# Radiation Oncology/Toxicity/Lung

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Radiation Induced Lung Toxicity

## Clinical Grading

RTOG
| Grade | Definition |
| 1 | Mild dry cough or DOE not requiring clinical intervention |
| 2 | Cough requiring narcotic antitussives or dyspnea not at rest |
| 3 | Severe cough not responsive to narcotics or dyspnea at rest; intermittent oxygen or steroids may be required |
| 4 | Continuous oxygen or assisted ventilation |
| 5 | Fatal |
* Acute phase (1–2 months post-RT )
** Exudative: vascular congestion, edema, inflammatory response
** Clinically silent
* Intermediate phase (2–9 months)
** Hyaline membrane formation
** Type II pneumocyte proliferation
** Macrophages fill air sacs
** Continued edema
* Reparative phase (6–9 months)
** Type I & II cells depleted
** Thickened basement membrane
** Capillary regeneration
* Late/Chronic (9+ months)
** Pulmonary fibrosis
** Type I pneumocytes (nondividing) replaced with scar tissue

## Pneumonitis In Lung Cancer
### SBRT Planning

* Udine, Italy; 2009 PMID 19954913 -- "Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: A timeline and pattern of CT changes." (Linda A, Eur J Radiol. 2009 Nov 30. [Epub ahead of print])
** Review of CT findings after SBRT. Different patterns and time-course than conventional fractionation
* Japanese Radiation Oncology Group; 2006 (1996–2002) PMID 16613661 -- "Characteristics of patients who developed radiation pneumonitis requiring steroid therapy after stereotactic irradiation for lung tumors." (Fujino M, Cancer J. 2006 Jan-Feb;12(1):41-6.)
** Retrospective. 156 patients, Stage I NSCLC, treated with SBRT. 12 (8%) patients required steroids. 31 patients randomly selected for comparison
** Outcome: No predictors from age, sex, tumor size, PS, FEV1, %FVC, BED or dose/fraction. V20 was median 8% (7-18%) vs. median 7% (2%-16%)
** Conclusion: No statistics predictive for development of pneumonitis requiring steroids

### IMRT Planning

* Peking University; 2010 (2005–2006) PMID 20462424 -- "Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy." (Shi A, Radiat Oncol. 2010 May 12;5(1):35. [Epub ahead of print])
** Retrospective. 94 locally advanced NSCLC (IIIA-IIIB), IMRT 60/30 or 63/35 with concurrent cisplatin-based or paclitaxel-based chemo. Primary outcome Grade 3+ acute radiation pneumonitis (by clinical symptoms and radiographic findings, interfering with ADL, requiring O2) within 6 months after therapy. LKB model used with TD50=30.5 Gy, m=0.3, n=1. Median F/U 10 months
** Outcome: G3+ pneumonitis 12%. Multivariate analysis NTCP value (<4% 1% vs >4% 43%) and V10 (<50% 6% vs >50% 29%) predictive
** Conclusion: NTCP value and V10 useful parameters for predicting severe acute radiation pneumonitis

### 2D/3D Planning

* Results reported vary in technique used, dosimetric parameters, grade of pneumonitis reported, and concurrent use of chemo
* Concurrent chemo appears to increase risk of pneumonitis
* Preliminarily, it may be reasonable to use the following guidelines when treating with 3D conformal radiation. These recommendations may not apply to patients treated with intensity modulated radiation therapy (IMRT).
** MLD (Mean lung dose in Gy): <20 Gy and probably <15 Gy
** V20 (Volume of lung receiving at least 20 Gy): <30% and probably <25%
** V30 (Volume of lung receiving at least 30 Gy): <20%
* Inferior tumor location seems to increase risk for pneumonitis
* DVH should be calculated on the combination of both lungs - GTV.
* There is some evidence that V5 may also be predictive of pneumonitis. IMRT typically increases V5, but decreases MLD. It is not yet clear how significant is the hazard of irradiating large volumes to low doses

