Serious side effects were reduced when research radiologists used a special technique to target the most radiation on anal cancer tumors, while sparing nearby normal tissue.

Reported at the recent 2011 Gastrointestinal Cancers Symposium in San Francisco, intensity-modulated radiation therapy (IMRT) did not reduce overall side effects during chemotherapy and radiation treatment, but it did cut down on the most serious bladder, bowel, and skin problems.

At the same time, IMRT was a good as traditional external beam radiation in preventing local recurrences and the need for colostomies.  Survival after two years was also similar to a previous study that did not use the technique.

The study (RTOG-0529) enrolled 63 patients in a clinical trial in an attempt to find out if dose-painted IMRT could reduce side effects from chemoradiation treatment for anal cancer.  Study results were compared to a similar RTOG trial (RTOG-9811) that used external beam radiation more broadly over the entire pelvic region of 325 anal cancer patients.

The primary goal of RTOG-0529 was to reduce all moderate to severe side effects from chemoradiation compared to the earlier RTOG-9811.  While the trial failed to accomplish that goal, it did reduce the most severe side effects.

After six weeks, 64 percent of patients had their tumors respond completely.  This rose to 81 percent 12 weeks after treatment.

Side Effects

Toxic side effects are graded from 0 to 5, with 2 being moderate and 3 more serious.  The primary goal of the reported study was to reduce grade 2 and higher toxicity compared to the earlier external beam radiotherapy trial.  While that goal was not accomplished, grade 3 and higher toxicity from treatment was cut significantly.

Comparing  RTOG-0529 (IMRT) to RTOG- 9811 (external beam radiotherapy or EBR):

• Grade 3 plus skin toxicity was reduced from 50 percent with EBR to 20 percent using IMRT.
• Grade 2 plus effects on blood counts was reduced from 80 percent to 70 percent.  (Radiation affects bone marrow and blood counts.)
• Grade 3 plus bladder and gastrointestinal side effects were halved from 40 percent to 20 percent.
• Because side effects were easier to manage, patients spent less time in treatment:  a median of 43 days with IMRT compared to 49 days with the earlier regimen.

Treatment Outcomes

Comparing results of the two trials after two years:

• 19 percent of patients had cancer return locally in their pelvic region in both trials
• 8 percent of IMRT patients needed a colostomy compared to 11 percent in the earlier EBR study
• Survival with IMRT was 86 percent compared to 91 percent with EBR.
• Survival without any cancer was 77 percent versus 75 percent.
• Survival without needing a colostomy was 84 percent versus 83 percent.
• 14 percent of patients in the IMRT study developed distant metastases compared to 9 percent with EBR.

IMRT isn’t simple.  There is a fairly steep learning curve for radiation oncologists.  RTOG-0529 was designed with so that radiation therapy plans had to be reviewed by experts before treatment began.  Over 80 percent of those plans needed revision.  However, at the end of treatment, reviews showed that only three treatments had major problems focusing radiation accurately.

Anal cancer is different from colon or rectal cancer and is treated differently.  Radiation combined with chemotherapy (5-FU and mitomycin) is standard treatment.  When cancer cells remain after chemoradiation, surgery may be necessary that includes a colostomy.  In 2010 about 5,260 people were expected to be diagnosed with anal cancer with 720 deaths.

During a press briefing before the GI Cancers Symposium, Lisa Kachnic, MD, of Boston University, who led the study, said,

Dose-painting IMRT with 5-FU and mitomycin-C for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising two-year outcomes. Dose-painting IMRT is feasible with rigorous quality assurance and continued education.

SOURCE:  Kachnic et al., Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal, 2011 GI Cancers Symposium, Abstract #368.

Dr. Kachnic discusses her conclusions during a presentation at the 2011 GI Cancers Symposium in San Francisco.

Surgeons at M.D. Anderson Cancer Center in Houston have identified 87 genes that someday may tell doctors whether or not rectal cancer patients need surgery after chemotherapy and radiation.  The panel of genes predicted patients whose cancer appeared to be completely destroyed by the combination of chemotherapy and radiation before surgery, what is called pathological complete response.

Before it can become routine practice, the gene panel will need to be checked in another group of patients and clinical trials will need to be conducted to see if patients who have pathological complete responses and no surgery do as well as those who do have surgery.

After presurgical chemoradiation treatments, about 1 in 5 rectal cancer patients will have all signs of cancer disappear in pathology tests after surgery.  But surgeons don’t know which patients those are until they operate and remove the rectal tumor and its attached tissue and lymph nodes.

