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D) He will not benefit from 5-FU therapy

The benefit of adjuvant chemotherapy for patients with Stage II Colon cancer is marginal. The NCCN panel believes that it is reasonable to accept the relative benefit of adjuvant therapy in Stage III disease as indirect evidence of benefit for Stage II disease, especially for those patients with high-risk features.

The QUASAR trial demonstrated a small benefit in OS for patients with Stage II disease treated with 5-FU/LV compared to patients not receiving adjuvant therapy (RR of recurrence at 2 years, 0.71; P=.01). In this trial though, 64% of patients had fever than 12 lymph nodes samples and it may have been that these patients had higher risk disease due to suboptimal surgery and therefore they derived benefit from adjuvant therapy.

Colon cancer patients with Stage II disease who have high-levels of microsatellite instability (MSI-H) or defective DNA mismatch repair have a good prognosis and do not benefit from 5-FU chemotherapy.

A group of investigators examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.

MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).

Overall, 70 (15%) of 457 patients exhibited dMMR.  Adjuvant therapy significantly improved DFS (HR=0.67; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; P = .04).

In the NCCN guidelines, patients with T1-T4, N0, M0 colon cancer that is MSI-High/MMR deficient should undergo observation after surgical extirpation of the tumor.

**Pearl: 15% of sporadic tumors are MSI

**Pearl: MSI-H tumors are often right-sided, have undifferentiated histology, present as stage II, and more

             often in females

**Pearl: Poorly differentiated histology is not considered a high-risk feature for patients with Stage II disease

              whose tumors are MSI-High

E) Give EP alone for 3 more cycles

Patients with Stage IIB, S1 NSGCT should be offered either BEP x 3 cycles or EP x 4 cycles. 

As he has developed bleomycin lung toxicity, one should not risk offering him more Bleomycin. One would not want him to develop pulmonary fibrosis which can be fatal. EP x 4 is a perfectly acceptable regimen. As he has completed 1 cycle of BEP already (with contains EP), one can give him 3 more cycles of EP and then stop therapy.

Bleomycin pulmonary toxicity can often start off as pneumonitis but can eventually progress to the development of fibrosis.  The incidence of bleomycin-induced pulmonary fibrosis can be as high as 10%. After stopping the drug, one can administer high-dose steroids to help the treat the inflammation.

**Pearl: 

If a patient has Intermediate- or Poor-risk Nonseminoma, one can substitute Ifosfamide for Bleomycin. This is known as the VIP regimen. It is mostly offered to patients who have a contraindication to receive Bleomycin.

B) HUS from Gemcitabine

Gemcitabine is a Pyrimidine analog. It is metabolized within cells to the active nucleoside forms: diphosphate and triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase. Gemcitabine triphosphate competes to be incorporated into DNA. In doing so, DNA synthesis is halted.

Hemolytic uremic syndrome (HUS) is a rare thrombotic condition that is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure.

In this condition, one will oftentimes see an elevated LDH, low haptoglobin and schistocytes on the peripheral blood smear. A renal biopsy would show microvascular damage of the arterioles and small arteries occluded by eosinophilic hyaline thrombi containing fibrin and platelet aggregate.

Several etiologies that can cause this condition include cancers, chemotherapy drugs and infections.

The mechanism of gemcitabine-induced HUS is unclear. Some posit that this chemotherapy medication may lead to microvascular endothelial damage or immunocomplex deposition.

There is no consensus as to the best treatment for Gemcitabine related HUS.

However, one should immediately discontinue gemcitabine if HUS is seen. Other potential therapies include steroids, FFP administration, plasmapheresis or hemodialysis. It is unclear how well these therapies work.

**Pearl: Mitomycin C can also cause HUS

E) Adjuvant Carboplatin + Paclitaxel +/- Avastin x 6 cycles

Carcinosarcomas consists of malignant epithelial and mesenchymal components.  They 

account for < 2% of malignant ovarian cancers.  These are rare tumors that carry a poor 

prognosis.