#### Radiographic

* Duke; 2005 PMID 15936538 -- Challenges in defining radiation pneumonitis in patients with lung cancer. (Kocak Z, Int J Radiat Oncol Biol Phys. 2005).
** Prospective study to evaluate RT-induced lung injury. 251 patients with 6+ months of follow-up
** 19% developed Grade 2+ SOB requiring treatment with steroids
** 66% had classic pneumonitis, but 28% had co-founding findings and 6% developed fibrosis
** Scoring of RT pneumonitis challenging in 28%

#### Models

* London (Ontario) (1993–2010) -- Chemo/RT
** 2013 PMID 22682812 -- "Predicting Radiation Pneumonitis After Chemoradiation Therapy for Lung Cancer: An International Individual Patient Data Meta-analysis." (Palma DA, Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):444-50.)
** Meta-analysis. 836 pts, 12 published sources.
** Used Lung volume = total lung - GTV (recalculated if other definitions used). Median dose 60 Gy, 2 Gy/fx; all pts treated with concurrent chemo. Median f/u 2.3 yr. Symptomatic pneumonitis in 29.8%; fatal pneumonitis in 1.9%
** Predictors: Lung V20, use of carbo/taxol (OR 3.33); trend for age.
| V20 | G2+ Pneumonitis | G5 (Fatal) Pneumonitis |
| < 20% | 18.4% | 0.0% |
| >20% - <29.99% | 30.3% | 1.0% |
| >30% - <39.99% | 32.6% | 2.9% |
| >= 40% | 35.9% | 3.5% |
* MD Anderson; 2008 PMID 18793959 -- "Analysis of radiation pneumonitis risk using a generalized Lyman model." (Tucker SL, Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):568-74.)
** 576 patients. Time to Grade 3+ pneumonitis computed. Smoking variable included. Lyman model developed
** Outcome: NTCP estimates up to 27% different with and without smoking variable. Volume parameter n=1, corresponding to mean lung dose
** Conclusion: Inclusion of nondosimetric risk factors and censored time-to-event data can markedly effect outcome predictions
* Washington U/RTOG 9311
** 2007 PMID 17689035 -- "A Nomogram to Predict Radiation Pneumonitis, Derived From a Combined Analysis of RTOG 9311 and Institutional Data." (Bradley JD, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):985-92.)
** Two data sets (WU 219, RTOG 9311 129)
** Pneumonitis model developed using one set did not predict for the other set. Combined set developed using MLD and superior-inferior location of tumor
* NCC Korea (2001–2002) -- Grade 3+
** 2005 PMID 15703313 -- "Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer." (Kim TH, Radiology. 2005 Apr;235(1):208-15.)
** 76 patients. Median dose 60/30. Chemo in 75%. Pneumonitis Grade 1 30%, Grade 2 14%, Grade 3 14%, Grade 4 1% (total 60%). For NTCP, used TD50=24.5Gy, m=0.18, n=0.87
** Univariate: MLD, V20, V30, V40, V50, and NTCP all associated. Multivariate only MLD
| MLD | Pneumonitis |
| <10 Gy | 0% |
| 10-15 Gy | 10% |
| >=15 Gy | 45% |
| NTCP Calculated | Pneumonitis Observed |
| <17% | 0% |
| 17-49% | 8% |
| >50% | 37% |
| V30 | Pneumonitis |
| <=25% | 0% |
| 25-34% | 11% |
| >=35% | 39% |
* Duke (1991–1999) -- All Grades
** 2001 PMID 11597805 -- "Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer." (Hernando ML, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):650-9.)
** 201 patients. Most patients with conventional fields, some with nonaxial and noncoplanar beams. RT dose >60 Gy in 85%. Chemo in 41% pre-RT, 18% concurrent/post-RT. Radiation pneumonitis in 19%. For NTCP model, used TD50=30.5, m=0.3, n=1
** Predictors: MLD, V30, and NTCP all correlated well on univariate, concordance 64%. No multivariate analysis. H/o smoking protective (SS)
| MLD | G1+ Pneumonitis |
| <10 Gy | 10% |
| 11-20 Gy | 16% |
| 21-30 Gy | 27% |
| >30 Gy | 44% |
| NTCP Calculated | Pneumonitis Observed |
| 1% | 10% |
| 5% | 18% |
| 13% | 16% |
| 34% | 33% |
| V30 | Pneumonitis |
| <=18% | 6% |
| >18% | 24% |
* Washington University (1991–95) -- Grade 2+
** 1999 PMID 10487552 &mdash' "Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)." Graham MV et al. Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):323-9.
** 99 pts treated with 3D-CRT. 42% had chemo. Endpoint was grade 2 or higher pneumonitis, which occurred in 20% at 2 years
** RT Technique: CTV included GTV + 7 mm as well as elective nodal volumes. PTV1 was CTV + 7–10 mm. There was also a PTV2 of 7–10 mm around GTV alone. Total Lung DVH includes both lungs with the PTV subtracted out.
** Predictors at 2 years: V20 only factor; location, Dmax, Dmean, Veff no correlation
** All Grade 3 had V20 >=32%, all Grade 5 had V20 >35%
| MLD | G2+ Pneumonitis |
| <10 Gy | 0% |
| 11-20 Gy | 9% |
| 21-30 Gy | 24% |
| >30 Gy | 25% |
| V20 | Grade 2 | Grade 3-5 | Overall |
| <22% | 0% | 0% | 0% |
| 22-31% | 8% | 0% | 8% |
| 32-40% | 13% | 5% | 18% |
| >40% | 19% | 23% | 42% |
* Multi-institutional -- Grade 2+
** 1998 PMID 9747813 -- "Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients." (Kwa SL, Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):1-9.)
** 540 patients (lung 399, esophagus 1, lymphoma 78, breast 59, other 3). Dose 20-92 Gy, dose/fraction 1.0-2.7 Gy
** Significant variability between centers
| MLD | G2+ Pneumonitis |
| 0-8 Gy | 5% |
| 8-16 Gy | 11% |
| 16-24 Gy | 18% |
| 24-36 Gy | 43% |
* Heidelberg (Germany) -- All Grades
** 1995 PMID 7673033 -- "Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis." (Oetzel D, Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):455-60.)
** 66 patients (46 lung, 20 esophagus). Doses 50-60 Gy. Majority no chemo. Pneumonitis 15%. For NTCP model, used TD50=24.5 Gy, m=0.18, n=0.87 for each lung separately
| MLD | All Pneumonitis |
| <15 Gy | 0% |
| 17.5-20 Gy | 13% |
| 22.5-25 Gy | 21% |
| >=27.5 Gy | 43% |
| NTCP Calculated | Pneumonitis Observed |
| <30% | 13% |
| >=30% | 29% |

