Thursday, April 30, 2009
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.
Hb concentrations and saturation
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.
Wednesday, April 29, 2009
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.
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.
Thursday, April 23, 2009
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.
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
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
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.
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
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).
Friday, April 17, 2009
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%
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.
Small Lesions (<5cm square)
2000 in 1-2 fx
3000 in 5-10fx
4000 in 10-16fx
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
long term toxicity should be on the order of 2% with modern treatment.
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
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.
8Gy x 1 offers good palliation to AIDS related KS. 40Gy in 20fx is more appropriate of endemic KS.
Thursday, April 16, 2009
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.
Friday, April 10, 2009
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.
Thursday, April 9, 2009
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
“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.
Friday, April 3, 2009
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.
- T1 - confined to nasopharynx
- T2 - extends to soft tissues
- T2a - extends to oropharynx and/or nasal cavity
- T2b - any tumor with parapharyngeal extension
- T2a - extends to oropharynx and/or nasal cavity
- 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
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.