Sarcoma

Question 1

What are the Stanford criteria?

Answer 1

1. Nuclear atypic
2. Coagulative necrosis
3. > 10 mitoses/hpf

Question 2

What are the frequency of LN metastases in MMMT and LMS?

Answer 2

GOG 40: Frequency of Lymph Node Metastases in Uterine Sarcoma, a retrospective cohort study of Stage I-II sarcomas.

Nodes MMMT LMS
Pelvic 15-20% 3-5%
Para-aortic 7% Not Avail

Question 3

What are the frequencies of LN and adnexal metastases with LMS?

Answer 3

GOG 40:

3. 5% LN mets
4. 5% adnexal mets.

This is why I omit lympadenectomy and offer ovarian conservation in appropriately selected LMS patients.

Question 4

What are the pathologic prognostic factors for LMS?

Answer 4

GOG 40: mitotic activity was the only significant predictive pathologic factor for LMS.

Question 5

What are the frequencies of LN and adnexal metastases with MMMT?

Answer 5

GOG 40:
20% LN mets
12% adnexal mets.

Question 6

What is your adjuvant treatment for LMS?

Answer 6

It depends on stage. For Stage I disease, I recommend observation alone. For Stage II-IV disease, I recommend adjuvant Doxorubicin, or Gemcitabine and Taxotere.

Question 7

Why do you offer observation alone for Stage I LMS?

Answer 7

There is prospective and retrospective data that has shown that there is no benefit from adjuvant treatment.

GOG 20 (Omura 1985): prospective, randomized trial of Stage I-II sarcomas-all types, who could get optional radiation therapy, who were then randomized to adjuvant doxorubicin vs no chemotherapy. There was no statistically significant difference in PFS or OS. *though trend towards PFS.

Little 2017: retrospective study of Stage I LMS patients who received Gem/Tax vs observation, and found no difference in PFS or OS.

EORTEC 55874 (2008): prospective, randomized trial of Stage I-II sarcoma all types, randomized to RT vs observation, and no effect on PFS or OS.

Question 8

Why do you recommend Gemcitabine/Taxotere for advanced-stage LMS? What is the dose?

Answer 8

Gem/Taxotere: gemcitabine (900 mg/m2 over 90 minutes on days 1 and 8) plus docetaxel (75 mg/m2 on day 8)

There have been several phase II trials showing ORR 20-30%. (GOG 131G, 87L)

Question 9

What is the role of bevacizumab in metastatic LMS?

Answer 9

There is limited/no role for bev in this disease.
Hensley 2015: Based on a prospective, randomized phase III trial which showed no improvement in PFS, OS, or ORR when bev was added to gem/taxotere.

Question 10

What is the primary alternative to Gem/Taxotere in the treatment of LMS?

Answer 10

Doxorubicin (75mg/m2 q3 weeks)

GeDDiS (2017): prospective, randomized trial of all-sarcomas, comparing gem/tax to doxorubicin.

Question 11

What are the prognostic factors of MMMT?

Answer 11

GOG 40: based on this retrospective, cohort study , prognostic factors are adnexal spread, LN spread, histologic type, and grade of the sarcoma.

Question 12

Where do most LMS recur?

Answer 12

Lungs (40% of recurrences, per GOG 40).

Question 13

What chemotherapy do you recommend for advanced stage MMMT?

Answer 13

I recommend carbo/taxol. There has been a prospective, randomized non-inferiority trial comparing carbo/taxol to the prior standard of care ifos/taxol, which demonstrated non-inferiority of carbo/taxol. The results of this study, GOG 261, were presented at ASCO 2019.

Previously, ifos/cis and then ifos/taxol were used.

GOG 108 (2000) was a prospective, randomized trial of advanced-stage MMMT getting ifos vs ifos/cis, and showed a small improvement in PFS, though it may have not been worth the toxicity.

GOG 117 (2005) was a phase II trial that showed that ifos/cis was a tolerable regimen.

GOG 161 (2007) was a prospective, randomized trial that compared ifos to ifos/taxol and found significant improvement in PFS and OS.

GOG 150 (2007) was a randomized trial of all stages of MMMT randomized to WAR vs ifos/cis. While there was no statistically significant difference, there was a trend in favor of chemotherapy.

GOG 232B (2010) was a phase II trial that demonstrated activity of carbo/taxol with ORR 54%.