#### Reviews

* Fox Chase, 1997 - PMID 9106589 — "Pulmonary radiation injury." Movsas B et al. Chest. 1997 Apr;111(4):1061-76.
* 1995 - PMID 7713782 — "Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems." McDonald S et al. Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1187-203.

#### Tips

* From Lynn Wilson (Yale):
** TOTAL LUNG: V20 <=30% but <35 acceptable, V10 <=40%, V5 <=60%, and mean lung dose <=17 Gy but <=20 acceptable
** Subtracts out PTV from total lung volume, and all calcs on uncorrected and corrected lung to evaluate differences. PTV is based in 4D CT/ITV methodology.

### Pulmonary Function

* Amsterdam; 2005 (The Netherlands) PMID 15936539 -- "Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival." (Borst GR, Int J Radiat Oncol Biol Phys. 2005)
** 34 patients had PFTs before RT, at 3 months, 18 months, and 36 months
** Outcome (3 mo, 18 mo, 36 mo): Decrease FEV1 (NS), 9%, 13%; DLCO -10%, -15%, -22%; alveolar volume -6%, -7%, -16%. No recovery of any parameter
** Conclusion: Significant decrease in pulmonary function at 3 months, progressive worsening to 18 and 36 months

## Pneumonitis In Breast Cancer

* Historically <=3% with standard RT alone
* Concern that concurrent or even sequential taxanes may increase pneumonitis risk, though data not clear