M.D. Anderson researchers assessed gene expression in tumor tissue from 46 patients with locally advanced rectal cancer.  They found that the expression of 87 genes was more common in those patients who had no cancer cells remaining in rectal tissue removed during surgery.

Currently standard treatment for locally advanced rectal cancer is chemotherapy and radiation followed by surgery to remove part of the rectum.  If the gene profile could identify patients who would have complete responses and clinical trials showed that not doing surgery was as effective as surgery in those patients, some patients with rectal cancer could be spared the risks, pain, and potential long-term effects of surgery.

Isabelle Bedrosian, MD, FACS, assistant professor of surgery at the University of Texas M.D. Anderson Cancer Center, explained,

We typically say that patients need chemotherapy, radiation therapy, and surgery to get the best outcomes. The upfront chemotherapy and radiation therapy helps shrink tumors down so they can be more easily removed surgically and decreases the chance that the tumor will come back in the pelvis.

Dr. Bedrosian continued,

Findings from this study suggest that we may have a new tool to say to a patient whose tumor has a specific DNA profile and who has had a complete clinical response to chemotherapy and radiation therapy that he may not need radical surgery.

Plans are underway to validate the gene panel in another group of patients.  If successful, clinical trials can be planned to compare recurrences and survival between groups of patients, whose tumors fit the gene profile, who do and do not have surgery.

Dr. Bedrosian’s study was reported at the American College of Surgeons Clinical Congress last week in Chicago.

What This Means for Patients

Discovering the genes that appear to predict pathological complete response is only the first step.  The genes will need to be independently verified in another group of patients.  Then randomized clinical trials will be necessary to see if outcomes like cancer returning in or near the rectum or cancer-free survival are the same whether or not patients have surgery.

So the gene testing is not yet ready for use in today’s patients.

At ASCO a number of studies showed the efficacy data of combining 5-FU or Xeloda with oxaliplatin in combination with radiation therapy in patients with rectal cancer.

Based on a German study published a couple of years ago, chemoradiation became the standard therapy for patients with resectable rectal cancer. The rate of sphincter-sparing surgeries and lower toxicities were the reason to prefer chemoradiation prior to surgery instead of adjuvant treatment after surgery.

Over the last couple of years many studies aimed to improve the efficacy of neoadjuvant chemoradiation therapies by intensifying the chemotherapy.  Standard therapy is 5-FU or Xeloda® (capecitabine). By adding oxaliplatin it was hoped that  the success rate of chemoradiation could be increased.

Success of neoadjuvant radiation is measured by a complete pathological response rate (complete disappearance of cancer cells). With 5-FU or Xeloda that can be reached in about 10-15% of the cases. Smaller studies have suggested that the addition of oxaliplatin could double the rate.

However the studies presented at ASCO a couple of weeks ago (ACCORD) did not show any significant difference when oxaliplatin was added. However there was interestingly a lower risk of developing metastases in the patients who received the additional oxaliplatin therapy. These findings may question the ongoing R-04 study which compares 5-FU to 5-FU plus oxaliplatin in combination with radiation therapy.

In the Southwest Oncology Group (SWOG) we have choosen another way. In the study just opened, we started with Xeloda, oxaliplatin and Erbitux (kras wild type), then we continue with the chemo and add radiation to have a both powerful systemic effect and a local effect.

Researchers tried to push the envelope in treating rectal and anal cancer by adding new or different chemotherapy to standard chemoradiotherapy.  However, two trials in rectal cancer and one in anal cancer were not able to improve complete response rates for chemoradiation.  Adding extra chemotherapy after radiation was finished didn’t improve relapse-free survival for anal cancer either.

• The STAR trial from Italy found that adding oxaliplatin to chemoradiotherapy before rectal surgery did nothing to improve the rate of complete responses found at surgery.  There was also no decrease in the number of patients who needed a permanent colostomy.  Serious diarrhea was significantly worse in the oxaliplatin arm. However, unexpectedly, more distant metastases were found at the time of surgery among patients who didn’t get oxaliplatin (16 patients with spread to lungs, liver, or peritoneal surfaces vs only 2 who got oxaliplatin prior to surgery.)  Survival data is not yet available.
• In France, researchers in the ACCORD trial combined both an increase in radiation to 50Gy and the addition of oxaliplatin to standard treatment of 45Gy and capecitabine in an attempt to improve pathological complete response rates for chemoradiotherapy before rectal cancer surgery.  However, there was no significant impact on tumor response at surgery and no decrease in colostomies.  Serious diarrhea was significant worse (3 percent with no oxaliplatin, 13 percent in the increased radiation with oxaliplatin.)  They did show that Xeloda® (capecitabine) can be substituted for infusional 5-FU in chemoradiotherapy regimens.
• A large trial of anal cancer in the United Kingdom tried to improve both complete response to chemoradiation and disease-free and overall survival by using cisplatin instead of standard mitomycin-C during radiotherapy and by randomly giving two doses of cisplatin and 5-FU after radiation treatment ended.  Response to chemoradiation was excellent with 95 percent of patients having a complete response with either mitomycin-C or cisplatin.  Furthermore, maintenance chemotherapy didn’t change relapse-free survival at three years, with 75 percent of patients without recurrences whether or not they had the extra chemo.  The research team concluded that mitomycin-C remains standard treatment for anal cancer.

