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Radiation Dose for Non-Small Cell Lung Cancer

There is no clearly established dose for lung cancer. (see RTOG L-0117 trial.) Most centers use a dose between 6000 and 7000cGy. The new NCCN dose guidelines go up to as high as 7740cGy to 8,380cGy (go here and here).

As per the discussion and study below (Hayman) the safe dose of radiation is related to what organs are treated and the volume of the lung included. Using CT guided. 3D conformal therapy, it is possible to avoid over-dosing the spinal cord and esophagus and to use higher doses.

The study below suggests that if large volumes of lung are included the dose should not exceed 65Gy, but if the volumes are smaller. the safe dose may be over 100Gy! The study from SKM showed doses over 80Gy may be important at least for early stages (go here.) The paper below from Duke (Maguire) describes using 160cGy bid to 73.6 and now 86Gy. Another paper from the Mayo Clinic found 74Gy plus Carbo/Taxol was safe (go here)

Toxicity and outcome results of RTOG 9311: A phase I–II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non–small-cell lung carcinoma
Bradley. IJROBP 2005;61:318

A total of 179 patients were enrolled in a Phase I–II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. The total lung volume was defined as the volume of both lungs minus the PTV. V20 was defined as the percentage of volume of normal lung receiving =20 Gy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V20).

Patients with a V20 <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V20 of 25–36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V20 =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method.

Results

The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V20. The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50–78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure.

Conclusions

The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V20 values of <25% (Group 1) and to 77.4 Gy for patients with V20 values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.

Dose Escalation in Non–Small-Cell Lung Cancer Using Three-Dimensional Conformal Radiation Therapy: Update of a Phase I Trial

James A. Hayman Journal of Clinical Oncology, Vol 19, Issue 1 (January), 2001: 127-136

From the Departments of Radiation Oncology and Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System, Ann Arbor, MI, and Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC.

When administered using conventional doses and treatment techniques, radiation therapy is generally associated with a poor outcome. In several recent randomized studies, the median survival after treatment with conventional radiation therapy alone has averaged only 8 to 10 months and the 2-year survival has only been in the range of 10% to 20%.Although treatment with conventional radiation therapy has been reported to result in local control rates of 65% to 80%, when Le Chevalier et al used a strict definition of local control (ie, complete clinical, radiographic, and pathologic response), they reported a local control rate of only 15% at 1 year. Although improvements in outcome have been achieved through the addition of chemotherapy, the magnitude of this benefit has been relatively modest (ie, a maximum of 4 months). Accordingly, there is still a tremendous need for improvements in the treatment of stage III NSCLC.

To improve on our current results, it is obvious that local control must be enhanced. One potential approach is to escalate the dose of radiation therapy. Evidence exists that increasing the dose of radiation therapy may lead to an improvement in local control. In a landmark trial conducted by the Radiation Therapy Oncology Group, patients with T1 to 3/N1 to 2 tumors were treated randomly with four different dose schedules. The best local control, clinical complete response, and 2-year survival were achieved with the highest total dose regimen (ie, 60 Gy in conventional fractionation). In addition, Vijayakumar et have shown that when local control is plotted against dose using data from published studies, a relationship between increasing dose and local control can be demonstrated. However, when dose escalation has been attempted using conventional treatment techniques and volumes, investigators have reported increased toxicity.

A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine.

RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions.

73.6 Gy and Beyond: Hyperfractionated, Accelerated Radiotherapy for Non–Small-Cell Lung Cancer

By Patrick D. Maguire, Lawrence B. Marks, Gregory S. Sibley, James E. Herndon II, Robert W. Clough, Kim L. Light, Maria L. Hernando, Philip A. Antoine, Mitchell S. Anscher

From the Department of Radiation Oncology and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC. Journal of Clinical Oncology, Vol 19, Issue 3 (February), 2001: 705-711

Between 1991 and 1998, 94 patients with unresectable NSCLC were prescribed   73.6 Gy via accelerated fractionation. Fifty were on a phase II protocol (P group); 44 were similarly treated off-protocol (NP group). The clinical target volume received 45 Gy at 1.25 Gy bid (6-hour interval). The gross target volume received 1.6 Gy bid to 73.6 to 80 Gy over 4.5 to 5 weeks using a concurrent boost technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated by the Kaplan-Meier method. Median follow-up durations for surviving P and NP patients were 67 and 16 months, respectively.

