5x5 rectal regimen

[Pewl]

Does anyone here actually use the European 5Gy x 5 preop rectal RT schedule? Most places I've seen int he US use the standard long course of preop 50.4Gy + boost. Is it a billing thing or is there some hidden benefit with long course RT that was found in the comparison trials?

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[medgator]

Does anyone here actually use the European 5Gy x 5 preop rectal RT schedule? Most places I've seen int he US use the standard long course of preop 50.4Gy + boost. Is it a billing thing or is there some hidden benefit with long course RT that was found in the comparison trials?

I doubt you'll find anyone doing 5x5 rectal in this country. As you stated, it was a european study. There is also this polish study that gets thrown around too, but the setup was a little strange: http://www.ncbi.nlm.nih.gov/pubmed/16983741

Bottom line, no. 1) It's all european data 2) Billing probably plays part of a role, as does the fact that we typical treat with neoadj chemo and RT, not just RT alone.

 

[Gfunk6]

Using 5 x 5 as described in the original Swedish/Dutch rectal trials leads to increased late toxicity (eg. fecal incontinence). WashU uses a more complex plan with IMRT. I've used it occasionally if pt is not a chemo candidate.

 

[medgator]

This months Red Journal has the WashU experience with 5 X 5 and chemotherapy; it is being done in some centers but pretty limited still here.

Interesting...looks like they do sequential with folfox

 

[medgator]

Using 5 x 5 as described in the original Swedish/Dutch rectal trials leads to increased late toxicity (eg. fecal incontinence). WashU uses a more complex plan with IMRT. I've used it occasionally if pt is not a chemo candidate.

A lot of the med oncs in my neck of the woods pretty much do xeloda on everyone now, which seems to be pretty reasonably tolerated even in some of the poorer ps pts

 

[radtothebone]

Does anyone here actually use the European 5Gy x 5 preop rectal RT schedule? Most places I've seen int he US use the standard long course of preop 50.4Gy + boost. Is it a billing thing or is there some hidden benefit with long course RT that was found in the comparison trials?

There's also the TROG study comparing the two regimens. Overall, they found no major difference in oncologic outcomes or toxicity. Long course may be better in distal tumors, but not powered to determine that question.

http://www.ncbi.nlm.nih.gov/pubmed/23008301

We use this in patients with oligometastatic disease at diagnosis (solitary liver/lung mets) or in those that may have borderline performance status.

 

[Pewl]

Yeah, the TROG and Polish studies are the ones that come to mind when comparing the short and long course. I agree that it's a 1) billing issue and 2) the addition of preop chemo with RT has shown survival benefit. It's probably kinda hard to give adequate chemo with short course RT.

 

[Pewl]

Using 5 x 5 as described in the original Swedish/Dutch rectal trials leads to increased late toxicity (eg. fecal incontinence). WashU uses a more complex plan with IMRT. I've used it occasionally if pt is not a chemo candidate.

The swedish/dutch studies were comparing preop 5x5 vs surgery alone, right? I wonder if there are other good comparison studies between short and long course aside from the Polish and TROG studies. I guess NCIC/UK compared preop 5x5 and postop long course..

 

[Neuronix]

Using 5 x 5 as described in the original Swedish/Dutch rectal trials leads to increased late toxicity (eg. fecal incontinence). WashU uses a more complex plan with IMRT. I've used it occasionally if pt is not a chemo candidate.

Could you give a reference for this? I agree that in the USA short course is widely believed to have higher toxicity, but radtothebone points out this hasn't been born out in the randomized studies. At GI ASCO there was a lot of talk about European trials in the locally advanced and metastatic setting of sequential 5x5 and chemo which we should be seeing data for in the next few years. I talked to some European investigators who thought 5x5 and 50.4 Gy fractionated courses were absolutely equivalent, and they couldn't understand why other parts of the world would want to subject their patients to such long treatments. I talked to some US investigators who thought 5x5 was more toxic based on "experience".

The swedish/dutch studies were comparing preop 5x5 vs surgery alone, right? I wonder if there are other good comparison studies between short and long course aside from the Polish and TROG studies. I guess NCIC/UK compared preop 5x5 and postop long course..

