Oncoanatomy: Mediastinum

AC presents the resident portion of the Oncoanatomy module on the Mediastinum

Anterior, middle and posterior mediastinal compartments have no intrinsic discriminating planes, however the division is useful for differential diagnosis. Primarily the middle compartment contains the heart, great vessels and airways, the anterior and posterior compartments are simply in front of or behind these structures.

Anterior Compartment
Contents include Internal mammary vessels, thymus, fat pad.
DDx for masses: 4Ts - Thymic lesions, Thyroid, Teratoma, (Terrible) Lymphoma PMBCL or Lymphoblastic lymphoma

Primary mediastinal b-cell lymphoma - variant of DLBCL. R-CHOP often used. Consolidative RT is often used. Outcomes may be more favorable than other variants of DLBCL. Peak age in the 30s and 40s.

Lymphoblastic Lymphoma: Pre B or C cells, blurred line between this and lyphoblastic lymphoma. Male predominance, peak incidence in 2nd and 3rd decades. Thymic origin CD7+, CD5+, CD2+. Mediastinal involvement in 60-70%. Treated along leukemic protocols (VPDC). Role of RT is unclear. In T-cell cases, CNS prophylaxis is indicated (intrathecal MTX +/- cranial RT).

Middle Mediastinum: Great vessels, Heart, Trachea and Airways.
Primarily metastasis or lyphoma.

Posterior Mediastinum: Esophagus, Lymph nodes, Fat, Sympathetic chains, the Azygous vein, Thoracic duct.
DDx: Neurogenic tumors, esophageal tumors, aortic lesions.

Hodgkin Lymphoma. Historically treated with RT alone with a 5yr survival of approximately 30%.

Mantle field: superior edge is at the mastoid tips, inferior at T9-10 spaces, lateral borders include the axillary nodal regions. Custom blocking is used for bilateral lungs, and humeral heads, shaped to include the bilateral hila. Lanrynx block is placed around 20Gy.

JAMA 2003;290:2831 (Hull) - 415pts with HL treated with RT or CTRT, with 80% recieving mantle fields. 10% developed CAD by 20 years. 6% had valvular dysfunction at 22yrs.

RT + doxorubicin. Myrehaug, Leukemia Lymphoma 49:1486. Doxorubicin seems to have a supra additive effect on cardiac toxicity with an HR for cardiac morbidity of 2.77 vs HR 1.82 with RT alone.

Monitoring Response to Thermodox using Optical Spectroscopy

Greg Palmer Ph.D. present his post-doc work in Dr. Dewhirst's Lab:

Optical spectoscopy involves measuring the reflectance, and fluorescence of tissue, and looking to provide structural and functional information. This is a non-invasive, near real-time, non-destructive measurement.

Three properties are measured: absorbance, scattering, and fluorescence.

Measurable Quantities:
Hb concentrations and saturation
NAD, NADPH
Collagen
Amino Acids
Extrinsic Fluorecence (doxorubicin and other drugs or contrast agents)
Size and density of scattering centers (collagen structure)

Depth may be done up to 5cm when utilizing infrared wavelengths (though with shorter wavelengths, we may be limited to millimeters).

Measurement within 10% can be arrived at via monte carlo model fit for hemoglobin concentrations. PO2 can thereby also be estimated. This contrasts to BOLD imaging which only measures relative change.

Note that the measurements are volume averaged, thus less sensitive to positition than an ependorf electrode.

Thermodox is doxorubicin encapsulated within a thermally sensitive liposome. This is given in combination with regional hyperthermia for directed chemotherapy delivery. As doxorubicin is fluorescent (593nm), measurements with optical spectroscopy can estimate in real time, regional drug concentrations may be estimated.

Concentrations as estimated by optical spectroscopy and correlated to HPLC assay as reference resulted in excellent correlation r=0.9, p=1e-20.

Hb saturation and concetration both are seen to increase after hyperthermia. In the setting of liposomal doxorubin, these do not increase, which may be a result of doxorubicin's direct affect on vasculature. One can see a dramatic increase in doxorubicin after application of hyperthermia to liposomal doxorubicin, much greater than free dox +HT, or free dox alone.

Ongoing clinical work is progressing in Head and Neck, Breast, and Cervical Cancer... stay tuned.

Optimal RT regimen for PCI in LS SCLC

Also in the Lancet Oncology this week:

The PCI collaborative group (RTOG, EORTC, &others), published their results in a randomization between three different PCI doses and schedules for patients with LS-SCLC.

720 patients with limited stage SCLC and complete response to thoracic RT with concurrent chemotherapy were randomized to:
1. 25Gy in 2.5Gy QD x 10
2. 36Gy in 2Gy QD x 18 or 1.5Gy BID x 24.

2-year incidence of brain metastases was 29% (95% CI 24–35) with 25Gy and 23% (18–29) with 36Gy (HR 0.80 [95% CI 0.57–1.11], p=0.18).

2-year OS was 42% (95% CI 37–48) with 25Gy and 37% (32–42) with 35Gy (HR 1.20 [1.00–1.44]; p=0.05). Deaths in the 35Gy seem to have been cancer related. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. Acute fatigue seen in 30% with 25Gy vs 34% with 35Gy, headache in 24% vs 28%, and nausea or vomiting 23% vs 28%.

Their conclusions were that 25Gy in 10 results in equivalent brain control and superior survival.

One comment that I would add to this is that brain mets did trend towards an improvement with higher dose, and that the deaths in the high dose arm are difficult to ascribe directly to the intervention. It is also interesting that there were more serious adverse event in the low dose arm, perhaps reflecting the larger dose per fraction? That said, the results are the results, and this trial should help us in PCI regimen selection.

