Hyperfractionated abdominal reirradiation for gastrointestinal malignancies

Given the recent advances in systemic therapy for several gastrointestinal malignancies, local recurrences (LR) can be life- and/or quality-of-life-limiting. For patients with pancreatic adenocarcinoma, LR occurs in 80% of patients within two years of curative-intent therapy, and 30% of these LR are isolated without distant metastasis (DM) [1‐3]. For patients with gastric cancer, LR rates are closer to 33%, although the majority of these patients also present with synchronous distant metastatic disease [4]. Younger patients and patients with larger tumor sizes are at highest risk for LR [5]. For patients with colon adenocarcinoma, LR rates are also approximately 32% following curative therapy [6].

The treatment of locally recurrent tumors in the abdomen varies depending on the specific histology, location and extend of recurrence as well as any prior treatments received. For pancreatic cancer recurring after resection, re-resection is favored if feasible, but radiation-based modalities are not recommended for patients who have received prior (chemo) radiation therapy [7]. Re-resection is also favored for locally recurrent gastric, colon and hepatobiliary cancers when feasible [8‐10]. The need for alternative treatment strategies arises as patients are often not surgical candidates at the time of local recurrence either because of technical operability or medical comorbidity. Additionally, effective palliation of symptomatic LR occurring in patients with concomitant regional or metastatic disease. Radiation therapy is one such alternative local modality, but its utilization in the treatment of recurrent abdominal tumors has been limited by the increasing use of primary radiation in the neoadjuvant or adjuvant settings for abdominal tumors in the pancreas, stomach, colon and hepatobiliary region.

Previous studies have established the safety and efficacy of reirradiation to the head and neck, pelvis, breast, brain, breast, and lung [11‐25]. However, reirradiation is not commonly used in patients with recurrent GI malignancies due to concerns of toxicity, with a cumulative radiation dose that exceeds established dose constraints. At our institution, a hyperfractionated accelerated reirradiation approach has been shown to be effective in the treatment of both recurrent rectal cancer and anal cancer [26‐28]. Patients treated with reirradiation for recurrent rectal cancer using 1.5Gy twice daily fractions to a total median dose of 39Gy demonstrated a 3-year freedom from local progression (FFLP) rate of 40% and a 3-year overall survival (OS) rate of 39% [27]. Patients who underwent reirradiation in twice 1.5Gy daily fractions for recurrent anal cancer demonstrated a 3-year FFLP of 56% and a 3-year OS of 60% [28].

Haque et al. first demonstrated the safety and efficacy of abdominal reirradiation in patients with gastrointestinal malignancies, showing a 1-yr rate of freedom from local progression of 50% and a 1-yr rate of overall survival of 62% [29]. This initial report, however, was small (n = 13) [29]. Our aim with the current study was to update this initial experience and report the efficacy and toxicity associated with this hyperfractionated, accelerated reirradiation approach to recurrent or new primary tumors in the abdomen.

Between January 1 2000 and January 1 2017, 24 patients with gastrointestinal cancer and a prior history of radiation therapy had undergone reirradiation using a hyperfractionated, accelerated approach. The hospital records for these treatments were reviewed with the approval of the University of Texas MD Anderson Cancer Center Institutional Review Board.

Twenty-four patients were included in our analysis with a median [interquartile range (IQR)] follow up of 16.8 [8–22.5] months.

The results of this retrospective review performed at a high-volume tertiary referral cancer center show that hyperfractionated, accelerated reirradiation can be safely delivered with acceptable toxicity rates for patients with recurrent or new primary abdominal tumors who have received prior abdominal radiation. These data expand upon our previously reported experience of the initial 13 patients treated was published in 2009. While abdominal reirradiation using this regimen was well tolerated, it appeared to have limited efficacy in terms of freedom from local progression and palliation of local symptoms.

These modest results suggest alternative regimens should be explored to provide patients with better radiation therapy options in the abdominal reirradiation setting. Although the hyperfractionated schedule has the potential radiobiologic benefit of reducing the risks of late toxicities from cumulative radiation doses [36], particularly to sensitive luminal gastrointestinal structures, some groups have reported encouraging reports with a hypofractionated stereotactic body radiation therapy (SBRT) approach. The majority of published data come from studies reporting on reirradiation for pancreatic cancer using hypofractioned SBRT. Lomiska et al. utilized a regimen consisting of a median dose of 22.5Gy in 3 fractions to recurrent tumors of the pancreas and reported a median overall survival of only 5.9 months, but freedom from local progression was excellent at 85.7% (12 of 14 evaluable patients). Grade 3 or greater acute toxicities were reported in fewer than 10% of patients [37]. Dagoglu et al. reported a median OS of 14 months, two year local control of 78% and G3 of greater acute toxicity rate of 10% in patients treated for unresectable locally recurrent pancreatic adenocarcinoma using a median of 25 Gy in a median of 5 fractions [38]. Wild et al. reported a median survival of 8.8 months in pancreatic adenocarcinoma patients reirradiated with SBRT using the same median SBRT dose of 25Gy in 5 fractions. Rates of freedom from local progression at 6 and 12 months after SBRT reirradiation were 78 and 62%, respectively. Effective symptom palliation (back or abdominal pain) was higher than in our series at 57%. Only 28% of patients experienced acute toxicities, but no patient experienced G3 or greater acute toxicity. Analysis of this cohort also suggested that a progression-free interval of > 9 months prior to isolated local recurrent or progression may predict for a greater benefit of SBRT reirradiation as their survival is more likely to be long enough for improved local control to be of meaningful benefit [39]. Most recently, Koong et al. showed that either single-fraction (25Gy × 1) or five-fraction (5–6.6Gy × 5) SBRT was effective in treating recurrent pancreatic cancer a median of 13 months after patients had received prior conventional radiotherapy. The median overall survival from reirradiation was 8.5 months, and the local failure rate was low at 19%. Distant progression was a much more common pattern of failure at 64%. Reirradiation was also well tolerated with this regimen, with only six (26%) of patients experiencing either grade 2 or grade 3 toxicities, and four of these patients were treated with the single fraction SBRT regimen [40].

While our study demonstrated comparable overall survival rates, the prior studies using SBRT for reirradiation of pancreatic adenocarcinoma reported superior freedom from local progression. While our study included patients with gastrointestinal malignancies, the majority (n = 14, 58.3%) of patients included in this study were treated for pancreatic adenocarcinoma, and we would thus expect our one year freedom from local progression to be comparable if not higher. Furthermore, although our serious (G3 or greater) toxicity rate was low, our study reported an overall acute toxicity rate higher than those reported using SBRT, with a 54% acute toxicity rate in our study compared to 10 to 28% reported by the SBRT studies [37‐40].

While this series represents the largest reported cohort of patients treated with hyperfractionated, accelerated abdominal reirradiation for recurrent or new primary abdominal malignancies, this study has several limitations that may limit its interpretation and broad applicability. The number of patients was relatively small, with only 24 patients treated over a 17 year period at a single institution. The cohort was relatively heterogeneous in terms of primary tumor type and prior treatment delivered. Additionally, acute toxicities were collected retrospectively based on hospital records and could have been underestimated. Follow up was not standardized, varied between patients, and late toxicities may have been underreported as well.

In conclusion, although our study shows that hyperfractionated, accelerated abdominal reirradiation is well-tolerated, this regimen provides local control for a limited duration and has a modest palliative effect. Emerging data regarding SBRT reirradiation in the abdomen are promising, and may provide improved local control with similarly low toxicity rates. Further study is needed regarding the safety and efficacy of this modality of recurrent pancreatic adenocarcinoma as well as other abdominal malignancies.