the required DAPT period, consider ibrutinib plus 81 mg of aspirin. 

5. For patients with recent drug-eluting stent placement, consider replacing ibrutinib with an alternative treatment strategy given the extended duration of recommended DAPT. 

6. Some authors initially trial ibrutinib at a lower dose (280 mg day
1 ) in patients on other antiplatelet agents or anticoagulants and slowly increase to treatment dose if bleeding does not occur. This dose-escalation strategy is based on in vitro data suggesting that the antiplatelet effects of ibrutinib are dose-dependent [18,19]. It is important to note, however, that there are no clinical data to endorse this practical strategy, and that studies have shown significant bleeding rates at both lower (420 mg day
1 ) [7,10–12] and higher (560 mg day
1 ) [8,9] doses of ibrutinib.

For patients potentially requiring ibrutinib concurrent with anticoagulation we propose the following:

1. For patients who require short courses of anticoagulation for a provoked VTE, consider postponing ibrutinib therapy if feasible and using an alternative agent in the interim. If overlapping with ibrutinib, we recommend using a DOAC such as apixaban given the smaller bleeding rates as compared with warfarin [55]. Avoid concurrent antiplatelet therapy unless there is a strong indication. 

2. For patients requiring extended anticoagulation for unprovoked VTE, consider using another agent or using a DOAC such as apixaban, again avoiding other antiplatelet agents unless strongly indicated. Half-dose apixaban can be safely used after 6 months of therapy and is likely to decrease bleeding risk [56]. 

3. Patients should be cautioned against the use of NSAIDs, fish oils and vitamin E, and inadvertent use of aspirin-containing products. 

4. Some authors initially trial ibrutinib at a lower dose (280 mg day
1 ) in patients on other antiplatelet or anticoagulants and slowly increase to treatment dose if bleeding does not occur. 

Management of elective and unplanned procedures 

Ibrutinib should be withheld for 7 days prior to major procedures as the antiplatelet effects of ibrutinib have been shown to be fully reversed after a week off therapy [19,20]. Ibrutinib can be restarted 1–3 days postoperatively [11,13]. The risk of bleeding during urgent, unplanned procedures can be mitigated with platelet transfusion to achieve 50% fresh platelets.

Patients on ibrutinib who develop atrial fibrillation.

 1. If patents have a high bleeding risk, including mandated use of DAPT, or a history of significant bleeding, consider using an alternative agent to ibrutinib and managing their atrial fibrillation per conventional guidelines.

 2. In patients who are to continue ibrutinib and have a sufficiently elevated stroke risk per standard models (CHA2DS2VASc score of 2 or greater), we recommend a DOAC be used as opposed to a vitamin K antagonist, without additional antiplatelet agents. We at our institution, as well as our colleagues across the USA, have successfully combined ibrutinib with DOACs in patients who develop atrial fibrillation. As discussed above, in this setting we use a dose-escalation strategy for ibrutinib (often starting at 280 mg/day), slowly increasing to standard treatment doses if bleeding does not occur. 

3. For patients at low risk of cardioembolic stroke (CHA2DS2VASc score of zero), we recommend continuing ibrutinib alone without the addition of anticoagulation or alternative antiplatelet agents.

 4. For patients at intermediate risk of cardioembolic stroke (CHA2DS2VASc score of 1), we recommend continuing ibrutinib alone or ibrutinib plus aspirin, based on patient and physician preferences and consideration of individualized risks. 

5. In patients requiring DAPT (e.g. those with recent coronary artery stenting) who develop atrial fibrillation and have a high risk of stroke, we recommend discontinuing ibrutinib because of the significant risk of bleeding and switching to alternative therapy for lymphoproliferative disorders. 

6. In patients with an indication for aspirin for cardioprotective benefit who develop atrial fibrillation with elevated stroke risk (CHA2DS2VASc score of 2 or greater), we recommend treating with a DOAC plus ibrutinib alone and stopping other antiplatelet agents. This is based on prospective data showing that single antiplatelet therapy with anticoagulation had equal efficacy and superior safety to dual antiplatelet therapy with anticoagulation.

