Brachytherapy for Soft Tissue Sarcoma

JD presents a patient with a high grade un-differentiated sarcoma of the R bicep. Treated initially with surgery, positive margins. Treated postoperatively to 70 Gy at that time. Recurred twice more with positive margins on resection each time (positive margin is at the neurovascular bundle).

Brought to resection again, this time with very close margins (2mm). Catheters were placed for LDR treatment.

IJROBP 2001;49:1033- ABS recommendations for brachytherapy in sarcoma. For recurrences LDR +/- EBRT. Positive margins reccomend LDR + EBRT. High Grade negative margins reccomend LDR +/- EBRT. Low Grade negative margins - consider observation of possibly LDR or EBRT.

Pisters JCO 1996 - Surgery +/- LDR for STS. n=164. 30% were recurrent, 40% were low grade, 15% had positive margins. PTV = tumor bed + 2cm. Catheters 1cm separation. 42-45Gy over 4-6 days. Loaded POD 5 or 6. Ir192 wires. 5year local control 82% vs 69%, p=0.04. Most recurrences occurs within 3-4 years. OS no difference largely due to the ability to salvage with amputation.

High Grade local control was 89% LDR vs 66% (SS), Low Grade 64% LDR vs 74% (NS). Wound complications were much lower is catheters were loaded after day 5 (and mid trial, due to this observation, they began loading later).

NL comments that this approach is not currently in use a MSKCC - rather pre or post op EBRT is used with LDR is selected scenarios.

Yang JCO 1998 - EBRT trail n=140, 45 Gy EBRT with 18 Gy LDR boost, concurrent doxorubicin, ifosphamide if high grade. Local control improved in both high grade and low grade. (10yr local control HG 100% vs 80% SS, LG 96% vs 67% SS). OS no difference.

Note that doxorubicin is not used with concurrent RT due to toxicity.

Multiple retrospective series report LC of 90% with EBRT and LDR boost.

Delaney IJROBP 2007 - retrospective of EBRT for recurrent (previously treated) STS - showed 80% LC with doses >64Gy.

Sindelar Arch Surg 1993;128:402 Retroperitoneal Sarcoma, n=37. randomized to postoperative 54Gy EBRT or 35Gy EBRT + 20Gy IORT. Infield local recurrence improved p<0.05, however all local recurrence NS. Increase GI toxicity in the EBRT arm, vs increased peripheral neuropathy in the IORT arm.

Retrospective series show 70-90% local control with HDR.

Our reccomendations for recurrent disease is highly individualized. Often IMRT is used in combination with either LDR or HDR optimization. Often times preoperative EBRT is given, then if positive or close margins are expected, catheters are placed intraoperatively, and loaded after POD 5 if final path shows concern.

Hyperthermia Symposium 4/9/09

These talks were part of a symposium hosted by Dr. Dewhirst at Duke.

Timo L.M. ten Hagen, PhD

Laboratory Experimental Surgical Oncology

Department of Surgery

Rotterdam, the Netherlands

“Manipulation of Tumor Response with Vaso-active Agents”

The problem is poor perfusion in regions with viable tumor. This causes both hypoxia and poor drug delivery.

Isolated limb profusion with high dose melphalan, TNF or other vasoactive drugs was the strategy used. Hyperthermia may also be used. Used in both melanoma and sarcoma of the extremities.

TNF, Histamine, IL-2, hyperthermia, and MMP antagonists (matrix metalloproteases) all act on tumor vasculature. At this time he showed images of a TNF treated patient with a lower extremity sarcoma, with normalization of the angiogram. TNF alone doesn't seem to cause any regression on its own, but in combination with melphalan, an additional effect on tumor is seen in animal models. Interestingly, interstitial pressure is not significantly changed.

Addition of Melfalan + TNF or doxorubcin +TNF one sees an improvement in drug accumulation in tumor. Distribution is also more homogeneous. In either TNF or histamine hemorrhage is also seen in the tumor specimens (increasing the vascular permeability?).

One problem is that chemotherapy agents such as melphalan, even with isolated perfusion, pharmacokinetics remain poor. Efforts now directed towards liposomal drugs.

TNF + doxil (liposomal doxorubicin) resulted in an increase in tumor response rate, as well as growth delay. In normal tissues, concentrations were low, except for the spleen (TNF may be activating macrophages in this organ). 100nm liposomes seem to give the best localization into tumor.

Side note – it is fortunately easy to image doxorubicin because it fluoresces. One can use liposomes labeled with DIO to demonstrate differential concentrations of the intact liposomes and free doxorubicin. One issue is that many liposomes hold onto their doxorubicin, and the drug is not release to the target – the nucleus. (Can Res 2007)

TNF is also a toxic systemic agent, also termed cachectin due to it's role in cancer associated cachexia. At high doses it can lead to hypotensive shock and multi-system organ failure.