5 year results of Temozolomide + RT for GBM

The EORTC-NCIC trial examining temozolomide + RT for GBM is updated in the Lancet Oncology this week with 5 year results.

To review this is a randomized phase III trial examining 60 Gy RT vs 60 Gy + concurrent temozolomide and 6 months adjuvant temozolomide (TMZ). This was the first real advance in GBMs for decades and was initially presented with a 2 year OS benefit in the NEJM 2005.

To review the final 5 year results: OS was 27.2% (95% CI 22.2—32.5) at 2 years, 16.0% (12.0—20.6) at 3 years, 12.1% (8.5—16.4) at 4 years, and 9.8% (6.4—14.0) at 5 years with RT+TMZ, versus 10.9% (7.6—14.8), 4·4% (2.4—7.2), 3.0% (1.4—5.7), and 1.9% (0.6—4.4) for RT alone (HR 0.6, 95% CI 0.5—0.7; p<0·00001).

All subgroups benefited, including those >60 years of age. Methylation of the MGMT promoter predicted for the most benefit.

10% long term survival may not seem like much, but the tail on this curve supports the hypothesis that GBM (at least with MGMT methylation), is a curable disease with RT + TMZ.

Bladder Preservation

MP presents today on Bladder Preservation Therapy:

Presents an 80 yo WM with BPH s/p several local therapies, developed hematuria. Cystoscopy revealed 3 nodulear lesions L posteriolateral bladder. TURBT demonstrated grade 3 transitional cell carcinoma with invasion into the muscularis propria.

T stage:
Ta - non-invasive papillary carcinoma
Tis - carcinoma in situ, "flat tumor"
T1 - invades subepithelial connective tissue
T2 - invades muscle
T2a - invades superficial muscle (inner half)
T2b - invades deep muscle (outer half)
T3 - invades perivesical tissue
T3a - microscopically
T3b - macroscopically (extravesical mass)
T4 - invades other organs
T4a - invades prostate, uterus, vagina
T4b - invades pelvic wall, abdominal wall
Nodes:
N1 - single LN, 2 cm or less
N2 - single LN 2-5 cm; or multiple LN <> 5 cm

Risk Factors: smoking, cytoxan, aromatic compounds, chronic irritation, s. hematobium
95% TCC, 5% SCC in the US

Options:
1.Partial Cystectomy
2.Radical Cystectomy
3.Bladder Preservation

Note there is an RCT which is accruing (the SPARE trial) randomizing between cystectomy and bladder preservation.

Partial Cystectomy – Smalden J Urol 2008. T2 and T1 high grade. in 25 selected pts 5yr CSS 84%, 5yr OS 70%. Primarily this is done with dome lesions. Invasion of the trigone is a contraindication.

Initial Work:
Shipley NEJM 1993: 53 pts 40Gy + CDDP, 28/53 with CR, 90% functioning bladder.
University Paris JCO 1993: 54 pts neoadjuvant CTRT, majority had pCR.

Bx proven muscle invasion → TURBT → XRT with CT → reevaluate at around 40-45Gy → if CR continuation of CTRT / if no CR cystectomy.

RTOG trial overview: T2-4 primary, no hydronephrosis

85-12 TURBT, CDDP/RT: CR 67%, 5yr OS 52% 4yr IBS 41%
88-02 TURBT, MCV, CDDP/RT: CR 76% 5yrOS 51% 5yr IBS 36%
89-03 TURBT, +/- MCV, CDDP/RT: CR 59% 5yr OS 49% 5yr IBS 38% (no difference between arms)

MCV – methotrexate, cisplatin, vinblastine

More RTOG:

95-06 TURBT, 5FU+CDDP+RT hypofx to 44Gy (Based on Paris experience): CR 67%, 3yr OS 83%, 3yr IBS 66%
97-06 TURBT, CDDP+BID RT, MCV: CR 74% 3 yr OS 61%, 3yr IBS 48%
99-06 TURBT, paclitaxel+CDDP+BID RT, CDDP/GEM: CR 84% 5yr OS 56%,

total dose 45.6Gy to pelvis, 64.8Gy to bladder tumor.

Rodel JCO 2002: 415 with T2-4 TURBT, CTRT or RT. 72% had CR and were observed. Cystectomy for all recurrences and persistent disease after CTRT. 1980s-2002 f/u 60months. 5yr OS around 50%, with about 40% IBS. 3% late Grade 3 GU toxicity.

R0 resections do better. Pts receiving CDDP did better than no chemo or Carbo.

Shipley Urol 60:2-88, 2002. CR rate 68%, DSS at 5 yrs. 5yr OS around 50%. 2/3 kept bladder. 46% had 5yr DSS.

The current US trial is looking at QD RT + Gem vs BID RT + CDDP/5FU. Also accuring in the UK is the SPARE trial (Cystectomy vs CTRT) and another looking at RT alone vs CTRT (with an additional dose question)

Conclusion: Bladder conservation results in similar 5yr OS of 50-60% compared to cystectomy. Concurrent CDDP based chemotherapy should be used. About 60-70% of patients will have an intact and functional bladder.

Initial fields were 4 field low pelvis (superior aspect at mid SI), to 38.6Gy, then boost tumor bed with 1.5cm margins to 64.8Gy. Weekly CDDP was used (doses 30-40mg/m2).

Cutaneous Topics in Radiation Oncology

Dr. Oleson speaks today about non-melanoma skin cancers and other cutaneous topics.