Stockholm III is still running. It's a three arm trial:
1. short-course RT (5 x 5 Gy) and surgery within 1 week
2. short-course RT and surgery after 4-8 weeks
3. long-course RT (25 x 2 Gy) and surgery after 4-8 weeks

There is acute toxicity data here: http://www.ncbi.nlm.nih.gov/pubmed/20155787

I don't have access to the paper from home, but their conclusion was: "Compliance was acceptable and severe acute toxicity was low, irrespective of fractionation. Short-course RT with immediate surgery had a tendency towards more postoperative complications, but only if surgery was delayed beyond 10 days after the start of RT." This is in line with what I've seen. That is: if a patient gets 5x5 and goes straight to surgery, they seem to do fine. If we do 5x5 and they don't go to surgery for whatever reason, we tend to get phone calls frequently about acute side effects in the 1-4 weeks after treatment before planned followup. To me, that seems to be the biggest argument for not doing it among my faculty. Maybe the error is in not having more frequent follow up after short course treatment. Whether that really bears out to more long-term toxicity doesn't seem to be supported by the data.

 

[Gfunk6]

Could you give a reference for this?

http://www.ncbi.nlm.nih.gov/pubmed/17849380?dopt=Abstract

 

[thaddeus]

http://www.ncbi.nlm.nih.gov/pubmed/17849380?dopt=Abstract

Dosen't this study just show that patients who get preop 5x5 have worse late GI toxicity than patients who are treated with surgery alone? It doesn't address which is better between tolerated between preop short-course or preop long-course RT.

 

[Palex80]

The argument that you shouldn't give 5x5 Gy, because chemo is important and you can't give that with 5x5 Gy is silly...

Chemo is important for rectal cancer, but WHEN to give it a fully other issue. The EORTC has looked into that subject in a randomized trial and did not find that chemo given before surgery offers a benefit over chemo given after surgery.
http://www.ncbi.nlm.nih.gov/pubmed/16971718

Current metaanalyses show no survival benefit through the addition of 5FU.
http://www.ncbi.nlm.nih.gov/pubmed/23450565

As far as toxicity of 5 x 5 Gy is concerned, please forget about all the old Swedish data. Look at the fields and the techniques the Swedes used and you will see why. Square open fields, ap/pa RT. Nowadays with CT-based planning, 3D (or even IMRT) you can spare tons of bowel from receiving high doses. The Swedes practically "fried" the entire bladder of the patients up to the full dose and probably hit a sizable amount of small bowel in the cranial parts of their fields. At least they spared the hips well, since they did ap/pa.

For the record:
I've done 5 x 5 Gy. It is well tolerated. Who I give it to? The 81 year old lady presenting with a cT3 cN0 cM0 rectal cancer, 7 cm from the anal verge. MRI shows good distance to mesorectal fascia.
I don't see a reason in putting her through 6 weeks of radiochemo.
Give her 5 x 5 Gy and operate.
The med. onc. can decide after surgery if he wants to give her chemo or not.

 

[Gfunk6]

For the meta-analysis quoted above, pre-operative CRT improved LC and pCR over RT alone. In RT we frequently use RT alone to improve LC without clear OS benefit (e.g. DCIS and melanoma).

Also no long term data on delivering 5x5 via IMRT or using with concurrent chemo. This is just one of many differences between US and Europe. We don't use BEACOPP either.

 

[Gfunk6]

Dosen't this study just show that patients who get preop 5x5 have worse late GI toxicity than patients who are treated with surgery alone? It doesn't address which is better between tolerated between preop short-course or preop long-course RT.

True, but until we see long term results > 10 years from the Polish data and the like, this is the best surrogate.

 

[Palex80]

For the meta-analysis quoted above, pre-operative CRT improved LC and pCR over RT alone. In RT we frequently use RT alone to improve LC without clear OS benefit (e.g. DCIS and melanoma).

The quoted survival benefit through the addition of 5FU to RT has been proven for the adjuvant situation, based on a study conducted at a timepoint when TME was not standard of care. Thus the added benefit of 5FU can be largely attributed to avoidance of local recurrences, which was major issue in the 70s + 80s , but is no longer a subject with modern surgery. That was the point I was trying to make here.
Surely we use RT often to enhance LC only but the point is that current studies do not show a decrease in regional failure if you do neoadjuvant 5 x 5 Gy instead of 50.4 Gy + 5FU. That's the point.
A significantly easier & less expensive treatment yields the same results in the majority of patients when it comes to locoregional failures. I would do 50.4 Gy + 5FU for a lot of patients still, like those with the low-lying tumors where you need the remission to help the surgeon resect the tumors better. But we are certainly overtreating a lot of patients with 50.4 Gy + 5FU instead of giving them a less aggressive approach. Why? Mainly because 50.4 Gy + 5FU pays better probably...

