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Radiation for small cell lung cancer: options, techniques, latest research
As outcomes for SCLC remain poor, oncologists and radiation oncologists weigh in on radiation treatment techniques.
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In the late 1970s researchers widely considered small cell lung cancer a potentially “curable” cancer. Three decades later physicians are still battling the disease, which accounts for about 20% of newly diagnosed lung cancer cases.
Radiation oncologists continue to face hurdles with treatment options. Earlier this year Zhongxing Liao, MD, presented an update on these options at the 9th Annual Oncology Update: Advances and Controversies in Park City, Utah. Liao discussed issues related to choosing the optimal radiation treatment and the accompanying toxicities, which she said is the biggest obstacle today.
The second biggest hurdle may be lack of solid comparative information on SCLC radiation treatment. This lack of data may be why many radiation oncologists are eagerly awaiting the results of a three-arm randomized study — CALGB 30610/RTOG 0538 — which is comparing the standard dose hyperfractionated accelerated radiation (45 Gy) with high–dose once daily (70 Gy) and high–dose accelerated fractionation (61.2 Gy).
HemOnc Today spoke with leading researchers to discuss the study and other hot topics in the field, such as a preferred radiation technique for treatment and the controversial use of elective nodal irradiation and prophylactic cranial irradiation.
“Outcomes for small cell lung cancer remain quite poor,” Anurag K. Singh, MD, director of clinical radiation research at Roswell Park Cancer Institute, Buffalo, N.Y., told HemOnc Today. “Therefore, we have much room for improvement in both radiation and systemic therapies.”
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Photo by Roswell Park Cancer Institute |
All of the oncologists interviewed for this article agreed that there is a lot to do before a “cure” for SCLC will be found.
Radiation treatment options
Currently, there are no data on direct comparison of conventional, accelerated fractionation and hyperfractionated regimens.
Definitive radiation therapy with concurrent chemotherapy is the standard of care for limited-stage SCLC. Of the radiation delivery options, hyperfractionated accelerated radiation with 1.5 Gy per fraction twice a day for 30 treatments in three weeks is considered the standard of care, according to Liao.
This is supported by data from a 1999 randomized trial published in The New England Journal of Medicine that compared once-daily radiation — 1.8 Gy per fraction, 25 fractions in five weeks — vs. the hyperfractionated accelerated radiation and found a 10% improvement on five-year survival. Liao said hyperfractionated accelerated radiation “should be used at all times if possible.”
However, due to a marked increase in acute toxicity this regimen has not been embraced by all radiation oncologists, according to Suneel Nagda, MD, assistant professor, department of radiation oncology at Loyola University Chicago Stritch School of Medicine.
“The optimal radiation therapy regimen is still unknown,” Nagda said. “Theoretically altered fractionation should be better due to the biology of SCLC, ie, rapidly proliferating tumor.”
Singh agreed. “Unfortunately, we do not know which scheme is optimal. In practice, the decision regarding type of radiation is often made based on considerations such as a patient’s ability to tolerate twice-daily radiation, availability of treatment slots and physician preference,” said Singh, associate professor at the University of Buffalo School of Medicine.
Liao uses a concomitant boost fractionation. In this regimen the first three weeks of radiation is given once a day at 1.8 Gy per fraction. For the next two weeks after that the patient is given 1.5 Gy to 1.8 Gy per fraction twice a day. This fractionation schedule is based on the premise that the SCLC could have accelerated repopulation during the previous couple of weeks of the treatment, because the initial treatment kills the easy cancer cells.
“These two schedules are aggressive treatments needed to fight the aggressiveness of small cell lung cancer,” she said.
The better results associated with a concomitant boost fractionation also have increased treatment toxicity, such as esophagitis, Liao noted. Therefore, in community hospitals, toxicity may prevent the adoption of this more effective schedule. When oncologists make a decision on treatment schedules, they should consider the patient’s general condition, estimate their tolerance for each treatment and their daily life issues, such as whether they have transportation to come to the hospital twice a day, Liao said.
