Toxicity, second cancers cause researchers to question radiation’s role in Hodgkin lymphoma
Radiation therapy has been an integral part of treatment for patients with early-stage Hodgkin lymphoma since the 1960s.
Up to 90% of patients treated with radiation and chemotherapy are cured.
However, many experience debilitating — and sometimes fatal — long-term side effects, such as cardiovascular disease, radiation fibrosis syndrome and second cancers. Concern about these risks are magnified because Hodgkin lymphoma most frequently occurs in those aged 20 to 34 years.
David J. Straus, MD, an internist and hematologic oncologist at Memorial Sloan Kettering Cancer Center, coauthored a viewpoint published last year in JAMA Oncology that suggested radiation therapy can be administered more safely and perhaps could be eliminated from the treatment of some patients with early-stage Hodgkin lymphoma.
“We are proposing a paradigm shift,” Straus told HemOnc Today. “If you only treat the residual masses or sites left after chemotherapy, you can drastically reduce the size of the radiation therapy portals and substantially reduce undesirable off-target exposure to other organs. Involved-field radiation therapy — even in its latest iterations as involved-nodal or involved-site radiation — still treats all the initial sites, even if they have been completely resolved with chemotherapy. Reducing the post-chemotherapy radiation portals to treat only the residual sites after chemotherapy will change the goal from systemic to local control.”
Decreasing the dose or using protons rather than photons will reduce exposure to adjacent organs, but reducing the size of the treatment portals will further reduce that risk.
“The only way to reduce risk is to drastically reduce the size of the fields,” Straus said. “If you just treat the residual sites, you can expose the heart and the breast to less than 1 Gy [of radiation]. This is a change in the paradigm, from thinking about radiation as a systemic therapy to using it for local control.”
Supporters of radiation therapy for Hodgkin lymphoma contend data used to argue against radiation are out of date and derived from treatment that took place in the 1960s. Subsequent advances have made therapy more precise and likely will reduce long-term morbidity and mortality, they argue.
HemOnc Today spoke with radiation oncologists and medical oncologists about the benefits vs. risks of radiation, whether some patients may be suitable for less intensive treatment, and how the development and adoption of alternative treatments could affect the use of radiation.
Risk vs. benefit
In 1962, Henry Kaplan, MD, a radiologist at Stanford University, pioneered the use of radiation therapy for patients with Hodgkin lymphoma, using a medical linear accelerator to treat all lymph node sites at risk.
His efforts — advanced before the development of systemic treatment — started the transformation of the disease from near-certain death sentence to potentially curable.
After the development of combined-modality treatment with chemotherapy and radiation, cure rates for Hodgkin lymphoma skyrocketed. Five-year OS rates, which were less than 10% in the 1960s, surged to nearly 80% in the mid-1980s and now stand at 90% for early-stage disease.
“Radiation was a tremendous contribution,” Straus said. “There was no alternative, and radiation did cure a substantial number of people.”
However, the association between radiation dose and cancer, cardiovascular disease and lung disease is better understood today.
Data from Schaapveld and colleagues — published in 2015 in The New England Journal of Medicine — showed cumulative incidence of second cancers in survivors of Hodgkin lymphoma 40 years after treatment was 48.5% (95% CI, 45.4-51.5). Further, the risk for a second cancer remained elevated for 35 years after treatment (standardized incidence ratio, 3.9; 95% CI, 2.8-5.4).
Other toxicities also are common. Gotti and colleagues found mediastinal radiation plus chemotherapy causes pulmonary toxicity in 10% to 25% of patients, and mantle-field or neck radiation causes thyroid abnormalities in 20% of patients.
A study by van Nimwegen and colleagues showed a mean heart dose of 20 Gy from mediastinal radiotherapy resulted in a 2.5-fold increased risk for coronary heart disease in survivors of Hodgkin lymphoma.
Researchers at Stanford — including Saul Rosenberg, MD, a medical oncologist who worked with Kaplan in the 1960s to develop the combination modalities that led to improved outcomes — reviewed developments in Hodgkin lymphoma treatments over 50 years.
Their work contained three actuarial curves for 3,000 patients with Hodgkin lymphoma. The top curves showed 40-year Hodgkin lymphoma survival reached 81.7%. The second curve, which represented 40-year freedom from relapse, was 69.7%. The bottom curve, which represented 40-year OS, was only 25.1%.
These data suggest patients are dying of causes other than lymphoma, such as cardiovascular disease or second cancers.
“The actuarial survival of people aged 65 or 70 years who have not received chest irradiation has to be better than 25%,” Straus said.