 Incidence of non-melanoma skin cancer is around 1,000,000

 Basal cell cancer 75%.
On the face usually these occur above the line from the earlobe to the angle of the mouth.
node mets in 0.1%. 5yr OS in LN + is around 10%
Subtypes:
Nodular-ulcerative 50%
Superficital 33%
Morpheaform has poorer prognosis incidence around 15%

 Squamous cell carcinoma incidence around 20% LN incidence <5%
5 yr survival around 25% in LN+ patients.
Below the line from earlobe to angle of mouth

 NCCN has a good table for risk factors in non-melanoma skin cancer.
Lesion size and location play into risk category.
H shaped area around the face is a higher risk area, eyes/nose/mouth/ears/jawline, not the cheeks or forehead or scalp.
H zone cancers tend to have vertical invasion, high nerve density, and the area is highly cosmetically important.

 Remember that with electrons, higher energies have less skin sparing, thus with low energies, bolus is ofter needed for skin cancers. Recall the rule of thumb that the Energy/3 is roughly the 80% PDD. Also recall that the drop off in bone, attenuation is approximately double that of water equivalent tissue. Penumbra is also an issue, particularly with small field size, and for a 5x5 field, the 80% line may not build up till 5mm into the field edge (Larger fields have less of this build up effect on the field edge).

 For head and neck skin cancers, try to immobilize with a mask. Due to gaps in the cone to skin distance, often times additional shielding can be placed directly on the skin for better collimation. Many of these issues can be avoided with the use of orthovoltage when available (which is the case at Duke University Medical Center). Recall that orthovoltage has approximately 20% greater biological effect and adjust all doses accordingly.

 CTV Margins (from the Mohs data)
SCC for diam <2cm, margin should be 4mm
SCC >2cm use 6mm
BCC <2cm use 4mm
BCC >2cm use 7mm
for morpheaform consider adding additional margin due to the indeterminant margins of this disease.

 So for CTV expansion of 4-7mm plus 5-10mm for penumbra to get to PTV, thus allow for 1–2cm around the lesion to the field edge.

 Fractionation:
Small Lesions (<5cm square)
2000 in 1-2 fx
3000 in 5-10fx
4000 in 10-16fx

Larger lesions
4500 in 15-18fx
5000 in 20-25fx
6000 in 20-30fx

Indications for RT in non-melanoma skin cancer:
Morrison, et al. Clin Plas Surgery 1997;24:719
H region- eyelids, nose, auricle
avoid in young patients due to development of telangectasias, and other long term cosmetic effects (though LP disputes that this is a big problem)
5y ST necrosis 34% for 5 x 10Gy
5y ST necrosis 3% for 45-54Gy in 9-18fx

Perineural invasion is a risk factor for failure in the first echelon nodes.

  Cartilage necrosis is probably over sold as a late effect – both JO and LP have only rarely seen this in their experience, including treatment of noses and ears.

  Locke IJROBP 2001;51:748
local control of 89%, less for recurrent lesions on the order of 80%. recommend 2.5Gy/day of 40-60Gy depending on lesion size.
Finizio Tumori 2002;88:48
96% local control    
Pinna – Silva IJROBP 2000;47:451
2y LC 87%, 5y LC 79%
limit dose/fx below 4gy to avoid cartilage necrosis
Nose - Tsao IJROBP 2002;52:973
2yr LC 90, 5yr LC 85%
<2cm 35Gy in 5fx
2-5cm 45Gy in 10fx
>5cm 50Gy in 25fx
good cosmesis

  long term toxicity should be on the order of 2% with modern treatment.

  Keloids:
definitive RT has poor results
recurrence after surgery is 50-80%
recurrence with postop RT 12-28%
BED goal of >30Gy per: Sakamoto, Rad Onc 2009 (in press)
8Gy x 2 or 6 Gy x 3
should start RT within 48hr
Freedom from recurrence with BED>30 at 10%, vs 40% for BED <30.

  Previous treatment doses were around 4Gy x 3, though perhaps given this data, we may consider increasing daily dose, in selected individuals.

  No reports of radiation induced cancers.

  Merkel Cell Carcinoma
Neuroendocrine tumor of the skin. Higher incidence in immuno-suppressed patients. High rates of LN and DM, intransit mets often seen. May have an association with the polyomavirus. 30% mortality

  LF seems to be improved with adjuvant RT after surgery compared to surgery alone. SLNB also recommended.

  CDDP + etoposide is often used, however data is lacking right now.
Poulsen IJROBP 2006;64:114 – prosepective study of S-RT-Cis/VP16. On MVA there was no benefit to the addition of CDDP/VP16, though the trial was likely underpowered to make any definitive conclusions.
Dose Recommendations: 66Gy gross disease, 60Gy microscopic disease, 50-56 for lymph nodes basins at risk

  Mycosis Fungoides/CTCL
TSE (total skin electron beam) is very useful, however is a specialized technique. Six positions described by Stanford group, then treated at extended distance with two different beams treating with the central ray off the patient superiorly and then inferiorly. A Lucite degrader is used just in front of the patient. May refer to EORTC consensus.

  Kaposis Sarcoma
8Gy x 1 offers good palliation to AIDS related KS. 40Gy in 20fx is more appropriate of endemic KS.

 

Reirradiation for Reccurrent H&N cancer

AC presents today on a case of recurrent nasopharyngeal cancer, treated initially with 65Gy in 1992. Pt experienced Lhermitte's sign (shooting shock like sensations, particularly with neck flexion). - Of note this is not associated with the later development of myelopathy.

in 2007 developed R ear fullness and decreased hearing. CT scan demonstrated mass in the R parapharyngeal space, extending superiorly to the sphenoid sinus and invasion into the clivus. There was also opacifation of the R mastoid air cells. MRI confirmed mass. Biopsies were only positive for radiation change.

in 2008 mass progressed, and at this time the mass was biopsy positive for recurrence NPC.