“Although there may be theoretical advantages to accelerated and hyperfractionated XRT for rapidly proliferating small cell lung cancer, the practicality makes it difficult to get patients through such a regimen two or three times daily. It is unclear what benefit would be gained with hypofractionation, except to possibly lessen the duration of treatment, particularly in a palliative setting. So, for most cases, conventional fractionation remains the treatment of choice,” said Khanh Nguyen, MD, assistant professor in the department of radiation oncology, City of Hope National Medical Center, Duarte, Calif.
Is ENI necessary?
The technique of elective nodal irradiation (ENI) has been maligned with controversy as well. ENI is the irradiation of nodal volumes potentially at risk of microscopic tumor spread but not already known to be involved with the primary tumor.
Nagda noted that unlike non–small cell lung cancer, ENI is typically omitted when treating SCLC due to the high doses of radiation therapy necessary to control the local tumor and the increased risk for radiation-related complications with large fields (ie, pneumonitis). “This practice has not necessarily translated to SCLC,” Nagda said. In SCLC, a fair volume of the mediastinum is typically included as there is usually gross disease involvement in the mediastinum. Therefore much of the mediastinum typically receives at least moderate dose of radiation therapy, probably leading to less isolated regional recurrences, even if ENI is omitted, Nagda added.
“There are no large scale studies — as there are in NSCLC — determining the risk of isolated nodal failure in those patients treated without ENI,” Nagda said. “I don’t believe that large volume ENI is necessary in the treatment of SCLC, but to what extent the volume of radiation therapy can be limited is controversial.
“The advantages of omitting ENI are that higher doses of radiation therapy can be delivered without markedly increasing risk of acute and long-term toxicity. The disadvantage of omitting ENI is that an isolated regional failure is difficult to treat with curative intention owing to the previous radiation therapy given,” Nagda said.
“The issue of ENI in SCLC relates mostly to coverage of the supraclavicular lymph nodes,” Singh said. “Isolated failures in the supraclavicular region do occur and have been reported. However, the rate of failure is fairly low and probably not worth the additional toxicity of covering that region in all patients.”
Liao agreed and said that since isolated nodal recurrence is rare after chemoradiation, ENI is not necessary.
“Most patients will have tumor return at the initial site of the primary tumor bulk, or distant spreading,” Liao said. “Adding elective nodal irradiation increases toxicity without adding too much for patient outcome. In addition, during the radiation, some nodal area gets incidental irradiation because radiation has to pass through these areas. At M.D. Anderson, we feel quite comfortable not giving elective nodal irradiation,” Liao said.
Anand Shivnani, MD, radiation oncologist at Baylor Medical Center at Irving Cancer Center Medical, in Texas, said the advantages of ENI do not outshine the problems.
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“My feeling is that we need better strategies to reduce distant and local relapses, where the majority of patients recur, before elective nodal irradiation becomes relevant,” Shivnani told HemOnc Today. “I do believe the elective nodal irradiation improves regional control. However, treating more of the mediastinum increases acute side effects, often to the point where treatment breaks may be needed, which we want to avoid. Until our systemic therapies improve, my feeling is that for most patients the benefit of elective nodal irradiation does not outweigh the risks; therefore, I do not routinely offer it.”
Conflicting data on ENI
The debate about the use of ENI is likely due to a large amount of conflicting data on the method, said Scott Herbert, MD, chief of radiation oncology at The Rosenfeld Cancer Center at Abington Memorial Hospital, Pa.
“We used to do ENI as a rule for all lung cancers, but there have been data showing that it is uncommon to fail in nodal sites that are not initially involved,” Herbert said.
The obvious downside to electively radiating the nodes is that the treatment volume is increased and more normal tissue is exposed to radiation, increasing the side effects of treatment, Herbert said.