The more tumors shrink during chemotherapy and radiation before rectal cancer surgery, the better the chance that patients will survive and be cancer-free five years later.

Doctors in Ireland developed a simple, three point, tumor regression grade or TRG, to measure the amount of change during chemoradiotherapy before surgery to remove rectal cancer.  After five years, all patients with the best tumor regression grade — complete or near complete response to chemoradiation — were alive and disease-free.

In a series of 126 patients with locally advanced rectal cancer (T3/T4 or spread into nearby lymph nodes), five year disease-free survival after chemoradiotherapy followed by surgery was 72 percent.  Seven percent of patients had cancer recur locally in or near the rectum.

After pathologists examined the surgical specimen, a standard score was used grade response to chemoradiation: complete or near-complete response (TRG1), partial response (TRG2), or no response (TRG3).

Patients with near or complete response (TRG1) had 100 percent disease-free survival at five years.  For those with partial (TRG2) response, five year DFS was 71 percent. No response (TRG3) led to a 66 percent disease-free survival.  Six in ten patients had some response to the presurgical chemoradiotherapy.

D. Beddy and colleagues concluded,

Tumor regression grade measured on a 3-point system predicts outcome after chemoradiotherapy and surgery for locally advanced rectal cancer.

SOURCE: Beddy et al., Annals of Surgical Oncology, Volume 15, Number 12, December 2008.

Although giving radiation before rectal cancer surgery reduces the risk that cancer will return in the rectum and nearby tissues, it does so at a cost.  Quality-of-life studies that accompanied a trial of a short course of radiation therapy before surgery  found more sexual and bowel problems with presurgical radiation.

During the Medical Research Council CR07 clinical trial, patients with rectal cancer were randomized to receive a short, five-day course of radiation before their surgery or surgery with chemoradiation afterwards only for those with cancer cells remaining in tissues outside the tumor . Three years later only 4 percent of the presurgical radiation group had cancer return locally compared to 11 percent of those treated with surgery and selective postsurgical chemoradiation.  Presurgical radiation patients were also more likely to be alive five years later — 78 percent of them survived compared to 72 percent of the patients who didn’t have radiotherapy before their surgery.

Three months after surgery both groups of men had issues with sexual functioning, which researchers attributed to the surgery.  Those difficulties returned to normal as patients recovered.  However,  additional problems with sexual function developed later for men who had presurgical radiation.  They declined over time, but some men still reported difficulties three years later.

Men had no less interest or enjoyment in sexual activities, but did have problems with function.  For both groups, men who had colostomies had worse function three months after surgery than men who had surgery that preserved anal sphincters.

Overall, bowel problems weren’t different between the two groups, but in one area radiation made a difference.  Eighteen months after surgery, patients who had radiation were more than twice as likely to have stool leakage and bowel incontinence (16.4 percent versus 6.5 percent).

Results of local recurrence at three and five years during the trial were first presented at ASCO in 2006.That report found that with the best surgery, which removed the rectum and its entire surrounding tissue, along with short-course preoperative radiotherapy, almost completely eliminated local recurrence.  Only one percent of the 1,350 patients in the study had cancer return in the rectum or local area around it when they received excellent surgery and presurgical radiation.

Without preoperative radiotherapy, 6 percent of patients had local recurrence.  When surgery was not optimal, 9 percent of patients with preoperative radiation and 19 percent of those who did not have radiotherapy had local recurrence three years later.

Discussing the results of the quality of life analysis at ASTRO, David Sebag-Montefiore, MD, a leader of the study and a radiation oncologist in Leeds, UK, said,

We know that this and other trials have consistently shown that radiation before surgery reduces the risk of local cancer returning. However, this has to be balanced against any negative side effects. The results of our quality of life study should help doctors and patients to discuss both the benefits and risks of pre-operative radiation before surgical removal of rectal cancer.

You can hear an interview with Dr. Sebag-Montefiore recorded at ASTRO on Medpage Today.