Another analysis of a large national database is poised to feed the long-running and sometimes acrimonious debate over whether consolidation radiation therapy (RT) following chemotherapy vs chemotherapy alone in early non-Hodgkin's lymphoma (NHL) improves overall survival (OS) enough to justify its potential for long-term toxicity.
New research suggests it does.
The new research focused on patients with diffuse, large B-cell lymphoma (DLBCL), which is the most common type of high-grade NHL.
Jon Vargo, MD, University of Pittsburgh Cancer Institute, in Pennsylvania, and colleagues analyzed 5- and 10-year OS rates in 59,255 patients with stage I and II DLBCL and found a clear survival advantage for patients who received chemotherapy plus consolidative RT compared with patients who received multiagent chemotherapy alone at both 5- and 10-year follow-up.
They note that there has been a trend in recent years toward reducing the use of consolidative RT after multiagent chemotherapy in DLBCL, but they now warn against this.
"Abandonment of combined-modality chemotherapy in favor of chemotherapy alone negatively affects patient survival," they write.
The study was published online August 10, 2015, in the Journal of Clinical Oncology.
National Cancer Data Base
For this study, the researchers identified 59,255 patients with stage I and II DLBCL from the National Cancer Data Base. Nearly half the patients (46%) had stage II disease; 42% had extranodal disease; 58% were older than 60 years.
Researchers restricted survival analyses to patients who lived at least 12 months or longer after their diagnosis to account for immortal time bias. They used a propensity score analysis to account for indication bias caused by lack of randomization.
The median follow-up period was 66 months for surviving patients, during which time there were 12,647 deaths in the survival outcome cohort.
"Chemotherapy was initiated at a median of 24 days after diagnosis...and RT was initiated at a median of 133 days after diagnosis," Dr Vargo reports.
In the combined-modality therapy group, the proportion of patients receiving more than 36.0 Gy significantly decreased from 62% in 1998 to 23% in 2012 (P < .001).
After adjustment for immortal time and indication bias, combined-modality chemotherapy plus RT led to 44% better OS than multiagent chemotherapy alone (P < .001), the investigators report.
Table. 5- and 10-year OS Rates in CMT vs Chemotherapy Alone
|Aggregate OS (All Patients)||CMT||Multiagent Chemotherapy Alone|
|5-year OS (95% CI)||79% (78% to 79%)||82% (82% to 83%)||75% (75% to 76%)|
|10-year OS (95% CI)||59% (58% to 59%)||64% (63% to 65%)||55% (54% to 56%)|
|P < .001||P < .001|
CMT, combined-modality therapy
On propensity score–adjusted, multivariable analysis, factors associated with improved odds of survival included treatment strategy, sex, income quartile, extranodal disease, and propensity score.
The difference in OS between the two strategies held when investigators looked at patients with stage I disease vs those with stage II disease; the year of diagnosis (1998-2002; 2003-2007, and 2008-2012), and whether or not patients had extranodal disease.
No Clear Good Way
Andrea Ng, MD, Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts, who is lead author of an accompanying editorial, told Medscape Medical News that she agrees that not all patients with DLBCL require consolidation RT.
"It's just that right now, there is no clear, good way to tease out which patients are the ones who would benefit from chemotherapy alone and those who would definitely need RT," she said.
The majority of studies undertaken in the rituximab era have looked at patients with DLBCL who had a complete response, as determined by positron-emission tomography (PET), to treatment with R-CHOP (rituximab plus cyclophosphamide doxorubicin, vincristine, and prednisone), she explained. With follow-up, there was still a benefit for those who received RT, she pointed out
Dr Ng emphasized that the doses of RT now used in DLBCL are significantly lower than in the past, and long-term toxicity is not nearly as worrisome as it might have been historically.
The debate over the value of adding RT consolidation after chemotherapy has been raging for some time among experts who treat Hodgkin's disease, as previously reported by Medscape Medical News. Some experts point to data that show an improved survival when RT is added, but others warn of the risk of late toxicity, as may occur in patients with in Hodgkin's disease, for which the radiotherapy is directed at the chest, increasing the risk for breast cancer at a later date.
Dr Ng emphasized that there are "pretty big differences" between Hodgkin's disease and NHL.
"Hodgkin's disease tends to present in the mediastinum, so the majority of Hodgkin's disease patients will get chest RT, whereas NHL can happen anywhere from head to toe, so RT to the chest is not really an issue for NHL patients," Dr Ng explained.
Moreover, population-based studies have looked at patients with NHL who did and who did not receive RT. Overall, the investigators could not find an increased secondary cancer risk with additional RT, Dr Ng added.
In addition, and importantly, patients with Hodgkin's disease tend to be in their 20s or early 30s, or even in their teens, whereas the median age of patients with NHL is 60 years, she pointed out.
Offering prolonged R-CHOP chemotherapy with its potential for doxorubicin-induced cardiotoxicity to older patients is not an option favored by medical oncologists, Dr Ng commented.
"We know that the cardiac toxicity from doxorubicin is dose-related, so you really don't want to put your NHL patients with a median age of 60 on high doses of Adriamycin," she explained.
"So for older patients, we give them just three cycles of abbreviated R-CHOP and a small amount of RT, and with the use of PET for restaging, we can go as low as 30 Gy for radiation," she said.
Of note, both Dr Vargo and Dr Ng singled out the UNFOLDER study (Unfavorable Low-Risk Patients Treated With Densification or R-Chemo Regimens trial), in which patients with bulky or extranodal disease or both were randomly assigned to receive R-CHOP-21 (R-CHOP every 3 weeks) or R-CHOP-14 (every 2 weeks), with or without consolidative RT.
Although data from the trial are not yet available, arms in which patients were not offered consolidative RT were discontinued after an interim analysis showed a higher rate of treatment failure without RT.
Dr Vargo and Dr Ng have disclosed no relevant financial relationships.