Pain meds on ibrutinib

Acceptable analgesics with no major adverse platelet effects include acetaminophen and opioids, as well as anti-epileptic drugs such as gabapentin, pregabalin and tricyclic antidepressants. COX2 inhibitors ok

Reference: Ibrutinib associated bleeding

High Risk Prostate cancer- ASCO education book 2020

 

1. High risk is defined ( NCCN) as:

T3a, Gleason 8 or higher, PSA> 20

Very high risk:

T3b, T4

2. Extended PLND: 

-unclear oncologic benefit, recommended if the probability of LN involvement> 2%.

-lymphoceles are more common after PLND

-accurate staging, potentially curative in limited LN involvement

3. Genomic assays in prostate cancer:

Men with unfavorable intermediate- and high-risk disease and life expectancy ≥ 10 years may consider the use of Decipher and Prolaris tumor-based molecular assays. This is in addition to favorable intermediate and low-risk disease.

4. Adjuvant versus salvage RT in high-risk disease after prostatectomy: bottom line is this: salvage is acceptable. Adjuvant XRT did not improve outcomes and resulted in clinically relevant GU toxicities.

Whole pelvis versus prostate only XRT- whole pelvis XRT if the estimated risk of nodal involvement > 15%. Ongoing RTOG study looking at this question along with ADT.

Image and intensity modulate RT are SOC. Brachytherapy results in improved biochemical outcomes, no impact on OS, but more GU toxicity. Hypofractionation i.e fewer fractions, but a higher dose ( 3.4 Gy versus standard of 2 Gy) results in more GI ( not GU toxicity).

5. Systemic therapy for high-risk disease: phase II trials looking at neoadjuvant and adjuvant agents such as abiraterone, enzalutamide, apalutamide have shown increased path CR and 3 yr metastases free survival of 98%. Therefore phase III trials are underway.

6. Neoadjuvant docetaxel in high-risk prostate cancer- PUNCH study. Not statistically significant. A strong signal of improved overall survival in patients receiving systemic therapy (HR, 0.66; 95% CI, 0.42–1.03)

RTP- HER 2 positive breast cancer module key points

 1. Enhertu or Trastuzumab-deruxtecan should be stopped when there is evidence of grade 1 ILD. DLCO should be done at baseline. Symptomatic ILD is at least grade 2. XRay or CT e/o ILD should prompt initiation of steroids. This is in contrast to ILD with checkpoint inhibitors.

2. Neratinib is approved in adjuvant and metastatic setting. At this point unclear if any the benefit in patients treated with pertuzumab and TDM1 in the adjuvant setting. Neratinib may be useful in ERBB2 mutated ( not amplified disease).

3. Tucatinib in the HER2 CLIMB study showed efficacy in both untreated and treated CNS mets with respect to PFS.

Quoted below from NEJM Feb 2020:

Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P=0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.

4. Margetuximab is approved in combination with chemo, however, the benefits were very modest ( less than a month in PFS) compared to Herceptin with chemo. The benefits were primarily in those with low-affinity CD16A-158F -genotypes.

ASH education book 2020- Aggressive B cell lymphoma

1. Patients above the age of 80 years are either unfit or frail. If < 80 years but unfit, start with a 25% to 50% dose reduction for cycle 1, and in those younger than 80 years of age,  attempt to escalate to at least 75% of standard dose with subsequent cycles if tolerated

2. Use simplified CGA testing to evaluate ADL, IADL. ECOG and Hb< 12 gm predict TRM

3. Mini-R CHOP TRM 8% with prephase steroids 60 mg day minus 7 to minus 4. OS 59&, PFS at 2 yr 47%. Standard CHP 18% TRM.

4. Mini R CHOP over 80 years if anthracycline not contraindicated

5. G-RCVP or R-CEOP if cardiac issues. BR is inferior. R CEOP produced inferior results in non GCB subtype

6. Supportive care: manage blood glucose carefully, more frequent follow-up, consider Bactrim and acyclovir prophylaxis.

7. ESA: erythropoietin could be considered in the very elderly or unfit who are experiencing significant treatment-related anemia. erythropoietin could be considered in the very elderly or unfit who are experiencing significant treatment-related anemia.

8. vitamin D enhances rituximab-mediated cellular cytotoxicity.  Vitamin D supplementation to maintain levels >30 ng/mL is recommended in this particularly vulnerable population.