Also no long term data on delivering 5x5 via IMRT or using with concurrent chemo.

You don't need concurrent chemo with 5 x 5 Gy! Why would you give chemo together with 5 x 5 Gy. This is not a treatment designed for high-risk, borderline resectable tumors. It's for the cT3 cN0 patients with their tumors in the middle third of the rectum, good reachable with an anterior approach, which largery are (over)treated nowadays with neoadjuvant long-term RCT.
As far as IMRT is concerned, well guess what, we don't have long term data on using 3D-conformal RT for 5 x 5 Gy either. Should I use Swedish-style ap/pa field arrangements, cause that's all we got published with long term follow up? Sure let me do that from now, gotta go and see if I can start-up our old betatron too. We are shutting down all of our Linacs, cause we don't have any long term data with them either...

This is just one of many differences between US and Europe. We don't use BEACOPP either.

[/quote]
That is not the same thing.
Is BEACOPP more effective than ABVD in terms of recurrence free survival? Yes, for a large majority of intermediate and advanced stage Hodgkins patients.
Is 50.4 Gy + 5FU more effective in terms of locoregional recurrence free survival than 5 x 5 Gy with postoperative 5 FU. No (with the exception of low-lying tumors near the anal canal, according to the Australian subgroup analysis).

Do I give BEACOPP all the time? Nope. Why? Because a lot of my Hodgkin's patients want to have kids.

 

[seper]

Completely agree. I never use 5 X 5 for curative cases. To be able say "it's well tolerated" you need to follow your pts > 5 years out, as referenced by Swedish study above.

 

[Palex80]

Completely agree. I never use 5 X 5 for curative cases. To be able say "it's well tolerated" you need to follow your pts > 5 years out, as referenced by Swedish study above.

Median follow up of the TROG trial when published at the end of 2012 was 5.9 years. An update will presumably follow in a couple of years.
Late toxicity was same for short and long term preoperative RT.

http://www.ncbi.nlm.nih.gov/pubmed/23008301

 

[seper]

that's interesting, thanks

 

[Gfunk6]

There is a nice 5 x 5 study published by WashU in the latest Red Journal.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24606849

Five Fractions of Radiation Therapy Followed by 4 Cycles of FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer.
Myerson RJ1, Tan B2, Hunt S3, Olsen J4, Birnbaum E3, Fleshman J3, Gao F5, Hall L4, Kodner I3, Lockhart AC2, Mutch M3, Naughton M2, Picus J2, Rigden C2, Safar B3, Sorscher S2, Suresh R2, Wang-Gillam A2, Parikh P4.
Author information

• 1Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: [email protected].
• 2Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
• 3Section of Colorectal Surgery, Washington University School of Medicine, St. Louis, Missouri.
• 4Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.
• 5Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri.

Abstract
BACKGROUND:
Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy.
METHODS AND MATERIALS:
Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of FOLFOX [5-fluorouracil, oxaliplatin, leucovorin]. Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls.
RESULTS:
76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%).
CONCLUSION:
This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.

Treatment delivery was via IMRT and after short-course RT, patients underwent x4 cycles of FOLFOX prior to surgery. They had a 25% pCR (both ypT0 and ypN0) which is pretty good. I'd like to see long-term follow-up of GI toxicity but this is a solid study. Also, post-operative chemotherapy was 'dealer's choice' so not sure how much (if any) additional cycles of FOLFOX patients received,.

 

[brendav]

For the record:
I've done 5 x 5 Gy. It is well tolerated. Who I give it to? The 81 year old lady presenting with a cT3 cN0 cM0 rectal cancer, 7 cm from the anal verge. MRI shows good distance to mesorectal fascia.
I don't see a reason in putting her through 6 weeks of radiochemo.
Give her 5 x 5 Gy and operate.
The med. onc. can decide after surgery if he wants to give her chemo or not.

Great discussion. How do your surgeons and rad oncs define the anatomic boundaries of the rectum? Seems to differ from study to study, practice to practice. There are many differing opinions even on consensus statements. Our staff uses a definition of lower rectum (0–5 cm), middle rectum (6–10 cm), and upper rectum (11–15 cm from the anal verge). This has never really made sense to me. Using this definition, doesn't the lower rectum then include the entire anal canal (since the anal verge is the distal most portion of the anal canal)? How do you anatomically differ rectal and anal cancers?