Chemo/Radiation Did Not Yield Increased Pelvic Malignancies in Rectal Cancer

In patients with rectal cancer, the median OS was 12 years in the chemotherapy and radiation therapy group vs 24 years in the chemotherapy alone group.

Concurrent chemotherapy with radiation therapy did not significantly increase the cumulative incidence of second pelvic malignancies, though it did increase the cumulative incidence of second non-pelvic malignancies compared with chemotherapy alone in patients with locally advanced rectal cancer, according to results from a study shared in the International Journal of Radiation Oncology, Biology, Physics.

In the concurrent chemotherapy group, the 5- and 10-year cumulative incidences of second pelvic malignancy development was 2.1% (95% CI, 1.4%-3.0%) and 5.8% (95% CI, 4.2%-7.6%); in the chemotherapy alone group, the rates were 2.3% (95% CI, 0.92%-4.8%) and 4.2% (95% CI, 1.3%-9.8%), respectively. This difference did not reach statistical significance (Gray’s Test P = .3).

A multivariable analysis showed that older age was associated with second pelvic malignancies (MV HR, 3.03; 95% CI, 1.39-6.60; P = .005), though chemotherapy alone was not significantly associated with fewer second pelvic malignancies (MV HR, 0.66; 95% CI, 0.30-1.44; P = .3).

Intensity-modulated radiation therapy and volumetric modulated arc therapy techniques were associated with reduced risk of second pelvic malignancies vs conventional and 3D conformal radiation therapy on univariable analysis (P = .014).

The most common second pelvic malignancies were prostate adenocarcinoma (31%; n = 23) and uterine cancer (28%; n = 21); uterine cancers were mostly serous, clear cell, or endometrioid, though 5 patients in the concurrent chemotherapy group developed carcinosarcomas.

The 10-year cumulative incidence of non-pelvic second malignancies was 11.0% (95% CI, 9.1%-14.1%) in the concurrent chemotherapy group and 4.4% (95% CI, 2.2%-7.9%) in the chemotherapy alone group (Gray’s Test P = .017).

Univariable analysis showed that being older than 50 was significantly associated with increased risk of second non-pelvic malignancies (HR, 2.48; 95% CI, 1.40-4.11; P ≤.001), and being male was associated with a decreased risk (HR, 0.61; 95% CI, 0.44-0.85; P = .004). Further, diabetes was associated with a second non-pelvic cancer (HR, 1.51; 95% CI, 1.05-2.19; P = .028), and abstaining from tobacco decreased the risk of second non-pelvic cancer (HR, 0.63; 95% CI, 0.43-0.91; P = .013).

The most common second non-pelvic cancers were lung cancer (24%; n = 35), breast cancer (15%; n = 21), and hematologic malignancies (13%; n = 19). While 77% of those who developed a second non-pelvic cancer did not have a diagnosis of any other cancer, 13% did also develop a second pelvic malignancy.

Regarding radiation dosimetry and technique, 21 patients who developed a second pelvic malignancy had a chemotherapy plan available; of the 21, 9 developed uterine cancer with a mean dose of 4800cGy (range, 4296-5087).

The median overall survival (OS) in the concurrent chemotherapy group was 12 years (95% CI, 11-13) vs 24 years (95% CI, 15-unreached) in the chemotherapy alone cohort. The 5- and 10-year OS rates for those who received concurrent chemotherapy for rectal cancer was 78% (95% CI, 76%-80%) and 58% (95% CI, 55%-61%), respectively; in those who received chemotherapy alone, the rates were 88% (95% CI, 84%-91%) and 76% (95% CI, 70%-82%).

The 10-year survival for those who did not develop second pelvic malignancies was 60% (95% CI, 57%-63%) vs 77% (95% CI, 67%-87%) in those who did develop a second pelvic malignancy (P = .042).

“These data serve as a foundation for future prospective studies evaluating ways to further reduce the risk of second malignancies in high-risk patients undergoing [concurrent chemotherapy] for rectal cancer,” wrote lead study author Carla Hajj, MD, of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, and coauthors, in the paper. “Areas of potential investigation include personalized treatments using more modern technologies such as proton beam [radiation therapy] or MRI-based treatment deliveries, lifestyle changes, and robust survivorship programs.”

The study included 2624 patients with locally advanced rectal cancer, of whom 460 were treated with chemotherapy without radiation therapy and 2164 received concurrent chemotherapy. The most common adjuvant chemotherapy regimens were folinic acid, fluorouracil (5FU), and oxaliplatin (FOLFOX; 60%), 5FU (32%), and capecitabine/oxaliplatin (CapeOx; 4%).

Eligible patients had disease treated with chemotherapy with or without pelvic radiation therapy who were identified from an institutional database by Cancer Database, ICD-9/10, and ICD-0 histologic diagnosis codes for “rectum” or “rectosigmoid”.

Patients were ineligible for participation if they had received prior pelvic radiation therapy or if their treatment was for recurrent disease.

Second malignancies were defined as those preceding the rectal cancer diagnosis date by more than 6 months, synchronous cancers were defined as within 6 months of diagnosis, and metachronous cancers were defined as occurring between 6 months and 2 years after diagnosis. A second cancer was defined as occurring more than 2 years after diagnosis of locally advanced rectal cancer. The development of a non-pelvic cancer did not preclude capturing the diagnosis of a second pelvic cancer.

Reference

Tringale KR, Patel KH, Hilal L, et al. Development of second malignancies following chemotherapy with or without radiation therapy for the treatment of locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. Published online July 19, 2025. doi:10.1016/j.ijrobp.2025.07.1424