15-50% of H&N cancers develop local failiures. Incidence of 2nd primary tumors is around 14%, with 1/3 of these in the H&N. (note that with NPC often recurrences are distant, and can be quite delayed).

Options include resection +/- RT, Reirradiaiton +/- CT, or palliative chemo. MS is <10 months, OS at 1 year is less than 35%.

Surgical salvage results in 5y OS of 10-25%. Operative mortality close to 5% (Goodwin, Laryngoscope 110:1, 2000.)

Reirradiation is primarily limited by normal tissue tolerance (carotid artery stenosis/rupture, osteoradionecrosis, non-healing ulceration, myelopathy). Disease free intervals of less than 6months suggests persistent disease, likely resistant to the initial treatment regimen.

Approach includes review of the initial treatment portals: was there a geographic miss? What were the doses to normal tissues.

Non-randomized series of postoperative RT after resection (in highly selected patients) result in 3y OS of approximately 44% (Kasperts Cancer 2006;106:1536. also De Crevoiseier Cancer 2001;91:2071.) Acute Grade 3-4 toxicities are around 50% reported, late effects are near 40%, but likely these are underreported. Actuarial calculations are lacking in this, and are a necessity for a true accounting.

Janot JCO 26:5518, 2008 - GORTEC group. 130 with complete resection after recurrence - randomized to observation vs 60Gy BID, with 5FU + HU (week on, week off style Chicago regimen). - Acute mucositis G3-4 28%. Late G 3-4 toxicity in the RT arm was approximately 40%. HR for LRC for RT was around 2.7 (60% at 2years for RT arm, SS), but no difference in overall survival. DFS was statistically improved and was the primary endpoint. Note that around 1/2 of the observation arm recieved salvage treatment with the same regimen, and this would dilute the OS benefit.

RTOG 9911 Langer JCO 25:4800, 2007. n=99. Recurrent unresectable cancer in prior RT field. Recieved 60Gy 1.5Gy BID with concurrent CDDP + paclitaxel (week on week off). Median f/u 24months. Acute grade 4 at 28%. Grade 4 late toxicity 17%, 8 treatment related deaths, many of these carotid rupture. 2yr OS 26%. Able to achieve a maximum dose to cord of 12Gy.

Sulman IJROBP 73:399, 2009. MDA series using IMRT in 78 patients. 2yr OS 58%, 2 yr LRC 64% (though many of these were recurrent and resectable). Median reirradiation dose was 60Gy.

Also MSKCC series (Lee, IJROBP 68:731, 2007), showed 2 yr OS 37%, with 70% treated with IMRT. Late toxicities at 15%. MVA showed association with improved LRC with IMRT (but this has some leadtime bias built in). Around 1/3 were treated after re-resection.

To return to the case - prescribed 70Gy to the tumor alone, with very tight margins close to 1-2mm, with daily OBI, weekly conebeam. Treated 6 fractions per week (ala DHANCA) with concurrent CDDP. No elective treatment due to the risk of severe morbidity.

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.

Nasopharynx

DPB presents a case of Nasopharynx for Resident Report this morning.

63 yo WF with history of R fullness. Biopsy of R level V positive for poorly differentiated carcinoma. CT of neck reveals bilaterally enlarged nodes. FOL reveals a mass in the R fossa of Rosenmeuller. EUA biopsy revealed poorly differentiated carcinoma and tested postive for EBV DNA. Staged as a T1N2.

Staging

• T1 - confined to nasopharynx
• T2 - extends to soft tissues
  • T2a - extends to oropharynx and/or nasal cavity
    
  • T2b - any tumor with parapharyngeal extension
• T3 - involves bony structures and/or paranasal sinuses
• T4 - intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space
  

• N1 - unilateral nodes, 6 cm or less, above the supraclavicular fossa
• N2 - bilateral nodes, 6 cm or less, above the supraclav fossa
• N3a - lymph node greater than 6 cm
• N3b - extension to the supraclav fossa
  

Special attention should be to the neurologic exam, as 20% have CN palsies.
Endemic to the Chinese population, and associated with EBV infection.
Obstruction of the Eustachion tube can cause a serous otitis media.
70-90% LN involvement, with 50% having bilateral involvement. Important to note that Level V is very frequently involved, and there is occaisional level IB involvement.

Teo IJROBP 1996 demonstrated that parapharyngeal invovlement was associated with worse DM and worse overall survival in the setting were other high risk factors were not present.

WHO classification of NP type 1 keratinizing squamous cell, type 2 non-keratinizing SCC, type 3 undifferentiated carcinoma. Lymphoepithelioma are carcinomas with a background of lymphocytes, and may have better outcomes.

For simulation, fusion of MRI with a planning CT with IV contrast is ideal.

Al-Sarraf Int 0099 stage III or IV, randomized to RT or RT+CT and adjuvant CT.
70Gy used to the primary at 1.8-2Gy day, 60Gy to nodes <2cm, 50Gy to elective nodal regions. CDDP 100mg/m2 x3 used during RT, adjuvant CDDP + FU (only 50% compliance however).
OS 78% vs 47% SS
Closed early due to survival benefit. PFS was also lower in the control arm than expected.

There are multiple other randomized trials from PMH and Asia which confirm benefit of RT. Metaanalysis in 2006 also showed a benefit to CT combined with RT, and suggests that concurrent may be the treatment of choice.