Many pathologists consider these tumors to be a variant of poorly differentiated epithelial ovarian cancer 

[metaplastic carcinoma].  

Patients with carcinosarcomas are not candidates for fertility-sparing surgery regardless of the age 

or stage.  Optimal surgical debulking is recommended for patients with this type of ovarian cancer.

Patients with carcinosarcomas should be treated with adjuvant Carboplatin/Taxol +/- Avastin.  This is the 

preferred adjuvant chemotherapy option.

Ovarian Carcinosarcoma: 

Stage I-IV: Patients should be offered chemotherapy with Carboplatin + Taxol 

                  One can substitute Docetaxel or Liposomal Doxorubicin for Taxol

Essentially, Ovarian carcinosarcomas and High-Grade Serous malignancies are treated similarly.  However, for a 

patient with a Stage I Ovarian Carcinosarcoma, one could consider 3-6 cycles of adjuvant Carboplatin/Taxol.

Although not preferred, the following are the other adjuvant chemotherapy options that can be offered to patients 

who have Ovarian Carcinosarcoma:

--Carboplatin + Ifosfamide

--Cisplatin + Ifosfamide

--Paclitaxel + Ifosfamide

D) Standard Radiation therapy and neoadjuvant or adjuvant Lomustine, Procarbazine,  

     and Vincristine (PCV) chemotherapy

Anaplastic oligodendrogliomas are chemotherapy-sensitive tumors. A phase III study (EORTC 26951) evaluated the benefit of adding adjuvant PCV x 6 cycles with RT vs. RT alone (59.4 Gy) to this cohort of patients. A total of 368 patients were enrolled. The overall survival favored the RT/PCV group (42.3 vs. 30.6 mo; HR=0.75).  

In the 80 patients whose Glioma harbored a 1p/19q codeletion, the overall survival favored PCV arm (Not reached vs. 112 mo; HR=0.56) . IDH mutational status was also of prognostic significance.

Gliomas that harbored the 1p/19q codeletion had a better prognosis.

RTOG 9402 randomized 291 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma to receive either PCV followed by immediate RT or RT alone. No difference in the median Overall survival was seen between either arm (4.6 years vs. 4.7 years; P=0.10). However, an unplanned subgroup analysis of the 126 patients whose tumors were 1p19q co-deleted found a doubling in the median Overall survival (14.7 vs. 7.3 years; HR=0.59; P=0.03) when PCV was added to RT as upfront treatment.

The NCCN panel recommends that PCV be administered after RT (as per EORTC 26951) since the intensive PCV regimen given prior to RT (RTOG 9402) was not tolerated as well.

The phase III CODEL study was designed to assess the efficacy of Temozolomide for the treatment of newly diagnosed anaplastic [Grade III] Oligodendrogliomas. The study was redesigned to compare RT + PCV to RT + Temozolomide in patients with anaplastic oligodendroglioma as well as low-grade oligodendroglioma. Results of this important study are pending.

Of note, the 2016 WHO classification of tumors of the CNS has deleted oligoastrocytoma as a category.

https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf

C) Concurrent chemoradiation with Cisplatin/Etoposide.  Radiation given in bid fractions for a total dose of

     45 Gy.  Consider PCI after completion of concurrent chemoradiation

Cisplatin/Etoposide is the preferred systemic chemotherapy option over Carboplatin/Etoposide when offering concurrent chemoradiation to patients who present with limited stage disease.  

For patients who present with Extensive stage disease, one can offer either Carboplatin or Cisplatin. This is an important distinction.

A seminal study (see the reference below) demonstrated that twice a day (hyperfractionated) radiation confers a survival benefit over daily radiation when treating patients with limited stage Small cell lung cancer.

--45 Gy in 3 weeks (1.5 Gy bid) > 45 Gy in 5 weeks (1.8 Gy daily) 

--5-year OS 26% with bid XRT vs. 16% for daily RT  (P=0.04)

However, these radiation doses were not biologically equivalent so this created some measure of controversy.