These data may be misleading, because many patients represented in those curves likely were treated with outdated forms of radiation.
“The long-term data that are quoted do not accurately represent the currently used radiation fields,” Peter M. Mauch, MD, professor of radiation oncology at Harvard Medical School and a member of the International Lymphoma Radiation Oncology Group (ILROG) steering committee, told HemOnc Today. “The modified fields that include involved-site radiotherapy are much smaller than the classic involved fields. The second tumor and cardiovascular data also are not from involved-field data but, rather, from when very large radiation fields were used as the main treatment for Hodgkin lymphoma.”
ILROG is currently working on plans to test the use of even smaller radiation fields, Mauch added.
The addition of radiation to chemotherapy reduces recurrence risk in patients with Hodgkin lymphoma.
Herbst and colleagues conducted a systematic review and meta-analysis of five randomized controlled trials composed of 1,245 patients. Results showed the addition of radiation to chemotherapy improved tumor control (HR = 0.41; 95% CI, 0.25-0.66) and OS (HR = 0.4; 95% CI, 0.27-0.61).
Among patients who experience recurrence — likely due to forgoing receipt of radiation — secondary chemotherapies are given at such an intense dose that long-term morbidities are just as common, if not more so, than they would be had the patient undergone first-line radiotherapy, Mauch said.
“[Second-line treatments are] extensive, take a lot of time out of people’s lives, only work half the time and are associated with long-term risks that will exceed anything you might see with initial treatment,” Mauch said.
The decision for young patients becomes whether they prefer combined radiation and chemotherapy upfront — and, thus, a reduced risk for recurrence but increased risk for late treatment effects — or a less intensive chemotherapy-only regimen that increases recurrence risk but has less impact on quality of life?
“It’s challenging because these are broad, therapeutic decisions that have to be made for patients based on existing data,” Peter Martin, MD, the Charles, Lillian and Betty Neuwirth clinical scholar in oncology and associate professor of medicine at Weill Cornell Medicine, and associate attending physician at NewYork-Presbyterian Hospital, said in an interview. “We are all making daily decisions based on less-than-perfect information.”
Data show select patients with early-stage Hodgkin lymphoma have excellent long-term OS without radiation, but there may be limitations to this evidence, Martin said.
In his practice, the decision to include radiation in frontline treatment is made on a patient-by-patient basis, Martin said.
“Most of us have certain biases, but we have to make decisions for individual patients based on the expected short-term and long-term risks and benefits of chemotherapy and radiotherapy,” he added.
Stephen M. Ansell, MD, PhD, professor of medicine at Mayo Clinic in Rochester, Minnesota, and a HemOnc Today Editorial Board member, agreed select patients can benefit from less intensive upfront therapy.
“Overall, we should always be looking at all the therapies that we give to patients to get the maximum benefit with the fewest long-term toxicities,” Ansell said. “Just like we have looked at ways to abbreviate chemotherapy, it is also appropriate to look for ways to change other therapies — including radiation — to minimize them or avoid them, and only use them for patients who really need it.
“This is not criticizing the use of radiation but, rather, it is identifying patients who can get away with very little treatment and still have excellent outcomes,” Ansell added.
PET to guide treatment
PET scans help identify patients who may be appropriate for less intensive therapy. Data show patients who are PET negative have a very low likelihood of disease recurrence.
The ongoing CALGB/Alliance 50604 study — for which Straus serves as the lead investigator — evaluates the use of PET to predict relapse and identify patients who may not need intensive therapy.
The trial — initial results of which were presented at the ASH Annual Meeting and Exposition in December — includes 164 patients with early-stage Hodgkin lymphoma.
Those who were PET negative (91%) after two cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy received two additional cycles of the same treatment. However, PET-positive patients received a more intensive BEACOPP regimen — bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone — plus 3,060 cGy involved-field radiation.
After a median follow-up of 2 years, only eight of the 131 patients (6%) treated with ABVD relapsed or progressed. This figure is on par with that seen among patients treated with prolonged chemotherapy or combined-modality treatment, Straus said.
Estimated 3-year PFS among PET-negative patients was 92%, which indicates the trial likely will meet the primary objective of a 3-year PFS of at least 85%.
The secondary objective is to improve outcomes among PET-positive patients who received escalated therapy (HR < 3.84). However, at the interim analysis, it does not appear that this endpoint will be met (HR = 6.04; 95% CI, 1.82-20.08).
“It does not look like intensifying treatment with more intensive chemotherapy with escalated BEACOPP and radiation therapy is really solving the problem,” Straus said. “Interim-PET negative is a very useful biomarker, but we do not know what to do about the small number of patients who are interim-PET positive.”
