Radiotherapy for Rectal Cancer and Secondary Malignancies

Roxanne Nelson

January 26, 2016

SAN FRANCISCO — A potential adverse effect of radiation therapy is the induction of a secondary malignancy, such as the risk for breast cancer in patients who have undergone chest radiation for Hodgkin's lymphoma.

However, for patients with rectal cancer, there was no increase in second tumors after radiotherapy, results from a Dutch study show. In fact, radiotherapy seemed to offer some degree of protection.

The findings were presented here at the Gastrointestinal Cancers Symposium 2016.

"We found a protective effect of radiotherapy on the development of second cancers, and we found this predominantly for prostate cancer," said lead investigator Anouk J.M. Rombouts, a medical student at Radboud University Medical Center in Nijmegen, the Netherlands.

In the large nationwide study, there was little difference between patients who had undergone radiation therapy and those who had not as far as the risk for a second pelvic tumor; the risk was actually somewhat lower with radiation than without (2.2% vs 3.4%).

Striking Results

These results are "very striking," said Claus Roedel, MD, director and chair of the Department of Radiotherapy and Oncology at the University of Frankfurt in Germany.

Although previous studies have shown an increased risk for second tumors associated with radiation therapy, in this study, the investigators "found the opposite, although their analysis is restricted to rectal cancer," Dr Roedel pointed out.

"The induction of secondary cancers after radiotherapy has traditionally been taken as one of the contra arguments against the use of radiotherapy in rectal cancer," he explained. "A trial by the Swedish Rectal Cancer Group suggested a twofold risk in the incidence of secondary cancer in the radiotherapy arm versus surgery alone" (J Clin Oncol. 2005;23:8697-8705).

And in a study of data on 650,000 patients from the Surveillance, Epidemiology and End Results (SEER) cancer registries, there was an excess of five second cancers per 1000 irradiated patients 15 years after diagnosis (Lancet Oncol. 2011;12:353-360).

Although "one can criticize the fact that the median follow-up of 6 years is too short" in the Dutch study, it is not an entirely new finding, Dr Roedel noted.

He cited another study from the SEER database of almost 21,000 patients with rectal cancers (Am J Clin Oncol. 2007;30:333-339). There was no increase in the risk for second cancers in patients who received radiotherapy, compared with those who received no radiotherapy (hazard ratio [HR], 1.02). However, these investigators noted that "the relative risk increased for second cancers of the corpus and cervix and decreased for prostate and breast cancers," Dr Roedel said.

Decreased Risk and Improved Survival

In their study, Rombouts and her colleagues looked at the association between radiotherapy for rectal cancer and the development of second primary pelvic tumors in a nationwide setting.

"Second tumors are seen in patients with all types of cancer," Rombouts said. It is believed that they are "the result of etiologic factors, such as genetic susceptibility and lifestyle, and it is thought that radiotherapy might play an important role."

Although it has been speculated that radiotherapy plays a role in the development of a second cancer, the literature remains inconsistent about the proportion of tumors that can be attributed to this treatment modality.

The investigators retrospectively reviewed data from a population-based cancer registry for all patients with nonmetastasized primary rectal cancer diagnosed from 1989 to 2007 who were treated surgically.

They used Fine and Gray's competing risk model to estimate the cumulative incidence of a second tumor; death was the competing event.

To compare the incidence of primary tumors in the study cohort with those in the general population — taking in account sex, age, and calendar year — standardized incidence ratios were calculated.

All second tumors that developed in the pelvis after diagnosis — including those in the urogenital system and the gastroenterological system, and those in the bony pelvis — were considered.

In the study cohort, 1713 patients (11.1%) who received radiotherapy developed a second tumor. Of these, 339 (2.2%) were pelvic tumors.

But there was little difference between patients who did not receive radiotherapy; 1942 of these patients (14.1%) developed a second tumor, 469 (3.4%) of which were pelvic tumors.

The risk for second cancers was compared with the overall incidence in the Dutch population. "We observed 4037 cancers in 20,691 observation years, and the number of expected cancers was 3555," Rombouts reported. "That equated to a standardized incident risk for any second tumor of 1.14, or a 23.3 per 10,000 excess cases per year."

"In other words, patients who had rectal cancer had a slightly higher chance of developing another tumor than people in the general population," she said.

The investigators also conducted a competing risk analysis. "We saw a lower risk of second cancers in patients who received radiotherapy, compared with those who didn't receive it," Rombouts said. The subhazard ratio (SHR) was 0.70.

Second pelvic tumors were also more common when radiotherapy was postoperative than when it was preoperative (SHR, 1.37).

In organ-specific analyses, second prostate tumors were less common in patients who received radiotherapy than in those who did not (SHR, 0.51). And the risk for a second primary rectosigmoid tumor was lower in those who received radiotherapy than in those who did not (SHR, 0.59).

"But in the whole cohort, there were only 25 patients with a second rectosigmoid cancer, so we think that this difference is less clinically relevant," Rombouts explained.

However, the chance of developing a second rectosigmoid tumor was higher in patients who received postoperative than preoperative radiation therapy (SHR, 2.25).

There were no relevant differences for any of the other specific cancer types included in the analysis.

Multivariable analysis confirmed these findings. Radiotherapy reduced the risk for second pelvic tumors (HR, 0.78), after correction for variables such as age, sex, year of incidence of rectal cancer, histology, pathologic tumor and node stage, and adjuvant chemotherapy.

The data should not be interpreted in such a way as to disavow the potential of radiotherapy to induce a second cancer.

However, sex-specific analyses revealed that the protective effect of radiotherapy remained for men (SHR, 0.59), but there was no protective or detrimental effect for women (SHR, 1.00).

In addition, overall survival was worse in patients who did not receive radiation than in those who did (HR, 1.22).

"The data should not be interpreted in such a way as to disavow the potential of radiotherapy to induce a second cancer," said Dr Roedel. Instead, it should be noted that "there is a balance between radiotherapy induction and radiotherapy inhibition of second cancers."

Dr Roedel has disclosed no relevant financial relationships. Coauthor Johannes de Wilt, MD, PhD, from Radboud University Medical Center, reports receiving research funding from Roche.

Gastrointestinal Cancers Symposium (GICS) 2016: Abstract 491. Presented January 23, 2016.


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