When BID fractionation is used, a total of 45 Gy is normally given and there should be at least a 6-hour interfraction interval to allow for repair of normal tissue. If one is using once-daily RT, higher doses of 60-70 Gy should be used.

Two randomized phase III trials did not demonstrate superiority of 66 Gy in 6.5 weeks/2 Gy daily (The European CONVERT trial) or 70 Gy/2 Gy daily (CALGB 30610/RTOG 0538) over 45 Gy in 3 weeks/1.5 Gy BID, but overall survival and toxicity were similar.

Recent randomized phase II trials suggest that higher dose accelerated RT of 60-65 Gy in 4-5 weeks given in BID or daily fractionation may produce increased overall or PFS compared to 45 Gy in 3 weeks in BID fractionation.

As mentioned above, the the randomized, phase III European CONVERT trial did not demonstrate superiority of 66 Gy (once daily) over 45 Gy (BID), but overall survival and toxicity were comparable.

https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf

Corinne Faivre-Finn et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.  Lancet Oncology 2017.

C) Continue therapy

The patient in this question has just started on immunotherapy with Ipilimumab. It would be premature to assume that the slight enlargement of her liver lesion represents true tumor progression. This patient should be continued on therapy. Responses to immunotherapy can sometimes be delayed.

It can take time before once sees a cancer respond to immunotherapy. One needs to be careful with stopping therapy too soon based on an interval CT imaging especially if it was performed for a possible non-oncologic reason.

Sometimes, responses can occur even after the initial appearance of radiologic evidence of disease progression. Pseudo-progression refers to cancer deposits that initially appear larger on a scan, perhaps due to the infiltration of the immune cells to the tumor location. However, these areas will likely regress with time. The patient had a CT scan performed to evaluate her issues with bloating. It was not a definitive restaging scan. Additionally, this CT scan took place after she received only 2 doses of Ipilimumab.

Ipilimumab is a humanized monoclonal IgG1 antibody that targets Cytotoxic T-lymphocyte antigen-4 (CTLA-4). CTLA-4 on T cells acts as a break for the normal immune system. By blocking CTLA-4, Ipilimumab unleashes the immune system leading to T-cell activation.

This drug attained FDA approval in 2011 as monotherapy (3 mg/kg) x 4 cycles for patients with unresectable or metastatic melanoma (both pre-treated or chemotherapy naïve patients).

B) Imatinib

Dermatofibrosarcoma protuberans (DFSP) is a tumor that occurs in the dermis layer of the skin.

Up to 5% of these tumors can metastasize. These tumors can initially appear as a bruise or pimple. Over 90% are slow growing tumors. A subset of DFSP can harbor a high-grade sarcomatous component.

The majority (> 90%) of these tumors will harbor t(17;22). This translocation fuses the collagen gene (COL1A1) with the platelet-derived growth factor (PDGF) gene. This results in a fusion protein that leads to a potent growth factor (PDGFRB).

The primary treatment for patients who present with localized disease is surgery to achieve negative margins. Surgical approaches include:

Excision with other forms of peripheral and deep en face margin assessment [PDEMA]

Mohs Micrographic surgery

Phase II data that evaluated the efficacy of Imatinib in the treatment of patients with locally advanced or metastatic DFSP revealed an objective response rate of almost 50%. The median time to progression was 1.7 years.

Imatinib is approved by the FDA for the treatment of unresectable, recurrent, and/or metastatic DFSP in adult patients.

Of note, patients with unresectable (but locoregional) DFSP can be offered neoadjuvant imatinib in hopes of downstaging the tumor to enable resection.

D) Radiation therapy

Follicular lymphomas usually do not present in a localized manner. When they do, one should consider local therapy with radiation as some studies show that this can lead to a long-term remission. 

Observation, single agent Rituximab, Rituximab/Lenalidomide or Rituximab (or Obinutuzumab) + chemotherapy are also options to consider.