Radford and colleagues evaluated a similar question in the RAPID trial. After three cycles of ABVD chemotherapy, PET-negative patients were randomly assigned to receive either radiation or no further treatment, whereas PET-positive patients received radiation and a fourth ABVD cycle.
Results — published in 2015 in The New England Journal of Medicine — showed no significant differences in 3-year PFS rates among PET-negative patients who did and did not receive radiation (94.6% vs. 90.8%).
Based on data from these trials, it is becoming clear there is a group of patients with low-risk disease who can be cured with less treatment, Martin said.
“The outcomes without radiation therapy can be very good,” he said. “That is not to say patients may not incur some additional benefit from involved-nodal radiotherapy, but it is definitely clear some young people can do very well without radiotherapy. It is hard in this day and age to advocate for the use of radiation therapy in all patients, especially with old-fashioned involved-field radiotherapy; however, you could still argue that is the standard of care in many centers.”
Researchers must wait to see how these new data, which include higher-risk patients, are incorporated into the standard of care and interpreted by the National Comprehensive Cancer Network, Martin added.
“I would not be surprised if more and more experts feel comfortable reducing the intensity of their therapy and dropping radiation therapy for younger patients who have evidence of early response to treatment,” he said.
Mauch, however, finds this approach troubling.
“If there is someone who is still PET positive after two of four cycles and their disease is regressing, not progressing, we use radiation like we usually would and their prognosis is very good,” he said. “We don’t use BEACOPP in our routine practices.”
One thing radiation oncologists do find compelling is the reduction in long-term effects due to modifications to radiation. Over time, smaller fields and dose reductions have improved the toxicity associated with radiotherapy.
Forty-year OS likely would exceed 50% — rather than 25.1% as found in the Rosenberg analysis — if the data only included patients treated with more modern treatments, Mauch said.
However, Straus referred to the Schaapveld data on risk for secondary malignancies, which showed the risk for a second solid cancer among survivors of Hodgkin lymphoma did not improve among patients treated in the 1990s compared with those treated in earlier periods.
He also cited data from van Nimwegen and colleagues, which showed each Gy of radiation dose increased the risk for coronary heart disease by 7.4%.
“These were probably the best papers ever published for cancer survivorship,” Straus said. “There is no safe dose of radiation. Even the most recent iteration of radiation, which can get the dose down as low as about 6 to 10 Gy, still doesn’t reduce the risk to potentially safe levels.”
The use of proton therapy instead of X-ray radiation further reduces radiation dose to adjacent organs and, thus, risk.
X-ray radiation is the most common form of radiation, sending packets of energy through the body. A typical patient with Hodgkin lymphoma has a large mass right in front of the heart. To treat this mass, patients receive radiation from the front, which also hits the heart.
“Proton radiation uses charged particles that have both mass and charge. They go a certain distance and then essentially stop,” Bradford S. Hoppe, MD, MPH, associate professor of radiation oncology at University of Florida, told HemOnc Today. “You get that entry dose, but you don’t get the exit dose. The integral dose — a measure that reflects dose and volume of tissue irradiated — is about 50% less with protons than with X-rays, so protons should result in fewer late effects.”
Proton radiation has not become a standard of care in part because only 14 centers in the United States have the technology, Hoppe said. However, that figure should increase to 30 in the next 3 years.
Also, proton therapy is not covered by most private insurers.
“I have to argue and go through many appeals to get protons covered for my patients,” Hoppe said. “The insurance companies say there are no randomized data to show protons should be used for Hodgkin lymphoma. That’s a flawed argument because what we’re trying to do is reduce late effects 30 years in the future, and no one is going to fund a randomized study looking at an endpoint 30 years from now.
“One problem is Hodgkin lymphoma is an ‘orphan disease,’ affecting only a small cohort of patients,” Hoppe added. “They do not have the same ability as patients with prostate cancer or breast cancer to publicize the need for advanced technologies of treatment that would influence the policy of insurance companies.”
Emerging alternative treatment options for Hodgkin lymphoma, which have yielded overwhelmingly positive early results, soon could make the radiation debate a moot point.
Brentuximab vedotin (Adcetris, Seattle Genetics) — a chemotherapy drug attached to an antibody that delivers chemotherapy directly to the tumor — has shown robust activity in relapsed and refractory Hodgkin lymphoma.
Younes and colleagues conducted a dose-escalation study to determine whether the addition of brentuximab vedotin to ABVD chemotherapy could reduce the number of therapy cycles patients received.