The second talk of the day was:

Lars Lindner, PhD

Department of Internal Medicine III

University Hospital Grosshadern

Munich, Germany

“Title: Potential of phosphatidyloligoglycerols in temperature sensitive liposomes”

Temperature sensitive liposomes are engineered to release contents at mild hyperthermic temperatures 40degrees.

Two Strategies for delivery

Interstitial drug release: Specificity controlled by increased vascular permeability in tumors, and which can be improved by the application of targeted heat. The cons to this approach include inefficient entrapment process, and high systemic drug load due to uptake by the reticular endothelial system (RES). In this approach, there is no need for quick drug release as the drug is within the interstitial compartment.

Intravascular drug release: has the potential to have a 100% drug delivery to the tumor region, however systemic recirculation is a limitation of this approach. It is important to have efficient drug release in this setting to maximize the targeting.

Phosphatidyloligoglycerols: three subtypes, and with PG2 and PG3 there are much more linear pharmacokinetics. By increasing the concentrations of PG2 and PG3, one can increase the rate of release with increase in temperature. These are development currently awaiting clinical applications.

Brachytherapy Rounds - Sarcoma Implant + Syed Template

Brachytherapy Rounds today covered implants for a sarcoma and a Syed template for vaginal cancer.

Case 1 (High Grade Sarcoma): The sarcoma was a large (24cm in greatest dimension) high grade sarcoma of the R thigh.  The mass was invading skin.  Biopsy confirmed prior to treatment.  He was planned to be treated preoperatively with 50Gy on the IGRT RTOG protocol for sarcomas.  Unfortunately during his external beam treatment had a bleed from his tumor at 32Gy, requiring urgent surgical intervention.

Intraoperatively catheters were placed so that his RT could be completed via HDR. 24 catheters were placed 1cm apart, transversly across the tumor bed.  Catheters extended to the skin on both sides and were tacked down in both the bed and on the skin.  Wound was covered with a wound vac - uncertain to date wether this will heal by secondary intention or by graft at some later date.

Margins on the resection were negative.

HDR dosing was 4Gy x 4 BID prescribed to 1cm in tissue.  Treatment was delayed till 1 week after resection.

Case 2 (Vaginal Adenocarcinoma): Pt with an adenocarcinoma of the RV septum.  Presented with postmenopausal bleeding in 5/2009.  Hx of fibroids, treated with TAHBSO in 2004.  Speculum exam was limited by mass effect in the vaginal and rectum.  EUS was performed revealing tumor extending 10cm along the RV septum extending distally just prior to the introitus.  Biopsy was positive for poorly differentiated adenocarcinoma.

There was a debate at to wether this was a vaginal primary vs. a rectal primary.  Per clinical exam and pathologic review, this was finally characterized as a vaginal primary.

Patient was thought to have a high risk of rectal obstruction during treatment and a diverting colostomy prior to initiation of treatment.  Treated with external beam RT - WPRT with concurrent cisplatin to 50.4Gy.  Pt was initially treated with APPA fields covering the inguinal/pelivic nodes and primary for 10 fx, and was then converted to IMRT to complete treatment.  Pt had a minimal response upon treatment completion.

Pt was then brought in for interstitial implant.  Preplanning was based on pretreatment imaging.  It is important to order the strands in advance and pre-plan placement of the catheters so that one can be ready on the date of implant.

On Date of implant: 

1. EUA is performed and gold seeds are placed at the proximal, distal and lateral extents of disease.  

2. Cylinder and and template are placed to get a gauge to how far the cylinder can be placed within the vaginal.  This was marked on the cylinder for reference.

3. Clinically it was determined that the catheters should extend 2cm beyond the cylinder.  A sample catheter was placed with the template on the OR table to measure how far from the hub of each catheter should be from the template surface.  (much further than this, one must consider having laparascopic confirmation that the catheters are not entering the peritoneal cavity)

3. 24 catheters were placed posteriorly along the RV septum, and around the cylinder.  After we were happy with the placment the trochars were removed.

4. Patient was brought for CT, and simulator confirmation of placement.

5. Rx was to the 50cGY/hour IDL x 50 hours planned

Unfortunately patient pulled the entire implant out at approximately 36hours.  Uncertain what happened at the time, appartently the patient recieved ativan and became disoriented.  Regardless, the implant was placed in the pig, and the room and patient was surveyed to ensure that all activity was in pig.

Plan is going to be to try to reconstruct the dose delivered and will boost with IMRT afterwards.