On study retrospectively evaluated the effectiveness of radiation in 177 patients with stage I or II follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma. Radiotherapy doses ranged from 35 to 50 Gy. The median survival time was 13.8 years. At 20 years, 37% patients were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence.

The NCCN guidelines listed ISRT as the preferred therapy for patients with Stage I or contiguous Stage II Follicular lymphoma that is grade 1-2.

E) Switch to a different TKI

This patient has relapsed disease. This is defined by any of the following:

--Any sign of loss of Hematologic response

--Any sign of loss of CCyR or its molecular response correlate defined as an increase in BCR-ABL1

  transcript to >1%

--1-log increase in BCR-ABL1 transcript levels with loss of MMR

At the 18-month follow-up mark, to see a cytogenetic relapse is disconcerting.  According to the NCCN guidelines, having a BRC-ABL1 > 10% at the 3-month mark connotes TKI resistance.

In situations like this, one needs to check for patient compliance to the TKI and other drug-drug interactions.  Prior to switching therapy for a presumed TKI failure, one should check the mutational status of BCR-ABL.  For second-line treatment for patients with TKI-resistant disease, one should switch to another alternate TKI that is tailored to the results of the BCR-ABL1 mutation testing.  These patients should also be evaluated for an allogeneic HCT.

There is a subset of BCR-ABL mutant clones associated with impaired responses to second-generation TKIs.

As an example, for patients who harbor a F317L mutation in BCR-ABL1, one would offer Nilotinib over Dasatinib or Bosutinib. If a patient has a G250E mutation, one would offer Dasatinib or possibly Nilotinib.

The Mutational status of BCR-ABL1 will inform on which TKIs may work:

E255K/V, F317V/I/C, F359V/C/I, T315A, Y253H: Use Bosutinib

T315I: Use Ponatinib, Asciminib, Omacetaxine, Allogeneic transplant

V299L, T315A, F317L/V/I/C: Use Nilotinib

Y253H, E255K/V, F359V/C/I: Use Dasatinib

The following mutations confer resistance to the following TKIs:

--Bosutinib will not work if a patient has a BCR-ABL1 mutation in T315I, V299L, G250E or F317L

--Dasatinib will not work if a patient has a BCR-ABL1 mutation in T315I/A, F317L/V/I/C or V299L

--Nilotinib will not work if a patient has a BCR-ABL1 mutation in T315I, Y253H, E255K/V, F359V/C/I

 https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf

D) ER-, PR-, Her2-

Hereditary breast ovarian cancer syndromes are autosomal dominant disorders. BRCA1 and BRCA2 are tumor suppressor genes whose role is to control cell growth and cell death. Mutations in these genes disenable this function leading to an increased cancer risk.  

There are several differences between BRCA1 and BRCA2 related tumors.

BRCA1-related breast cancers are mostly triple negative.  

BRCA2-related breast cancers are mostly ER+.

BRCA1: Located on chromosome 17

              >60% risk of the development of female Breast cancer

              40-60% risk of the development of Ovarian cancer

              <5% risk of the development of Pancreatic cancer

               7-26% risk of the development of Prostate cancer

BRCA2: On chromosome 13

              > 60% risk of the development of female breast cancer

              1.8% to 7.1% risk of the development of Male breast cancer

              13-29% risk of the development of Ovarian cancer

               5-10% risk of the development of Pancreatic cancer

               19-61% risk of the development of Prostate cancer

               Increased risk of developing Melanoma

https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

B) Her tumor meets all the criteria where one would not offer her RAI therapy

RAI as adjuvant therapy is not offered to every patient with differentiated thyroid cancer. The size cutoff to offer it is often 4 cm in size, which she clearly is not close to having. All her clinical and pathologic features are favorable so one would not offer her adjuvant RAI.  

RAI does have toxicity, so one needs to carefully assess if a patient will truly benefit from it as adjuvant therapy.