Results published in The Lancet showed 95% of patients who received ABVD plus brentuximab vedotin achieved complete remission, as did 96% of patients assigned brentuximab vedotin plus AVD chemotherapy. However, 44% of patients in the ABVD arm experienced pulmonary toxicity, leading researchers to conclude that bleomycin should not be combined with brentuximab vedotin.
The checkpoint inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) — already approved for other cancers — have induced promising response rates in Hodgkin lymphoma.
Preliminary results of a phase 1b trial presented at the ASH Annual Meeting and Exposition in 2014 by Moskowitz and colleagues showed 66% of patients with Hodgkin lymphoma demonstrated a response with pembrolizumab.
A study by Ansell and colleagues — published in 2015 in The New England Journal of Medicine — showed 87% of patients with relapsed or refractory Hodgkin lymphoma responded to nivolumab.
“It may be down the line that these novel therapies will usurp radiation therapy and move the field forward,” Ansell said. “But, one has to be critical and cautious because these drugs could bring on more toxicity, such as immune effects and neuropathy, without improving OS.
“Things that appear to be a good idea are only a good idea if they can be proved in a randomized comparison with standard approaches,” he added.
Despite the hype surrounding immunotherapies, advances in modern radiotherapy should not be overlooked, Hoppe said.
“These agents are going to be important contributions to treatment and will help us reduce the use of radiation, but not necessarily eliminate it,” Hoppe said. “We don’t have sufficient short-term or long-term data regarding the risks of these drugs, so these early results should be interpreted with caution.
“How we use radiation and these drugs may change over time, but in the next decade, as those therapies are introduced in first-line therapy, there also will be long-term data emerging from modern radiation techniques,” Hoppe added. “So, we’ll be able to assess the true value of these treatment approaches.”
These assessments will require medical oncologists and radiation oncologists to collaborate, perhaps blurring the lines in the radiation debate.
Straus has attempted to do this in his collaboration at Memorial Sloan Kettering with radiation oncologist Oren Cahlon, MD, with whom he co-authored the JAMA Oncology viewpoint last year.
Overall, the debate itself may be overblown, as both sides have done tremendous work to advance Hodgkin lymphoma treatment, Martin said.
The efforts of all Hodgkin lymphoma clinicians — regardless of their position on radiation — should be to find curative and nontoxic treatments.
“I don’t think questions about what is more beneficial — chemotherapy or radiation — should stop us from pushing ahead to find better ways of doing things,” Ansell said. “My hope is that 5 years from now, we are not using ABVD chemotherapy or radiation, but rather that we have new approaches with better results and no relapses. The whole package ... needs to be evaluated on an ongoing basis.”– by Anthony SanFilippo
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Moskowitz CH, et al. Abstract 290. Presented at: ASH Annual Meeting and Exposition; Dec. 5-9, 2014; San Francisco.
Radford J, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1408648.
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Straus DJ and Cahlon O. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.4794.
Straus DJ, et al. Abstract 578. Presented at: ASH Annual Meeting and Exposition, Dec. 5-8, 2015, Orlando, Fla.
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For more information:
Stephen M. Ansell, MD, PhD, can be reached at email@example.com.
Bradford S. Hoppe, MD, MPH, can be reached at firstname.lastname@example.org.
Peter Martin, MD, can be reached at email@example.com.
Peter M. Mauch, MD, can be reached at firstname.lastname@example.org.
David J. Straus, MD, can be reached at email@example.com.
Disclosure: Ansell, Hoppe, Martin, Mauch and Straus report no relevant financial disclosures.
Should patients with advanced Hodgkin lymphoma receive consolidation radiotherapy?
The role of radiation in advanced Hodgkin lymphoma is dependent on the response to chemotherapy, not its type.
Radiation therapy (RT) is a local therapy; therefore, it is imperative to identify who might benefit from RT among patients with advanced Hodgkin lymphoma (stage III or IV) and a large disease distribution. Large radiation fields are nothing but a source of unacceptable long-term toxicities.
The question is: Is adding radiation to a regimen like ABVD comparable to BEACOPP without radiation?
There is no study that tested this question in a randomized way, so we have to analyze the available data — which are limited — and use our medical judgment to come up with a recommendation.
Here is what we know from the literature:
1. It seems an effective/intensive regimen like BEACOPP can overcome the adversity of the initial bulk based on the German Hodgkin Study Group (GHSG) HD12 trial. A subgroup analysis showed the CT residual mass at completion of chemotherapy benefited from RT, whereas initial bulk did not in those who achieved complete response (CR). EORTC reached a similar conclusion. After MOPP-ABV, only patients who did not achieve CR benefited from radiation. It seems achieving CR — not the type of chemotherapy — is key to determine the need for RT.
