Holger Hof,       Cancer 2007;110:148

The clinical results after stereotactic single-dose radiotherapy of nonsmall-cell lung cancer (NSCLC) stages I and II were evaluated.
Forty-two patients with biopsy-proven NSCLC received stereotactic radiotherapy. Patients were treated in a stereotactic body frame and breathing motion was reduced by abdominal compression. The single doses used ranged between 19 and 30 Gy/isocenter.

After a median follow-up period of 15 months the actuarial overall survival rates and disease-free survival rates were 74.5%, 65.4%, 37.4%, and 70.2%, 49.1%, 49.1% at 12, 24, and 36 months after therapy, respectively. The actuarial local tumor control rates were 89.5%, 67.9%, and 67.9% at 12, 24, and 36 months after therapy, respectively. A significant difference (P = .032) in local tumor control was found for patients receiving 26-30 Gy (n = 32) compared with doses of less than 26 Gy (n = 10). The effect of the tumor volume on local tumor control was also evaluated. Although the difference was not statistically significant (P = .078), the subgroup of tumors with a tumor volume of less than 12 cm³ (n = 10) experienced no tumor recurrence. Thirteen (31%) patients developed metastases during follow-up, whereas isolated regional lymph node recurrence was only encountered in 2 patients. No clinically significant treatment-associated side effects were documented.
Stereotactic single-dose radiotherapy is a safe and effective treatment option for patients with early stage NSCLC not suitable for surgery. Especially for small tumor volumes it seems to be equally effective as hypofractionated radiotherapy, while minimizing the overall treatment time.

The initial tumor (a) shows significant reduction in size 6 weeks after treatment (b). Three months later, normal tissue reactions of the surrounding lung tissue are seen (c), which dissolve over the next months, leading to perifocal fibrotic changes without solid tumor rests 2 years after treatment (d).

With a delay of 2 to 4 days after treatment planning the actual treatment was performed, applying a single fraction. For verification of the patient position, an additional CT scan of the tumor region was performed, with deviations of bony landmarks exceeding 2 mm or tumor positions outside the previously measured range of mobility being corrected by patient repositioning. After successful completion the patient was immediately brought to the treatment room in identical position. Target point setup was accomplished by using stereotactic coordinates. An additional position verification was performed at the linear accelerator (LINAC) by orthogonal portal images being compared with digitally reconstructed radiographs (DRR) of the planning CT. Treatment was performed using a Siemens Mevatron LINAC (Siemens, Concord, Erlangen, Germany) with a dose rate of 200 MU/minute and an integrated motorized multileaf-collimator. The total dose applied ranged from 19 to 30 Gy to the isocenter, which equals about 15.2 to 24 Gy to the PTV-surrounding 80%-isodose. In the following, doses refer to the isocenter, if not otherwise mentioned. One patient received 19 Gy, 2 patients 22 Gy, 7 patients 24 Gy, 14 patients 26 Gy, 10 patients 28 Gy, and 8 patients 30 Gy.For determination of the influence of the radiation dose on local tumor control, patients receiving doses of less than 26 Gy (n = 10) were compared with patients receiving 26 to 30 Gy (n = 32). In the log-rank test a statistically significant difference (P = .032) was seen. Patients receiving less than 26 Gy had an actuarial local tumor control rate of 62.5% at 12 months and of 50% at 24 months and longer. Patients receiving 26 Gy or more had a local tumor control rate of 100% at 12 months and of 72% at 24 months and longer