RAI is typically recommended if any of the following features are present:

1) Gross extrathyroidal extension

2) Primary tumor >4 cm 

3) Postoperative unstimulated Tg> 10 ng/mL

4) Bulky or >5 positive lymph nodes

5) Significant N1b disease

6) Vascular invasion

One would selectively recommend adjuvant RAI if any of the following features are seen:

Tumor 2-4 cm

High risk histology (ie, poorly differentiated, tall cell, columnar cell, hobnail variant, diffuse sclerosing, and insular)

Lymphatic invasion

Cervical lymph node metastases

Macroscopic multifocality (one focus > 1 cm)

Postoperative unstimulated thyroglobulin 1-10 ng/mL

Microscopic positive margin

RAI is not typically recommended if all the following are present:

--Classic papillary thyroid cancer 

--Largest primary tumor <2 cm in size

--Intrathyroidal

--Unifocal or multifocal (all foci ≤ 1 cm)

--No detectable Tg antibodies

--Postoperative unstimulated Tg < 1 ng/mL or stimulated Tg < 2 ng/mL

--Negative postoperative ultrasound, if done

B) FPN

Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations in the ferroportin-1 (FPN) gene. Ferroportin’s role in the body is to transfer iron from the intestine and macrophages into the bloodstream.

There are two different phenotypes of Ferroportin disease.

Macrophage type: 

Loss-of-function mutations of ferroportin are thought to produce a molecule that either does not traffic appropriately to the cell surface or that has limited ability to export iron.

This results in excess accumulation of iron in macrophages, that results in high serum ferritin, normal to reduced transferrin saturation (TSAT), and mild anemia. In young females, hypochromic microcytic anemia may develop that is responsive to iron supplementation. This has also been called macrophage-type (M-type) and is now considered the real ferroportin disease, which is no longer included among HH because of the distinct phenotype.

Hepatic-type (Non-classical):

Gain-of-function mutations produce a ferroportin protein that is resistant to hepcidin and retains full iron export capability. The mutation may affect the binding site for hepcidin (C326) or occurs in its proximity. Iron overload is similarly to what is seen in patients with classic HH.

This results in increased TSAT, high levels of ferritin and hepcidin, and hepatic iron overload. As mentioned above, this is similarl to what is seen in patients with classical HH, although patients with Hepatic-type of iron overload may have a more severe disease phenotype. A liver biopsy in patients with this condition will reveal increased hepatocyte iron. 

In patients with Ferroportin disease/Macrophage type, unlike what is seen in patients with classical hemochromatosis, the iron is considerably more prominent in the Kupffer cells than in the hepatocytes. In addition, the fibrosis is primarily sinusoidal.

Ferroportin is the iron transport channel mainly expressed in macrophages and hepatocytes and on the basolateral surface of intestinal enterocytes that is blocked by hepcidin. Ferroportin has also been implicated in the transport of other ions such as manganese.

In the Macrophage type of Ferroportin disease, mutations in FPN1 limit but does not impair the iron export in enterocytes, but it does severely affect the iron transfer in macrophages. This leads to iron trapping in tissue macrophages with reduced iron release to serum transferrin. Hence, patients with this disease have low transferrin saturation. They will often have normal/low transferrin saturation, mild anemia and mild organ disease.

A hallmark feature of this variant of Ferroportin disease is marked iron accumulation in hepatic Kupffer cells, but not as much iron accumulation in the hepatocytes. This is opposite to what is seen in patients with classical hemochromatosis.

The differential diagnosis for this condition includes hereditary hemochromatosis, the syndrome commonly due to either HFE, TfR2, HJV, HAMP or gain of function mutation in FPN1. In these conditions, the elevated ferritin levels is seen in concert with a high transferrin saturation, iron-spared macrophages, and progressive liver parenchymal cell iron load.

These conditions (HFE, TfR2, HJV, HAMP or non-classical FPN1) share a similar pathogenic basis (lack of hepcidin function-activity), biochemical expressivity (high transferrin saturation and high serum ferritin), liver pathologic features (iron accumulation in parenchymal cells with iron-spared Kupffer cells until late stage), damage and disease of distinct target organs (liver, heart, endocrine glands, joints).