IMRT experience from UCSF from Lee IJROBP 2002, shows promising control rates, with dosimetric sparing of critical normal structures. There is also a randomized trial on this subject from Hong Kong (see link). This demonstrates significant improvement in objective measures of salivary flow, though the quality of life was no different amoung the arms.

SBRT for Lung and Liver Mets

The Current Issue of the JCO has three phase I/II reports of SBRT for Liver and Lung metastases with excellent long term control:

1. 20Gy x 3 for Liver Mets

2. 20Gy x 3 for Lung Mets

3. 4.6 - 10Gy x 6 for Liver Mets

Also see the accompanying editorial.

SRS rounds

Here are notes of papers and issues brought up in SRS rounds today. Discussion centered around a 42 yo patient with breast cancer treated 3 years ago, with a single symptomatic met close to the motor strip.

The standard of care for oligometastases is consideration of surgery if feasible - Patchell study demonstrating survival advantage to surgery in addition to WBRT.

Plenty of data on SRS and WBRT combinations, none compare directly to surgery. SRS doses are defined by RTOG 9005. <20mm 24Gy, 20-30mm 18Gy, 30-40mm 15Gy.

Conformality Index is volume encompassed by the prescription isodose line divided by the volume of the PTV. Goal of Rx is to be less than 2, though this can be impossible for very small lesions, and a CI of 3-4 would be acceptable.

GTV to PTV expansions are 1mm as per Baumert BG, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):187-94 - pathologic study of 45 pts, 76 mets. demonstrating that for most histologies microscopic extension was <1mm, except for melanoma and SCLC which were greater.

Process at Duke is to use a non-invasive frame for immobilization. With this scans can be performed prior to SRS delivery and the patient does not have to wait all day in the department with a head frame on. The exceptions are for very small targets near critical structures - trigeminal neuralgia patients and acoustic neuromas for example. In these cases we will still use an invasive frame.

Thin cut SRS protocol MRI with contrast is obtained and fused with the planning image. Often for small convex tumors, 4-5 dynamic conformal arcs offer a simple solution. Remember that the MLC shapes must include a dosimetric margin. For larger concave targets, such as AVMs, IMRS (intensity modulated radiosurgery) may be utilized for better conformality and for sparing normal brain.

With this approach, patients can come in at a scheduled treatment time, and complete treatment in a few hours.

All plans are reviewed with a Neurosurgeon, and if there is concern about proximity to the motor strip, we will ofter back off the dose. For the lesion presented, measuring 1.4cm, we backed the dose off to 20Gy.

Limit on the brainstem is a conservative 12Gy in a single fraction, and for optic apparatus our limit is 8Gy.

Quick rundown of SRS doses:
Mets <2cm 24Gy
Mets 2-3cm 18Gy
Mets 3-4cm 15Gy
Acoustic Neuroma 12.5Gy (54Gy fractionated)
Meningioma 15-16Gy (50.4Gy fractionated benign, 54-60Gy fractionated malignant)
AVM 20 Gy marginal dose (keep V12 less than 26cc for most sites, refer to this Flickinger paper)

Journal Club - MRC C07 lancet 2009

Journal Club - MRC CR07 lancet 2009

presents a pt with moderately differentiated invasive adeno carcinoma. uT3 by EUS, one 8mm LN. 8cm from verge. What is the ideal sequence of treatment.

Reviewed the Swedish rectal trial. 1187 pt with resectable rectal cancer, randomized to 5Gy x 5 preop vs surgery alone. Improvement in LR, CSS, and OS. Update JCO 2005; 23:5644, looking at R0 surgical subset, all endpoints are maintained. However, no TME was used.

Dutch Rectal trial. All undergoing TME 1861 patients. Randomized to preop 5Gy x 5 vs surgery alone. NEJM 2001;345:368. LR at 6yrs 11% vs 6% p<0.001.

Preop vs Postop: German trial NEJM 2004;351:1731. Preop 50.4Gy with 5FU, vs Postop 55.8Gy with 5FU. LR 13 vs 6% SS. 90% compliance to CT or RT in the preop group, 50% compliance in the postop group.

Are we overtreating some patients. Probably – This MRC trial is aimed at determining this.

1998-2005.

1350pts randomize to surgery first with CTRT to follow if margins <=1mm, vs. Preop RT 5Gy x 5. 92% of surgeries were with TME technique. 40% in preop group got chemotherapy, 45% in the postop group got chemotherapy.

Primary endpoint LR, secondary – OS, DFS, toxicities, etc.

Started as a non-inferiority trial, but changed to a superiority trial for 5Gy x 5. 2.5% improvement in LR at 5 years. Margins was 10 vs 12% (NS).

LR HR 0.39 p<0.001. p="0.013." p="0.4).">

Pathologic Assessment (Quirke Lancet 2009). Looked at true TME plane vs intramesorectal vs intra muscularis propria: 3yLR 13% vs 7% vs 4% p=0.0039. In the optimal group: True TME + preoperative RT resulted in 3yr LR of 1%.

So with the staging that was performed, we cannot select patients who do not need RT.

Brachytherapy for Cervical Cancer

AC presents on complications of brachytherapy for cervical cancer.

Reviews the treatement of a IIIB cervical cancer (invovlement of the sidewall).

Treat to 45Gy with 1.8 Gy/day and 40mg/m2 CDDP weekly.  Follow by a T&O boost to an additional 40 Gy to point A.  Sidewall boost to an additional 5-10Gy (with a goal of 60-65Gy to point B).  

