Re-irradiation: Pluses and Minuses
|•||Patients who can undergo surgical resection before re-irradiation are most likely to benefit from the latter.|
|•||Look for a minimal six-month interval between initial radiation and possible date for re-irradiation.|
|•||Patients with large, bulky tumors (> 2 cm) are not likely to benefit from re-irradiation.|
|•||Future research needs to focus on the causes of radiation resistance.|
Concerns about toxicity and uncertain benefits kept re-irradiation out of the head and neck treatment mix for some time, said Sharon Spencer, MD, a professor and clinical director at the Comprehensive Cancer Center, University of Alabama in Birmingham (UAB). Early experiments with re-irradiation in nasopharyngeal carcinoma turned in survival rates ranging from 15% to 38%. Later work with interstitial re-irradiation using iridium-192 showed that local control could be achieved in about 50% of patients, but toxicity in soft tissues was still an issue (Radiology 86:900-903, 1966; Radiol Clin (Basel) 46:390-397, 1977; Cancer 39:2443-2450, 1977).
In fact, an overarching theme in the story of re-irradiation in this population is that decent survival rates can certainly be achieved, but they come at a cost of high toxicity. "I think as radiation oncologists, we get sweaty palms when a patient [with recurrent or metastatic disease] shows up in our clinic, especially when they've had radiation before. We hope that our surgeons can help us and resect the tumor so that we don't have to subject them to new treatment with radiation," Dr. Spencer said.
The combination of hyperthermia with interstitial irradiation has turned in a respectable five-year survival rate in a select group of patients.
"If you look at the patients who do the best with interstitial treatments, the size of the tumor really tells you what will happen. If [the tumor] is less than 2 cm, your recurrence rate is fairly low at 17%," Dr. Spencer said. "But if it's greater than 2 cm in size, you still have a pretty high recurrence rate. And then bigger tumors are prone to higher complication rates."
A retrospective, 32-year study conducted in the 1970s reported that nasopharyngeal cancer patients with large tumors, skull invasion, and cranial nerve problems were not candidates for re-irradiation. But in patients who were eligible, re-irradiation was done in conjunction with intracavitary radiation, usually with radium or cobalt, Dr. Spencer said. "And you could get in fairly high doses for re-irradiation and respectable five-year survival rates," he added, although complications included local soft tissue and bone necrosis (AJR Am J Roentgenol 126:107-115, 1976).
Brachytherapy is important for those patients with disease in non-nasopharyngeal sites, although survival rates do vary in published reports. For instance, a study done in the larynx demonstrated a fairly good local control rate of 61% and a survival rate at five years of 93%. Another study of external-beam radiation therapy (EBRT) and brachytherapy turned in a 20% five-year survival rate. The survival rate for patients treated with brachytherapy in subsequent trials has ranged from 61% to 91% (Radio Clin North Am 16:209-218, 1978; Radiother Oncol 23:6-15, 1992).
Dr. Spencer called attention to research led by Bahman Emami, MD, and Kenneth R. Stevens, Jr., MD. Dr. Emami's group treated 99 surgically salvaged patients with EBRT only and achieved a local control rate of 21% and a five-year survival rate of 20% (Laryngoscope 97:85-88, 1987).
"Dr. Stevens looked at about 100 patients that were treated with EBRT plus or minus brachytherapy," she said. "And he was able to note a five-year survival in his new second primary cancer patients of 37%," although in those with recurrent disease, the survival rate dropped to 17%. Nine of the 100 patients developed severe adverse normal tissue effects from re-irradiation, which Dr. Stevens' group deemed substantial but acceptable (Int J Radiat Oncol Biol Phys 29:687-689, 1994).
Relapsed patients who are not candidates for surgical resection are most likely not eligible for interstitial radiation, Dr. Spencer said. The next option would be radiation with chemotherapy. Investigators at the University of Chicago were pioneers in this field, delivering good outcomes in patients with poor prognosis using hydroxyurea, 5-FU, and radiation therapy. Eleven patients had recurrent disease after previous surgery, radiotherapy, or chemotherapy, and five patients had not received previous local therapy. Of 15 patients available for evaluation, nine had a complete response and that included five patients who had earlier local therapy. Five had a partial response, and one failed to respond. Toxicities included mild myelosuppression and mucositis (Otolaryngol Head Neck Surg 98:295-298, 1988).
Dr. Spencer and colleagues at UAB reproduced the Chicago data, looking at different dose strategies and treatment schedules: 40 Gy once a day, then 48 Gy twice a day, and 60 Gy twice a day, along with hydroxyurea and bolus 5-FU on an every-other-week schedule.
"We started out with 35 patients and were able to get most of the patients through all four courses of the treatment, but you can see, of course, there were some toxicities: 11 out of 25 had some neutropenia, and there was a death due to secondary neutropenia. And when we looked at our later complications greater than grade 3, there were four late complications: esophageal strictures, trismus, and a patient who continued to have TI [tubulointerstitial] disease. The survival at one year was 45% and at two years, 20%," she said (Int J Radiat Oncol Biol Phys 22:1051-1056, 1992).
Dr. Spencer led the RTOG 96-10 trial that treated previously irradiated patients with recurrent disease or a second primary with four weekly cycles of 5-FU (300 mg/m2 IV bolus) and hydroxyurea (1.5 g bid) along with 60 Gy in 1.5 Gy twice-daily fractions. Grade 4 toxicity occurred in 17.7% of patients, and grade 5 in 7.6%. The estimated five-year survival rate was 3.8%. The authors noted that patients who entered the study at less than one year from initial radiotherapy had a median survival of 9.8 months (Head Neck 30:281-288, 2008).
Finally, there is stereotactic body radiation therapy (SBRT) and IMRT. Researchers at Houston's M.D. Anderson Cancer Center looked at about 74 patients, some postoperatively, who were treated with concurrent chemoradiation. While outcomes were respectable, 20% of the toxicity was described as severe, Dr. Spencer pointed out (Semin Oncol 30:101-108, supplement 18, 2003).
As for SBRT, research is still pending. Multiple studies have used doses ranging from 25 to 30 Gy given in three to five fractions with toxicity ranging from 4% to 24%. Overall survival has been good, but Dr. Spencer cautioned that these results apply to patients who are specially selected for SBRT (Am J Clin Oncol online, October 23, 2009; Int J Radiat Oncol Biol Phys 74:1348-1355, 2009, and online, January 5, 2010).
While all toxicity needs to be looked at closely, spinal toxicity and late toxicity are particular areas of concern. Animal data indicate that hyperfractionated therapy can reduce spinal toxicity. A meta-analysis of four previous studies found that a cumulative BED [biologically effective dose] of 130 to 125 Gy2 is safe for the spinal cord if the initial dose does not exceed 90 Gy2 (Int J Radiat Oncol Biol Phys 66:1446-1449, 2006).
For late-effect toxicity, myelopathy has been seen two years after re-irradiation, so these patients require some longer follow up, Dr. Spencer said. In RTOG 96-10, late effects included mucosal toxicities, laryngeal and pharyngeal toxicities, and one case of hearing loss. Another RTOG trial (91-11) looked at some of the factors associated with severe late toxicities and came up with older age, advanced T stage, larynx/hypopharynx as the primary site, and neck dissection after concurrent chemoradiation (J Clin Oncol 26:3582-3589, 2008).