### With taxanes

* Harvard
** 2006 PMID 16243442 -- "Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer." (Burstein HJ, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):496-504. Epub 2005 Oct 21.)
*** Retrospective. 40 patients, operable Stage II-III BCA, protocol-based concurrent paclitaxel with RT. Either paclitaxel 60 mg/m2 QW x12 or paclitaxel 135–175 mg/m2 Q3W x4. Standard RT fields
*** Outcome: Weekly paclitaxel dose-limiting toxicity in 25%, including 3 symptomatic pneumonitis. No dose-limiting toxicity with paclitaxel Q3W, but still 8% Grade 2 pneumonitis. Any grade pneumonitis 18% overall; tangents 8% vs. nodal fields 22%
*** Conclusion: Concurrent treatment with paclitaxel not possible weekly; may be possible Q3W, but caution is warranted due to pulmonary injury
** 2005 PMID 15890579 -- "Is a reduction in radiation lung volume and dose necessary with paclitaxel chemotherapy for node-positive breast cancer?" (Taghian AG, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):386-91.)
*** Retrospective case-control. 41 patients from PMID 11734597 (paclitaxel/RT) compared with 192 controls (standard chemotherapy/RT)
*** Outcome: Pneumonitis in paclitaxel 15% vs. standard chemo 1%. Effective lung tolerance reduced by 24%. No significant dosimetric predictors
*** Conclusion: Use of paclitaxel chemo and RT likely increases incidence of RP
** 2001 (1993–1999) PMID 11734597 -- "Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel." (Taghian AG, J Natl Cancer Inst. 2001 Dec 5;93(23):1806-11.)
*** Retrospective. 41 patients treated with RT and adjuvant CT including paclitaxel (given concurrently n=21 or sequentially n=20). Sequentially treated patients received paclitaxel 175 mg/m2 Q3W or 70–80 mg/m2 QW. RT to breast-CW and IM nodes; 30 patients also SCV field. Pneumonitis incidence compared to database
*** Pneumonitis risk: Grade 2-3: paclitaxel 15% vs. control 1% (SS). Mean time-to-pneumonitis 5 months. Sequential use pneumonitis risk 16%, however, majority of patients had IM and regional lymphatics irradiated
*** Conclusion: use of paclitaxel and RT should be undertaken with caution
* MD Anderson; 2004 PMID 15547180 -- "Clinically relevant pneumonitis after sequential paclitaxel-based chemotherapy and radiotherapy in breast cancer patients." (Yu TK, J Natl Cancer Inst. 2004 Nov 17;96(22):1676-81.)
** Retrospective. 189 BCA patients enrolled in Phase III trial of T-FAC vs FAC. Clinically relevant radiation pneumonitis scored blindly
** Outcome: Pneumonitis rate paclitaxel-FAC 5% vs. FAC 4% (NS). Radiographic changes 39% vs. 24% (SS)
** Conclusion: Patients treated with sequential paclitaxel, FAC and RT have very low rate of clinically relevant radiation pneumonitis
* Providence Holy Cross, California; 2003 PMID 12603378 -- "Breast-conserving therapy with adjuvant paclitaxel and radiation therapy: feasibility of concurrent treatment." (Ellerbroek N, Breast J. 2003 Mar-Apr;9(2):74-8.)
** Retrospective. 24 patients. Chemo AC x4 cycles followed by concurrent paclitaxel 175 mg/m2 Q3W with RT. SCV field in 62%
** Outcome: No cases of pneumonitis
** Conclusion: Concurrent treatment was well tolerated
* New York University; 2003 PMID 12610186 -- "Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial." (Formenti SC, J Clin Oncol. 2003 Mar 1;21(5):864-70.)
** Prospective. 44 patients, Stage IIB-III LABC. Neoadjuvant paclitaxel 30 mg/m2 BIW + concurrent RT 45/25, followed by MRM
** Toxicity: Desquamation 7%, hypersensitivity 2%, stomatitis 2%. No pneumonitis reported
** Conclusion: Twice-weekly paclitaxel and concurrent RT is feasible and effective
* William Beaumont; 2002 (1998–1999) PMID 12047471 -- "Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy." (Hanna YM, Breast J. 2002 May-Jun;8(3):149-53.)
** Retrospective. 20 patients, concurrent paclitaxel 175 mg/m2 Q3W and RT
** Outcome: Radiation pneumonitis 20% (PMRT 17%, BCT 33%)
** Conclusion: Concurrent RT and paclitaxel should be approached cautiously

### Images

* New England Journal of Medicine, Images in Clinical Medicine 2009