For dosimetry, patients regularly undergo CT after implant.  Occaisionally one can see a perforation of the superior aspect of the uterus.  The Uterus usually sounds to around 8cm maximum, and one usually will set the flange to just below the sound.  

DPB makes the point that often perfs are created during the sounding process, and emphasises that the sound should be held lightly with 2 fingers and the thumb to reduce the risk of perforation.

Risks: Hemmorhage, Infection, and Irradiation of adjacent structures.

Clinically Detecting a Perforation: 

• Loss of resistance during instrumentation
  
• Extension into the uterus for greater than expected distance
  
• Severe caginal bleeding
  
• Perioperative Hypotension
  
• Signs of infection
  

Detection on plain films can be challenging due to indivdual variation in anatomy.

U/S may be used per Fox Chase - with a full bladder a transabdominal u/s may be used throughout the placement of the tandem.

Granai Ob Gyn 1990 75(1):110.  50 placements.  10% frank perforation per u/s, 24% with myometrial penetration, and 34% with suboptimal positioning of the tandem.  U/S affected management in 21/50 placements.  In follow up 73 placements were performed with real-time U/S guidance, and only 1 was suboptimally placed.

Barnes Int J Gyn Cancer 2007;17:821.  CT detection series.  124 LDR insertions - compared Rad Oncs clinical impression with CT findings.  14% had perfed by CT.  MD concern sensitivity 53%, specificity 84%.  MD concern, >=60yo, tumor size.

Irvin 2003; Gyn Onc 90:113.  Laparoscopic series from UVA to ensure correct tandem placement.  

Kim 1983; Radiology 147:249.  622 pt 1971-1981, UAB.  14 perforations, managed by halting the application, and close monitoring.  1 had pelvic abscess, 1 had pyometria.  Only 7 were given prophylactic antibiotics, and none of these had complications.

Jhingran & Eifel.  2000;IJROBP 46(5):1177.  4043 pt undergoing LDR.  113 (3%) had perforation, in 50% tandem was repositioned and treatment proceeded, 41% had the tandem removed and successfully reinserted later.  9% were unable to undergo brachytherapy.  Demonstrated that there were increased risks with older age.   Thromboembolisms seen in 0.3% (11pts).  

What about HDR - 169pt from Wisconsin, Petereit 1998;IJROBP 42(5):1025. 822 placements.  19 perforations seen by US (2% of insertions, 11% of patients). Routine antibiotic prophylaxis was not used.  Age and PS were associated with complications

In Summary: Perforation occurs in 2-4% of insertions, with an increase of up to 10-15% with prospecitive imaging surveillance.  Age >60 is a risk factor.  Conservative repositioning may be performed without clinically relavent complications.  For limited fundal perforations, based on experience from Dr. Montana at Duke, the tandem may be loaded with a spacer at the superiormost location without repositioning, provided that dosimetry is accpetable.

  

Proton Therapy - Jatinder Palta PhD

Dr. Jatinder Palta from U. Florida gave an excellent talk today about "the Promises and Perils of Proton Therapy"

UF has had a proton facility operational in the last 2 years.

Reviewed the hyperbole associated with press releases around proton facilities.  Particular claims: Precise 3D treatment with "millimeter" accuracy acheivable, it is superior to other options.

Bragg Peak: A phenomena of a heavy charged particle - Entrance dose is at a steady low level, and dose is largely deposited at the end of path with no exit.  Platter to peak ratios is 1:3-5 for protons.  For carbon ions this ratio is much better 1:10-12

Protons do scatter from a pencil beam, and increases with increased depth.  Proton penumbra is 5-8mm, which is similar to a 6MeV photon ~6mm.

20% of protons interact with atomic nuclei producing fragmentation.  Effect is to smear out the bragg peak slightly, however more significantly results in increased neutron doses.  This is much greater than with photon therapy - and have theoretical radiobiologic risks.

Usually setup includes a cyclotron (15-20 million$ alone) and multiple treatment rooms/gantries to maximize efficiency.  Synchrotron is an alternative to the cyclotron.  Fortunately, protons can be steered quite ably with a magnetic field.  Gantrys are ~100 tons due to the mass required to bend the particles at speed into a useable angle.

Treatment abilities: 50x50x50cc treatable volume.  +/- 3 degree pitch and roll.

Pristine Proton Bragg Peaks:

100Mev range 4.3cm

250Mev range 28.5cm

Need either lateral scanning or a scanning beam to get a spread in the 2 dimension X and Y in the Beams Eye View.  Also need some sort of range modulator / variable range shifter to treat the Z depth of the tumor within the patient.  This results in the "Spread Out Bragg Peak."  This results in a good depth coverage, however results in an increased entrance dose.  Fall off remains 2-4mm.

Thus the primary advantage is not in the reduction in entrance dose, which dissappears with the use of the SOBP, but rather the reduction in the exit dose.

High dose area extends proximally.  Thus the confromality is acheiveable with only the distal edge of the target, unless one uses IMPT or a scanning beam.  A disadvantage to the scanning beam is an increase in the 'interplay' effect - target motion in the middle of the treatment delivery resulting in inhomogeneities in the target.

Comparing protons and IMRT:

Primarily the dosimetric comparisons have been using treatment planning software primarily.  With IMRT dose homogeneity is inversely related to normal tissue sparing.  IMPT may be able to improve this relationship, and reduce the number of fields required.

"The promise of protons is that they stop.  The peril of protons is that we don't always know where..."

This is relavent with minor setup changes and misalignment.  The exactness of the treatment is dependent upon the exactness of setup.  Whereas with photons, dose distribution is smeared in these scenarios.  With Protons this creates a binary effect of dose or no dose on a given day with setup variations.

