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.