An abdominal MRI for patient’s with Ferroportin disease can show iron loading in the spleen, spine and liver.

A non-aggressive phlebotomy regimen is recommended, with careful monitoring of the transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.

Of note, non-classical Ferroportin disease occurs with mutations in ferroportin that are resistant to inhibition by the iron regulatory molecule hepcidin, retaining full iron export capability. Patients will normally have high levels of ferritin and hepcidin, increased transferrin saturation, and typical deposition of iron in the hepatic parenchyma. This has also been called hepatic-type ferroportin disease.

https://www.uptodate.com/contents/hfe-and-other-hemochromatosis-genes?search=ferroportin%20disease&sectionRank=1&usage_type=default&anchor=H16&source=machineLearning&selectedTitle=1~17&display_rank=1#H16

D) Wash the pRBC product prior to giving the transfusion

IgA is concentrated mostly in the mucosal secretions and is believed to be important in the immune function of the mucosal barrier. 

A minority of IgA-deficient individuals are symptomatic. These patients may develop recurrent sinopulmonary infections, autoimmune disorders, gastrointestinal disorders, allergic diseases and rare anaphylactic reactions to blood products.

There are two levels of severity of IgA deficiency that are recognized. A serum IgA level < 7 mg/dL is considered to represent a severe deficiency. 

IgA deficiency is the most common human immunodeficiency. The presence of anti-IgA that occurs in an IgA deficient recipient can lead to anaphylaxis if blood products are administered to that patient. This occurs as the anti-IgA antibody of the host reacts against the IgA antigen contained in the donor red cell units.  

Most patients with selective IgA deficiency do not form anti-IgA antibodies. These antibodies are usually only found in patients who have undetectable levels of serum IgA. 

Patients with selective IgA deficiency can develop urticaria, wheezing, shock and cardiac arrest after receiving transfusion(s). If this were to happen, one must stop the transfusion immediately. Patients may need to receive Epinephrine. One critical point is that patients with IgA deficiency who are transfused with plasma products that contain IgA, will have an _immediate_ reaction to the blood product.

Patients with severe IgA deficiency can experience infusion reactions to blood products containing small amounts of IgA, typically in located in the plasma in the following products: Whole blood, Red blood cells, Granulocytes, Platelets, FFP, Cryoprecipitate and IVIG.

By washing the donor red cell units with saline, centrifuge or removal of the supernatant, the IgA antibodies will be removed. However, this will shorten the shelf-life of red blood cells to less than 24 hours.

Indications to wash Red blood cells:

--Severe allergic reactions

--Removal of maternal antibodies for fetal transfusion 

  (Hemolytic disease of newborn, Neonatal alloimmune thrombocytopenia)

**Pearl:

Patients who should be screened for anti-IgA antibodies are those patients with severe sIgAD and in patients with partial sIgAD who have experienced an infusion reaction to a blood product in the past. Screening for anti-IgA antibodies allows clinicians to identify patients at risk for infusion reactions and helps these patients become informed about the potential risks of receiving blood products.

https://www.uptodate.com/contents/selective-iga-deficiency-management-and-prognosis?search=febrile%20non-hemolytic%20reaction&topicRef=7947&source=related_link#H6475461

E) Choice B or C

For patients who present with muscle invasive urothelial cancer (T2, T3, T4), the standard of care is to provide neoadjuvant Cisplatin based chemotherapy (dose-dense MVAC preferred) followed by a cystectomy.

Guidelines have suggested that if a patient with muscle invasive urothelial cancer is not deemed to be a candidate for Cisplatin (ie, renal dysfunction), then he or she should not receive neoadjuvant chemotherapy. Carboplatin for this malignancy is not felt to be adequate treatment and should not be substituted for Cisplatin.

The data on the benefit of offering adjuvant chemotherapy for bladder cancer is less robust. However, guidelines do suggest that for those patients who do not receive neoadjuvant chemotherapy, one can consider offering adjuvant chemotherapy based on post-operative pathology. Patients with a T3 to T4 tumor or positive nodes can be considered for adjuvant chemotherapy if they did not receive any preoperatively.