Carbon -> Carbon 11, which decays with a positron.  This may be imaged with a conventional PET scanner shortly after treatment.  Dosimetry can be estimated and the variation in rectal DVHs with prostate treatment is on the order of 50-90%.

This can also be affected by tumors regressing during treatment.  Frequent/scheduled replanning is a matter of ongoing research.

Challenges:

- CT number (HU) conversion to stopping power, effect is much greater on proton therapy than photon therapy.  Needs much better calibration than with photons.

- Dose heterogeneity correction

- Inter and Intra fractional motion of targets and normal tissue

- Uncertainties in immobilization devices - these may affect proton ranges

- PTVs need to be more precisely defined.  Dr. Palta reccomends a physician and physicist sitting down to discuss every individual treatment plan.

- Error bars may need to be considered on dose distributions

For prostate treatments, lateral beams are used.  Due to the uncertainties, a 1cm margin was used - much greated that that needed with IMRT.

Graves Ophthalmopathy Review in NEJM

You may want to check out this review from NEJM this week on Grave's Ophthalmopathy.  They review the literature on all interventions including RT.  And for the record- the inservice exam asked about it - a standard dose is 20Gy in 2Gy/fx.

Preop short course RT vs Selective Postop CTRT for Rectal Cancer

The Lancet has two articles today reporting the results of the MRC CR07 and NCIC-CTG C016 trials.

The first reports the primary results of the trial:
1350 patients with operable adenocarcinoma of the rectum randomized to
1. 25 Gy in five fractions preop versus2. Selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) for positive radial marginsMedian follow-up = 4 years. 
61% reduction in the relative risk of local recurrence for patients receiving preoperative radiotherapy (HR 0·39, 95% CI 0·27—0·58, p<0·0001)
3 year reduction in local recurrence was of 6·2% (95% CI 5·3—7·1) (4·4% preoperative radiotherapy vs 10·6% selective postoperative chemoradiotherapy)
Disease-free survival improvement of 24% for patients receiving preoperative radiotherapy (HR 0·76, 95% CI 0·62—0·94, p=0·013
3 years DFS difference of 6·0% (95% CI 5·3—6·8) (77·5% vs 71·5%)
Overall survival did no different (HR 0·91, 95% CI 0·73—1·13, p=0·40)
Thus this suggests that at least currently we are unable to select out patients that might be spared RT.

 The Second is from pathologist Phil Quirke who reports on the surgical quality and it's affect on local recurrence.
1156 patient tumors underwent rigorous pathologic examination:
128 (11%) had + margin
the mesorectal plane was achieved in 604 (52%)
intramesorectal plane in 398 (34%)
muscularis propria plane in 154 (13%)
Negative Margin vs Positive margin: LR Hazard ratio (HR) was 0·32 (95% CI 0·16—0·63, p=0·0011), 3yr LR 6% (5—8%) and 17% (10—26%) respectively
TME LR HR was 0·32 (0·16—0·64), intramesorectal plane LR HR was 0·48 (0·25—0·93). 3yr LR was 4% (3—6%) for TME, 7% (5—11%) for intramesorectal, and 13% (8—21%) for muscularis propria groups.
All subgroups benefited from preop RT.
good TME + preop RT resulted in 3yr LR of 1%Thus good surgery + preop RT results in the best LR rates in this disease.

Vulvar Cancer

JP presents a case of Vulvar Cancer - 60 yo WF with vulvar pruritis x 1 year.  SCC 7mm diam, 1.5cm depth.  deep margin at resection was 2mm.  T1bNx.  Then underwent a bilateral inguinal node dissection - negative.

Questions what to treat if at all, nodes, primary?

Vulvar cancer 3-5% of gyn malignancies.  3500/year.  80-90% scc.  Occaisional bartholin glands Adenocarcinomas.  Most HPV related.  Smoking, Lichen Sclerosis.  

IA <=2cm primary <=1mm invasion

IB <=2cm primary >1mm invasion

II >2cm

III unilateral inguinal nodes, lower urethra, vagina, anus (N1)

IVA bilater inguinal, upper urethra/bladder, rectum, pubic bone (T4 or N2)

IVB pelvic nodes, DM

"single incision" - radical vulvectomy and bil inguinal dissection- 50% incidence breakdown, 10-15% extremity lymphedema

"triple incision" for excision of primary and for each LN sampling

local recurrence series: 

UCLA Heaps Gyn Onc 1990 - 135 pt with inv SCC of vulva.  (majority I or II)  margins >= 8mm was 0% LR, <8mm>

Also associated 9.1mm invasion, tumor thickness >1cm, keratinization >= 25%, mitosis >10/HPF

Pittsburg 1997 Faul IJROBP - 62 with close of postive margins (<8mm).>

close margins LR 33% obs vs 5% RT (SS)

pos margins LF 76% obs vs 32% RT (SS)

Case: Treated primary to 50Gy at 2Gy/fx  AP/PA. 

New Case:

35 yo with HIV/AIDS, vulvar mass for 3 weeks.  R mass extending to clitoris.  biopsy +SCC.  PET CT demonstrated activity in primary and bilateral nodes.  Rad Hemi- Vulvecomy with L inguinal Dissection.  4cm primary with 8mm invasion, margin was 2mm.  1/2 LN positive on the Left.  Staged as pT2N1 (though R not dissected).

Treating the Pelvis:

nodal risks

for tumors of >= 2cm, risk of inguinal nodes are dependent on depth of invasion: <1mm> 5mm 37.5%.