Only few data on the outcome after stereotactic single-dose radiotherapy of early stage lung tumors have been published so far. Wulf  reported on the results of stereotactic radiotherapy of 92 lung lesions (metastases and primary lung cancers), of which 31 were treated with single doses of 26 Gy prescribed to the 80%-isodose in a similar setup as our patients. Remarkably, no tumor recurrence was noticed after a median follow-up of 14 months. Hara  reported on 59 malignant lung tumors treated with single-dose radiotherapy, although only 11 of the tumors included were primary lung tumors. Whereas the 1-year and 2-year local progression-free rates (LPFRs) were 93% and 78%, respectively, they found an LPFR at 2 years of only 52% in patients treated with 20 or 25 Gy total dose, whereas the LPFR in patients receiving 30 Gy or more was 83%. This indicates a dose dependency even for high single doses. Our data support that finding, showing significantly higher local tumor control rates in the group receiving 26-30 Gy compared with patients receiving less than 26 Gy. Normalizing the doses we applied to the PTV-surrounding 80%-isodose resulted in significantly lower radiation doses, ranging from 15.2 to 24 Gy, which could be responsible for the somewhat inferior local control rates compared with the publications mentioned above. Also, the pencil beam algorithm used for dose calculation could overestimate the dose to some extent. The effectiveness of dose escalation is also demonstrated for hypofractionated radiation schemes. In a retrospective analysis, Onishi  evaluated 245 patients from 13 centers with early stage lung tumors treated with a wide variety of doses per fraction (ranging from 3-12 Gy) and fraction numbers (ranging from 1-25). For comparison of the dose effect they calculated a BED based on a linear-quadratic model. As a result a significant difference in local disease recurrence was found for tumors receiving less vs more than a BED of 100 Gy (26.4% vs 8.1%). Also, Wulf  concluded that there is a steep increase in tumor control probability for radiation doses above a BED of 94 Gy at the isocenter. A similar result is seen when transforming the single doses we used to BED. Whereas the group with doses ranging from 26 to 30 Gy had a BED at the isocenter of close to 100 Gy up to 120 Gy, the group receiving less than 26 Gy had a BED at the isocenter of only 81.6 Gy or less. This confirms the impact of the 100 Gy BED on local tumor control. In a phase 1 study by McGarry  47 patients with stage Ia or Ib lung carcinomas received stereotactic radiotherapy in 3 fractions, starting with a dose of 8 Gy per fraction up to a dose of 24 Gy per fraction in stage Ib tumors. Only 1 failure occurred in the group receiving 16 Gy or higher doses, whereas 9 local failures were seen in the group receiving less than 16 Gy per fraction.

To what extent the tumor volume has an influence on local tumor control remains unclear. Whereas in the data we present tumors smaller than 12 cm³ show a better outcome than bigger tumors, these results are not statistically significant and can only give a hint as to the importance of the tumor volume. A reason for the statistically insignificant comparison between T1 and T2 tumors could be that some tumors of the T1 group exceeded the size of 12 cm³. Wulf  treated 20 patients with stage I-II NSCLC using a hypofractionated treatment approach consisting of 3 fractions of 10-12.5 Gy each (only 1 patient received a single-dose treatment of 26 Gy). Although these patients had relatively large tumors, with a median CTV of 80 cm³ and a range of 5 to 277 cm³, actuarial local tumor control rates of 92% 12 months and longer after treatment could be achieved (median follow-up, 11 months). This could imply that hypofractionated radiotherapy is superior to single-dose therapy in large tumor volumes, where the effects of fractionation like reoxygenation and redistribution gain importance. Nevertheless, the patient numbers are much too small to date to provide sufficient reliability on this issue. For smaller tumor volumes of less than 12 cm³ our data show comparably high tumor control rates, as was shown for tumors treated with hypofractionation.

The influence of dose escalation on the overall survival after radiotherapy of early stage lung cancer was also shown in a retrospective analysis of 156 patients treated with conventional radiotherapy, indicating the achievement of local control and high radiation doses to be significant prognostic factors Nagata  treated 45 patients with stage I lung cancer with a total dose of 48 Gy in 4 fractions. Besides a high local tumor control rate of 98% after a median follow-up of 30 months, disease-free and overall survival rates for stage Ia tumors after 1 and 3 years were as high as 80% and 72%, and 92% and 83%, respectively. Even for stage Ib tumors the disease-free and overall survival rates were relatively high, with 92% and 71%, and 82% and 72%, respectively. Compared with a surgical series that achieved survival rates of more than 50% after 5 years, these data seem to be at least comparable. Contrary to expectations, our data cannot validate these results, showing much lower survival rates. However, from our point of view the reason is not the single-dose fractionation scheme used or the applied total dose, which would also have an impact on the local tumor control rates, but patient selection. Presumably, the bad overall medical condition of the patients before treatment, as only patients not amenable to surgery were treated, plays an important role in the survival outcome. This deduction is supported by the long-term results of DFS, which were superior to overall survival. Another reason could be a possible initial underestimation of the tumor stage, as discussed below, although the fact that the subgroup of patients not experiencing metastatic disease had no better survival than the rest of the group reduces this suggestion.