2. How do we define CR in the PET era? One could argue that only PET-positive patients at completion of chemotherapy should receive radiation. The counter would be that research has shown PET-negative large residual CT masses still carry adversity. Magagnoli and colleagues found a residual mass larger than 4 cm predicted worse outcomes. Milgrom and colleagues found that a ratio of initial/end of therapy of larger than 0.35 yielded a worse outcome.
Using PET to determine final response, researchers of the GHSG HD15 trial showed adding RT to PET-positive masses larger than 2.5 cm only led to 11% of patients receiving RT. These patients had an inferior outcome compared with PET-negative patients, but better outcome than the series reported by Gallamini and colleagues with positive-PET findings.
3. Based on the limited role that radiation can play, paying attention to radiation delivery to avoid toxicity is a priority. This can be achieved by abandoning involved-field RT and by using involved-site RT according to modern guidelines. Additionally, current techniques — such as inverse planning, breath hold technique or proton therapy — can better target the area of interest with small margins and very limited dose to surrounding organs.
I would suggest use of modern RT in advanced-stage disease to sites of CT-residual soft tissue volume ratio greater than 0.35 coupled with a Deauville of 4 or 5 unless progressive disease is identified. Those patients would need salvage chemotherapy.
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Bouthaina Dabaja, MD, is associate professor and section chief of hematology in the department of radiation oncology at The University of Texas MD Anderson Cancer Center. She can be reached at firstname.lastname@example.org. Disclosure: Dabaja reports no relevant financial disclosures.
The place of consolidation radiotherapy in the treatment of advanced Hodgkin lymphoma is being progressively refined.
Patients with bulky disease or who are left with residual masses at the completion of chemotherapy traditionally have been treated with radiotherapy on the grounds that this appeared to diminish the risk for recurrence. However, randomized studies by EORTC and the German Hodgkin Study Group (GHSG) showed that, for patients with a complete response to chemotherapy assessed by CT imaging, consolidation radiotherapy is not beneficial. Those with residual masses larger than 2.5 cm in diameter appeared to benefit in terms of disease control, if not OS.
This approach has changed, as the undesirable late effects of radiotherapy — particularly the risk for second malignancies and accelerated coronary artery disease — have become apparent in a population of patients who enjoy a high probability of cure from lymphoma and who present predominantly in the first 4 decades of life.
We now have the possibility of assessment by functional imaging using FDG-PET scanning, which has provided further information about the risk for recurrence in masses that remain visible by CT scanning. Data from the GHSG HD15 study showed that, for patients with small residual masses and a negative PET scan following BEACOPP chemotherapy, consolidation radiotherapy can be omitted safely, with the freedom from treatment failure being the same as that for patients with complete radiological remission. The evidence for this approach after the less intensive ABVD regimen is less clear. A randomized trial by Gallamini and colleagues showed no significant difference in early recurrence rates for patients who achieved a negative interim PET scan and continued ABVD alone compared with those who received consolidation radiotherapy.
Advanced Hodgkin lymphoma is a systemic illness, whereas the use of radiotherapy is predominantly for curative treatment of localized disease. There is certainly a place for the consolidation of remission for patients with a localized FDG-avid region following chemotherapy, but it remains unclear whether this is best done with radiotherapy or a different systemic treatment, either a conventional salvage chemotherapy regimen, or incorporating one of the very active new treatments such as brentuximab vedotin (Adcetris, Seattle Genetics). The risk for having low-level disease at sites not evident on the PET scan would favor the use of more systemic therapy, but no direct comparison of the two different approaches has been conducted in the modern era.
Aleman BM, et al. N Engl J Med. 2003;348:2396-2406.
Borchmann P, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.33.9549.
Engert A, et al. Lancet. 2012;doi:10.1016/S0140-6736(11)61940-5.
Franklin J, et al. Ann Oncol. 2006;17:1749-60.
Gallamini A, et al. Abstract 118. Presented at: 13th International Conference on Malignant Lymphoma; June 17-21, 2015; Palazzo dei Congressi, Lugano, Switzerland.
van Nimwegen FA, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.63.4444.
Peter Johnson, MD, FRCP, FMedSci, is professor of medical oncology at Cancer Research UK Centre and Southampton General Hospital. He can be reached at email@example.com. Disclosure: Johnson reports no relevant financial disclosures.