Question 14

What are other treatment options for advanced LMS?

Answer 14

1. Gem/Taxotere
2. Doxorubicin
3. Ifos (ORR 15-30%)
4. Trabectadin
5. Dacarbazine
6. Endocrine therapy with ORR 10%

Question 15

Describe the pathology (or slide) of MMMT.

Answer 15

MMMT is comprised of malignant epithelial and mesenchymal elements.

Question 16

Ifosphamide

1) Dose
2) Mechanism
3) Toxicity
4) Metabolites
5) Treatment

Answer 16

1) ifosfamide (1.6 g/m2 daily for three days) plus paclitaxel (135 mg/m2 on day 1) for up to eight 21-day cycles; or 2g/m2 for three days if used as a single agent
2)
3) hemorrhagic cystitis, nephrotoxicity which manifests as hypophosphatemia, polyuria, and metabolic acidosis
4) Chloroacetaldehyde is directly toxic to the tubular cells. Acrolein is is toxic to the bladder
5) Mesna to bind acrolein. Limit dose of ifos - Clinically significant nephrotoxicity is more likely to occur at a total dose above 60 g/m2 and severe nephrotoxicity above 120 g/m2.

Question 17

Practice case: MMMT on EMB.

1) Work-up?
2) Surgical management if limited to the uterus? If metastatic?
3) Adjuvant treatment based on stage?
4) Recurrence?

Answer 17

1) CA-125 and CT C/A/P
2) TH, BSO, PPLND if limited to the uterus. TH BSO and debulking if beyond the uterus
3) Per NCCN guidelines, I recommend chemo+VBT for Stage I disease, and chemo+EBRT for Stage II and above.

Question 18

Practice case: LMS on myomectomy.

1) Work-up?
2) Surgical management?
3) Adjuvant treatment based on stage?
4) Recurrence?

Answer 18

1) CT C/A/P
2) TH, BS. Ovarian conservation is appropriate. No LND indicated.
3) Per NCCN guidelines, no adjuvant treatment for Stage I-II, chemotherapy for Stage III-IV
4) If resectable, offer surgery.

Question 19

Practice case: ESS on hysterectomy.

1) Work-up?
2) Surgical management?
3) Adjuvant treatment?

Answer 19

2) Recommend BSO and these are hormonally active tumors.
3) Depends on grade and stage. If LG-ESS, recommend estrogen blockade with Megace. If HG-EGG or UUS, recommend chemotherapy.

Question 20

Trabectadin

1) Dose
2) Mechanism
3) Toxicity

Answer 20

Answer

2) alkylating agent; interrupts DNA nucleotide excision repair machinery
3) severe and fatal neutropenic sepsis; rhabdomyolysis and hepatotoxicity; skin and soft tissue necrosis following extravasation; and heart failure.

Question 21

Dacarbazine

1) Dose
2) Mechanism
3) Toxicity

Answer 21

Answer

2) alkylating agent
3) – major side effect is nausea and vomiting.
- - requires good venous access because of the potential for chemical phlebitis.
- - Bone marrow suppression is usually only modest, and alopecia and fatigue are minimal

Question 22

Gemcitabine

1) Dose
2) Mechanism
3) Toxicity

Answer 22

1) 900mg/m2
2) Antimetabolite, a nucleoside analog.
- blocks DNA synthesis
- incorporates into DNA and causes strand termination
3) BM suppression, stomatitis, diarrhea
- Rare: TTP

Question 23

Doxorubicin

1) Dose
2) Mechanism
3) Toxicity

Answer 23

1) 60mg/m2 q3weeks
2) Anthracycline
- Topo II inhibition leads to DS breaks
- DNA intercalation
- Free radical
3) Neutropenia (dose-limiting), BM suppression, n/v
- Vesicant!
- Radiation recall!
- CM! Dose-dependent

Lifetime max: 360mg/m2
DC if EF < 50% AND decreases by 10%

Question 24

Pathology: how do you determine benign ESN from ESS?

Answer 24

ESN: well-circumscribed, pushing margins.

ESS: infiltrative margins with or without angioinvasion

Question 25

Ifosphamide

1) Dose
2) Mechanism
3) Toxicity

Answer 25

1) 2.5g/m2
2) alkylating agent
3) hemorrhagic cystitis, BM suppression, n/v, alopecia
- rate: secondary leukemia