Of note, if a patient undergoes an initial cystectomy and has a tumor that is pT2 or less with no nodal involvement or LVI, then adjuvant chemotherapy is not recommended. This is important as often a Medical Oncologist will see a patient only after the patient has undergone a cystectomy. Unfortunately, in these cases there was no opportunity to give neoadjuvant chemotherapy.  

This patient has a T2 urothelial cancer and is not a candidate for Cisplatin.  One would proceed with surgery/cystectomy or concurrent chemoradiation with 5-FU/Mitomycin C or low-dose Gemcitabine after a maximal debulking TURBT. Concurrent chemoradiation does has Category 1 evidence to offer in this setting as does neoadjuvant Cisplatin-based chemotherapy followed by a radical cystectomy. However, given his renal dysfunction, he is not a candidate for Cisplatin.

The guidelines for Cisplatin dosing based on renal dysfunction are not standard. However, some guidelines recommend the following:

GFR (ml/min) >60     Give 100% of the dose

                       45-59  Give 75% of the dose

                       <45     Consider Carboplatin [Depending on the tumor type]

Some will use split dose cisplatin in patients who have a low CrCl. One needs to be careful offering Cisplatin to patients with a CrCl that is < 60 mL/min.

For patients on dialysis, one will normally give 50% of the Cisplatin dose. Dialysis should be performed within 3 hours after giving the dose of Cisplatin.

E) Emicizumab

The FDA has approved emicizumab-kxwh for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with and without factor VIII inhibitors.

Emicizumab bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in patients with hemophilia A. 

Patients enrolled in the HAVEN 1 study were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.

A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events among participants who were randomly assigned to emicizumab prophylaxis versus 23.3 events among those assigned to no prophylaxis. This represents a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). 

A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). 

Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.

As mentioned above, Emicizumab also has FDA approval for patients with Hemophilia A who do not have an inhibitor.

The HAVEN 3 study tested emicizumab as prophylaxis in 152 patients aged 12 years or older with severe hemophilia A (Factor VIII activity <1%) who did not have an inhibitor. Most of these patients were only receiving episodic therapy for bleeding.

Compared with controls receiving only episodic therapy with factor VIII, individuals assigned to emicizumab prophylaxis had a dramatically reduced annualized bleeding rate (38 events versus 1.5 and 1.3 events at the two dosing protocols [1.5 mg/kg once weekly or 3 mg/kg every other week, respectively)

All controls had at least one bleeding event during the study (24 weeks), whereas more than half of participants in both emicizumab groups had no bleeding events during the study. 

In the group of 48 patients who had been receiving routine factor VIII prophylaxis, transition to emicizumab reduced the annualized bleeding rate by 68 percent.

Johannes Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017; 377:809-818

D) Durvalumab

Most patients with Stage III unresectable, NSCLC will have subsequent disease progression despite receiving definitive chemoradiotherapy.

The PACIFIC study was a phase 3 study that compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.

Patients were randomly assigned in a 2:1 ratio, to receive durvalumab (10 mg/kg) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy.

Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo).

The median progression-free survival from randomization was 16.8 months with durvalumab versus 5.6 months with placebo (HR=0.52; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%.

The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months).

The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively).

A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.

Of import, the PD-L1 status of the tumor does not influence whether or not to offer Durvalumab as consolidation therapy. So, even though the patient in this question has a PD-L1 TPS score of 0%, he should absolutely be considered for Durvalumab.

D) Gemzar + Platinum

Collecting (Bellini) duct carcinoma is a rare subtype of renal cell cancer. It acts aggressively and up to 40% of patients have metastatic disease at initial presentation. Patients with this malignancy will normally have a poor prognosis. Collecting duct carcinoma shares biologic features with urothelial carcinoma.