RESULTS: Total doses received were  72 Gy in 97% of patients. The median OS by stage was 34, 13, and 12 months for stages I/II, IIIa, and IIIb, respectively. LPFS was significantly longer for patients with T1 lesions (median, 43 months) versus T2-4 (median, 7 to 10 months; P = .01). Results were similar in the P and NP groups. Acute grade  3 toxicity included esophagus (14 patients; 15%), lung (three patients; 3% [one grade 5]), and skin (four patients; 4%). Grade  3 late toxicity in 86 assessable patients included esophagus (three patients; 3%), lung (15 patients; 17% [three grade 5]), skin (five patients; 6%), heart (two patients; 2%), and nerve (one patient; 1%).

CONCLUSION: This regimen yielded favorable survival results, particularly for T1 lesions. Acute grade  3 toxicity seems greater than for conventional RT, though most patients recovered. Late grade  3 pulmonary toxicity occurred in 17%. Because of continued locoregional recurrences, we are currently using doses  86 Gy.

Impact of tumor control on survival in carcinoma of the lung treated with irradiation.

Perez CA, Bauer M, Edelstein S, Gillespie BW, Birch R  Int J Radiat Oncol Biol Phys 1986 Apr;12(4):539-47

The long-term results in tumor response, intrathoracic tumor control and survival are reported in patients with medically inoperable or unresectable non-oat cell and small cell carcinoma of the lung. In 376 patients with stages T1-3, NO-2 carcinoma of the lung tumors, accessioned to a Radiation Therapy Oncology Group (RTOG) randomized study to evaluate different doses of irradiation, a higher complete response rate (24%), intrathoracic tumor control (67%) and three year survival (15%) was observed with 6000 cGy, compared with lower doses of irradiation (4000 or 5000 cGy). Increased survival was noted in patients with complete tumor response. Three year survival in complete responders was 23%, in partial responders, 10%, and in patients with stable disease, 5%. Patients treated with 6000 cGy had an overall intrathoracic failure rate of 33% at 3 years, compared with 42% for those treated with 5000 cGy, 44% for patients receiving 4000 cGy with split course, and 52% for those treated with 4000 cGy continuous course (p = 0.02). Patients surviving 6 or 12 months exhibited a statistically significant increased survival when the intrathoracic tumor was controlled. Patients treated with 5000-6000 cGy, showing tumor control, had a three year survival of 22%, versus 10%, if they had intrathoracic failure (p = 0.05). In patients treated with 4000 cGy (split or continuous), the respective survival was 20% and 10%, if the intrathoracic tumor was controlled (p = 0.001). In patients surviving 12 months after treatment with 5000-6000 cGy, on whom the intrathoracic tumor was controlled, the median survival was 29 months, in contrast to 18 months, if they developed intrathoracic failure (p = 0.05). In patients treated with 4000 cGy, the median survival was 23 months with control and 18 months without control of the intrathoracic tumor [corrected] (p = 0.008). In another RTOG study for patients with more advanced tumors (T4 or N3), those with local tumor control at 12 months had a three year survival rate of 25%, compared with 5% for those with thoracic failures. These differences are statistically significant (p = 0.006). Higher doses of irradiation yield a greater proportion of complete response, higher intrathoracic tumor control and better survival in non-oat cell medically inoperable or unresectable carcinoma of the lung

A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11

JD Cox, N Azarnia, RW Byhardt, KH Shin, B Emami and TF Pajak
University of Texas MD Anderson Cancer Center, Houston 77030. Journal of Clinical Oncology, Vol 8, 1543-1555

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.