“If there is a benefit in terms of cancer outcome, this is a risk worth taking,” he said. However, if oncologists are not changing the outcome but only increasing the morbidity of treatment, ENI is not something that should be done. With better imaging, including PET/CT scans, oncologists have a much better idea of the extent of involvement at the time of diagnosis. However, PET scans are often not the best studies for SCLC, as they are for NSCLC, according to Herbert.
“I tend to treat non–small cell lung cancer without elective nodal radiation as I feel PET imaging is an excellent tool for localizing disease. However, since we don’t have the benefit of PET imaging for small cell lung cancer and disease tends to be central, I tend to treat patients with small cell lung cancer with elective nodal radiation to the mediastinum and hilum,” Herbert said.
“For histology such as small cell lung cancer, where regional and systemic spread may be quite high, omitting ‘elective’ nodal radiation may be a mistake,” Nguyen said.
“Even for non–small cell history, the data supporting omission of elective nodal irradiation are sparse,” Nguyen said. “Salvaging a mediastinal or hilar nodal recurrence can be quite challenging, given the dose limits of surrounding critical organs. Thus, it may be more prudent to address regional irradiation for high-risk patients upfront,” Nguyen said.
Prophylactic cranial irradiation
Brain metastases are a frequent problem in patients with SCLC. Increasing data support the use of prophylactic cranial irradiation to prevent intracranial relapse and to improve survival both for patients who achieve a complete response after initial therapy and for those who have a more limited response.
Ben Slotman, MD, PhD, chairman of radiation oncology department at VU University Medical Center, Amsterdam, Netherlands, was an investigator on a randomized study published in The New England Journal of Medicine in 2007 that examined prophylactic cranial irradiation in patients with extensive SCLC who had a response to chemotherapy.
One hundred forty-three patients in two groups aged 18 to 75 had been diagnosed with extensive SCLC. Patients in the irradiation group had a lower risk of symptomatic brain metastases (HR=0.27; 95% CI, 0.16-0.44). The cumulative risk of brain metastases within one year was 14.6% in the irradiation group (95% CI, 8.3-20.9) vs. 40.4% in the control group (95% CI, 32.1-48.6). Irradiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization (all times measured from randomization, which was after completion of chemotherapy).
The one-year survival rate was 27.1% (95% CI, 19.4-35.5) in the irradiation group, and 13.3% (95% CI, 8.1-19.9) in the control group. Irradiation had adverse effects but did not have a clinically significant effect on global health status.
“Prophylactic cranial irradiation should be given to all — limited or extensive — SCLC patients who have responded to chemotherapy, because it reduces the risk of intracranial relapse, improves survival and is generally well tolerated,” Slotman told HemOnc Today.
Craig W. Stevens, MD, PhD, professor and chair in the department of radiation oncology at H. Lee Moffitt Cancer Center, Tampa, Fla., said that for unclear reasons, patients with SCLC start treatment with lower neurocognitive scores than age-matched controls. However, prophylactic cranial irradiation does not appear to exacerbate this problem, according to Stevens.
“We routinely offer prophylactic cranial irradiation to all patients with limited-stage disease who have an excellent response,” he said.
“In contrast, we do not routinely offer prophylactic cranial irradiation to extensive-stage patients who have a complete or near complete response. The controversial European study [Slotman, et al], published in The New England Journal of Medicine last year, demonstrated an improvement in overall survival for those patients who underwent prophylactic cranial irradiation. However, the brain was not routinely imaged prior to prophylactic cranial irradiation treatment, as is the standard in the United States. This fact potentially confounds their results,” Stevens said.
Optimal radiation for PCI
Herbert said the data are very strong for prophylactic cranial irradiation. Recent reports showing a benefit in survival with prophylactic cranial irradiation in patients with extensive disease has expanded its usage to most patients with SCLC.