For collecting duct or medullary subtype of kidney cancer, partial responses have been observed with cytotoxic chemotherapy (Carboplatin + Gemcitabine, Carboplatin + Paclitaxel, or Cisplatin + Gemcitabine) and other platinum-based chemotherapies currently used for urothelial carcinomas.

One group performed a systematic review of the literature on the management options for collecting duct cancer.

The best studied therapy was felt to be Gemcitabine/Cisplatin. The role of targeted therapy (tyrosine kinase inhibitors such as sunitinib or sorafenib) and immunotherapy in the management of collecting duct carcinoma has not been as well established.

A prospective multicentre phase II study evaluated the efficacy of gemcitabine and either cisplatin or carboplatin on Stage IV collecting duct cancer.

Participants received 21-day cycles of gemcitabine 1250 mg/m² on days 1 and 8, plus cisplatin or carboplatin 70 mg/m² (based on renal function) on day 1 (n = 23 gemcitabine, n = 12 cisplatin, n = 6 carboplatin, and n = 5 cisplatin then carboplatin). Participants underwent a median of 6 cycles of treatment (range: 1–8 cycles).

Participating patients achieved a 26% partial or complete response rate with 1 complete response. Another 10 patients (44%) experienced disease stabilization, and 7 had progressive disease (30%). Progression-free survival was 7.1 months and overall survival was 10.5 months.

C) Mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma defined by cyclin D1 (CCND1) overexpression. The characteristic translocation seen in this lymphoma is t(11;14).

The Mantle Cell Lymphoma International Prognostic Index (MIPI) has been designed to stratify MCL patients into risk groups (low, intermediate or high risk) based on clinical prognostic factors, such as age, performance status, Wbc count and lactate dehydrogenase (LDH) level.

Ki-67 expression over 30% predicts for a more aggressive clinical course. TP53 mutation and blastoid subtype are also associated with Mantle cell displaying a more aggressive behavior.

In addition to CCND1, SOX11 is a diagnostic antigen in MCL. Cyclin D1- (CCND1 negative) mantle cell lymphomas are not well characterized. SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1 negative variant. Data sets have demonstrated that Cyclin D1 negative MCL patients are clinically and biologically similar to the conventional cyclin D1(+) MCL.

The most common biomarker for indolent disease:

SOX11- [IGHV mutated]

Typical clinical presentation for indolent, SOX11+ Mantle cell lymphoma is:

Leukemic non-nodal CLL-like with splenomegaly, GI or Blood/Bone marrow involvement only, low tumor burden, Ki67 proliferation fraction <10%

Many patients with indolent Mantle Cell Lymphoma can be observed.

D) Xarelto 15 mg po bid x 3 weeks then 20 mg po daily

Xarelto is a factor Xa inhibitor that is a highly effective medication used in the treatment of patients who develop a DVT/PE.

It is an approved medication that is given in the following situations:

--To reduce the risk of stroke and embolism in patients with nonvalvular atrial fibrillation

--Treatment of a DVT and PE and for the reduction in the risk of recurrence of a DVT and of PE

--DVT prophylaxis for patients who are undergoing knee/hip replacement surgery

Given this patient’s history of HIT, it would not be ideal to rechallenge him with heparin or low-molecular weight heparin.

Coumadin needs several days to become therapeutic and thus the patient would need a bridge with a heparin product for at least 5 days.

One advantage of Xarelto (or any of the Direct Oral anticoagulants) is that no bridging therapy is needed and it can be given as monotherapy. Xarelto has been shown to be an effective medication for those patients who have a history of HIT (or who have a current diagnosis of HIT).

Mothers who are nursing should either discontinue this drug or stop nursing. Patients with renal impairment will need to avoid or adjust the dose of this medication based on CrCl and treatment indication. Patients with severe hepatic impairment (Child-Pugh B and C hepatic impairment or with any degree of hepatic disease associated with coagulopathy), should avoid using this medication.

For patients being treated for DVT, PE and for the reduction in the risk of recurrence of DVT and of PE, one should avoid Xarelto if they have a CrCl <30 mL/min.