The use of very high radiation doses always comprises the risk of inducing normal tissue toxicities. That the occurrence of clinically relevant toxicities is not induced by high doses alone but is also influenced by the extent of the treated volume is shown by McGarry  Whereas no significant toxicities were seen in patients with T1 tumors, dose-limiting toxicities grade 3 occurred in 3 of 5 patients, with T2 tumors larger than 5 cm receiving 72 Gy total dose. In our treatment we were far below target doses as large as these, so the absence of relevant toxicities in our patient group is not surprising. The low rate of adverse events is also documented in other publications: In the patient group treated by Nagata  no pulmonary complications CTC grade 3 or higher were encountered; only 2 patients experienced CTC grade 2 toxicities. In contrast to the low rate of clinically symptomatic changes, a vast majority of patients was diagnosed with localized perifocal normal tissue changes. These changes seem not to be extensive enough to cause symptoms but the difficulty of separating them from tumor remains. Takeda  examined 22 pulmonary lesions treated with hypofractionated stereotactic radiotherapy. Subsequent CT scans revealed the occurrence of ground-glass opacities 3 to 4 months after therapy in 18% of cases. These corresponded closely with the planning target volume but were unevenly distributed. Afterward, these opacities either dissolved or evolved into dense consolidations. These dense consolidations even occurred in 73% of all cases after a follow-up of 3 to 8 months. Contrary to the early changes, these densities did not dissolve but persisted, even after some shrinking. Similar findings were seen in our patient group, where 64.3% of all patients developed dense areas in the treated region. As these densities can hardly be differentiated from possible tumor rests, we performed no further discrimination of the local tumor control between partial and complete response. Clinically, patients did not show increased side effects, so the use of single-dose radiotherapy is not prohibitive from the standpoint of normal tissue tolerance. In fact, even further dose escalation should be tolerable, as the data by McGarry suggest that dose-limiting toxicities occur at much higher dose levels.

The low rate of normal tissue toxicities also justifies treatment under shallow breathing, using a simple means for breathing reduction, like abdominal compression, as we did. The extent to which patients will further benefit concerning treatment sequelae is arguable, despite the fact that more sophisticated treatment methods such as gating techniques or tumor tracking will allow for further normal tissue sparing.

An important question in the local treatment of lung tumors is the possible extent of microscopic metastasis. Whereas conventional radiotherapy often includes lymphatic drainage in the radiation field, stereotactic radiotherapy must be restricted to the visible tumor region because of the high radiation doses used. For early stage lung cancer data exist suggesting that an elective nodal irradiation can be omitted, as isolated regional tumor recurrence is relatively rare.  Still, conventional CT scans can underestimate the existence of regional or distant metastases. There are reports that conclude that up to 25% of patients undergoing surgery for clinical stage I tumors harbor lymph node metastases at the time of treatment. A means of detecting occult disease could be the positron emission tomography (PET) scan. A study examining 91 patients with clinical stage I lung cancer by PET scans led to a surprising upstaging of 22 patients (24%) to stage IIIA or IIIB. In our patient cohort a relatively large number experienced regional or distant metastases during follow-up. It therefore can be assumed that some of these patients were already initially underestimated concerning their tumor stage, as no PET examination was performed regularly. The effect a consequent exertion of fluorodeoxyglucose (FDG)-PET in patient selection has on the incidence of metastases during follow-up is documented by Zimmermann  In a group of 30 patients treated with hypofractionated stereotactic radiotherapy for stage I NSCLC, all patients received an initial FDG-PET examination. During a median follow-up period of 18 months, 5 patients (17%) developed distant metastasis, only 2 of them in regional lymph nodes. Despite the relatively high number of metastases in our patient group, only 2 developed isolated regional lymph node metastases, supporting the opinion that an elective nodal irradiation can be omitted in early stage NSCLC.

Stereotactic single-dose radiotherapy for early stage lung tumors is an effective and safe treatment option for patients not amenable to surgery. Especially for small tumor volumes it seems to be comparably effective to hypofractionated treatment regimes. To what extent this also applies to bigger volumes is unclear. A significant influence of dose escalation on tumor control probability was shown. Despite the high single doses, no severe toxicities occurred, indicating that there is room for further dose escalation. For a final decision, longer follow-up on possible late toxicities in patients receiving very high doses up to 30 Gy/Isocenter (24 Gy/80%-isodose) will be useful. Concerning patient selection, adequate measures, eg, PET, should be adopted to avoid treatment of patients with advanced disease.