Cloquet's node: most superior deep inguinal node.

GOG 37: Homseley 1986. 

s/p radical vulvectomy & bil superficial and deep inguinal dissection found to have + inguinal LNs 

114 pts randomized to:

Pelvic node dissection - PLND (15/53 patients had + pelvic LNs)

RT (45-50 Gy to inguinal nodes and pelvic nodes BUT NOT vulvar region)

50% of patients were cN0 (PE not sensitive for groin node mets) 

Groin recurrence PLND 13/55 vs  RT 3/59 (p=0.02) 

OS (2) PLND 54% vs RT 68% (p=0.03) 

on subset analysis those with only 1 node positive did not benefit from RT.

GOG 88: Stehman 1992. 

Resectable vulvar SCC; Excluded T1 lesions unless LVI or >5mm invasion; s/p radical vulvectomy

58 pts randomized to 

Bilateral groin dissection, RT if positive

Bilateral groin irradiation 

50 Gy/ 25fx, with 50% of dose given with 12-13 MeV electrons; Rx'd to 3 cm 

5/25 patients had + nodes in Arm A and were treated with RT

OS (88% disection vs 66% RT) and DFS (92% disection vs 70% RT) were better in the dissected + selective RT arm, with a large portion of local failures of the RT arm were in the groin.

University of Washington Anatomic Study

Examined CT scan of 50 patients undergoing treatment for Gynecologic Cancer

Koh IJROBP 1993;27:969-974

demonstrates that in most of the patients in GOG 88 were probably undertreated as most nodal basins are much deeper than 3cm.

 

to be continued...

History of Cervical Cancer Treatment

Dr. Montana presents on the history of cervical cancer treatment.

Timeline:

1895 Roentgen discovers x-rays

1896 Becquerel discovers natural radiation

1898 Polonium and Radium discovered by Marie and Pierre Curie

Polonium is named after Marie's native Poland.

1934 Discovery of artificial or induced radioactivity Irene and Frederic Joliot-Curie

1903 intracavitary brachytherapy was first used for treatment of a gynecologic cancer - Margaret Cleaves

1903 Alexander Graham Bell proposes interstitial brachytherapy as a treatment for neoplasm

Aspects of Cervical Cancer which make it ideal for brachytherapy : Accessibility, Radiosensitive, Tolerance of normal tissues, and an Orderly pattern of Spread.

Competing systems of Brachytherapy.

Paris  - tandem of rubber, colpostats fabricated of cork with paraffin coating.  tandem loading 6.66 13.33 13.33, colpostats 13.33 and 13.33.  120 hour insertion - dose was 7200 mg*hrs.

Stockholm - metal tandem and colpostats.  tandem as ~40mg, vaginal plaque was loaded at 70mg.  Applications of 20-30hrs of 3 applications over 3 weeks.  6844 - 7266 mg*hrs.

Manchester - rubber tandem and ovoids.  units of radium 1unit=5mg radium.  tandem was 2-2-1, ovoids 3-5 depending on size.  7200 r were prescibed to point A (2cm superior to the flange or top of the ovoids, along the axis of tandem, 2cm laterally to the axis of the tandem).  Packing was used to distance critical normal tissues. 

Significant cure rates began occuring in the late 1910s to mid 1920s.  By the 1940s 5 year OS was ~35%.

MD Anderson - Fletcher grew up in France - initially came to Memorial for practice, and gathered experience at Stockholm and Manchester system.  Developed the a preloaded applicator, which forms the basis of our current system.  Fletcher was a big proponent of the mg*hrs system, though point A began to dominate Rx points.   Loading was 1.2 to 1 ratio of uterine to vaginal cavity activity.  Introduced vaginal mucosa, bladder, and rectal dose tolerance.  Also tailored mg*hours in combination with EBRT to stage of disease.

Herman Suit - Introduced afterloaded applicator to reduce exposure to physicians. 

1963 - afterloading brachytherapy

1974 - HDR brachytherapy

1976 - afterloading transperineal

1977 - 3D treatment planning

1996 - IMRT 

Future Directions should be geared towards reducing cost of current state of the art treatments (vaccines - concurrent chemotherapy) so that these innovations can be disseminated to the developing world. 

CT vs CTRT before surgery for Esophageal Cancer

In this week's JCO there is an important article comparing two approaches for esophageal cancer.

Initially presented at ASCO 2007, this is a German trial from Stahl, randomizing uT3-4NXM0 adenocarcinoma of the lower esophagus or gastric cardia to induction chemotherapy (CDDP+5FU+leucovorin x 15 weeks) followed by surgery (arm A) vs chemotherapy (same x 12 weeks) followed by chemoradiotherapy (30Gy @ 2Gy/day with concurrent CDDP+etoposide) followed by surgery. 

Power calculation: Primary outcome was overall survival time, and 354 patients were needed to detect anincrease in 3-year survival from 25% to 35% by addition of radiation therapy.  Unfortunately the trial failed to meet accrual goals and closed.

Results: Median f/u 4years. CTRT associated with increased pCR rates (15.6% v 2.0%) and pN0 disease (64.4% v 37.7%).  3-year survival rate from 27.7% to 47.4% (p =0.07).  Postoperative mortality 10.2% CTRT v 3.8% CT (p=0.26).

This is an important trial as there are now competing philosophies in the treatment of gastric and esophageal adenocarcinoma, perioperative chemotherapy as in the MAGIC trial, and preoperative CTRT as in the CALGB approach.  This is an underpowered trial with a very provocative survival result.  Though stastically insignificant, this difference would be extremely clinically significant.