“Previously, we were only offering prophylactic cranial irradiation to patients with limited-stage disease who achieved an excellent response to chemotherapy and thoracic radiation,” Herbert said.
“Studies have shown that prophylactic cranial irradiation decreases the risk of brain metastases and increases overall survival in this group of patients. Now there is a role for prophylactic cranial irradiation in almost all patients who respond to initial treatment,” he said.
Herbert noted the recent publication of an RTOG trial (06023) looking at the optimal radiation schedule for prophylactic cranial irradiation. It compared three different schedules: two weeks of daily treatment, 3.5 weeks of daily treatment, and twice daily treatment. There was no difference among the three schedules. Most experts think that that the shortest, lowest-dose schedule — once daily, 250 cGy per day for 10 fractions over two weeks for a total of 2,500 cGy — should represent the standard of care as it was equally effective with the least chance for causing cognitive injury, he said.
“Typically, I will treat patients with limited stage disease with thoracic radiation starting with the second cycle of chemotherapy,” Herbert said. “Patients will receive the third of four cycles of chemotherapy during the thoracic radiation. After radiation is completed, patients receive their final cycle of chemotherapy. They are then restaged (including an MRI of the brain) and prophylactic cranial irradiation is offered.
“For patients with extensive stage disease at presentation, I will restage them after six cycles of chemotherapy and offer prophylactic cranial irradiation if there is a favorable response to treatment,” Herbert said.
Nguyen, however, warns oncologists not to get ahead of themselves.
“Although randomized trials and meta-analyses may support prophylactic cranial irradiation, clinical judgment should be the prevailing factor in determining whether to offer patients such treatment,” Nguyen said. “Patients with good performance status and reasonable life expectancy may benefit from such an approach, but it remains difficult to know who those patients are.”
Singh said he believes prophylactic cranial irradiation should be offered to all patients with SCLC who have a 90% or greater response to initial therapy. Given the survival advantage, it should be considered in patients who have a more partial response as well, he said.
High-dose TRT
Another issue in treating SCLC has been with the typical radiation therapy dose increasing from approximately 45 Gy to more than 70 Gy during the last two decades.
According to Nagda, the rise in dosage is due in part to increasing notice of a relatively high risk of intrathoracic failure after lower-dose radiation therapy and improvement in radiation therapy techniques — such as the ability to deliver more conformal and safer radiation therapy.
Liao agreed that even though doses of 60 Gy to 70 Gy are often used, little data are available that compare efficacy, toxicity or influence on survival.
“After 45 Gy, we know that about 40% to 50% of patients will have their tumor come back at the original site of the tumor,” Liao said.
“We also know that high radiation dose will decrease this treatment failure. Therefore, it is logical to escalate the total dose of radiation. The concomitant boost schedule is one way to achieve this goal.”
“Depending on the results of the trial, we may still be left with the question of whether a slightly lower dose of conventionally fractionated radiation therapy can be just as effective in the setting of SCLC,” Nagda said.
“It’s unclear whether high radiation therapy doses at standard fractionation will be of any benefit for small cell lung cancer,” Nguyen said. “Because it has a high propensity for systemic spread, increasing the duration of a local treatment may delay the resumption of higher doses of chemotherapy, thus potentially hindering the effectiveness of combined modality treatment.”
For patients with SCLC, local-regional recurrence is still a big problem, according to Stevens.
“More dosage may well be important, but intensity of treatment matters too,” said Stevens, adding that accelerated regimens may be just as important as dose in SCLC because of its rapid doubling time.
“We eagerly await the results of the RTOG comparison,” Stevens said. –by Angelo Milone
For more information:
- Liao, Z. Update on small cell lung cancer and the use of radiation. Presented at: the 9th Annual Oncology Update: Advances and Controversies; 2009; Park City, Utah.
- Slotman B. N Engl J Med. 2007;357:664-672.
- Turrisi A. N Engl J Med. 1999; 340:265-271.