Reduction of Bone Marrow Suppression for Patients with Stage III NSCLC Treated by Protons and Chemotherapy Compared with IMRT and Chemotherapy

English

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 23 de mayo del 2008

Presenter: Ritsuko Komaki, MD
Presenter's Affiliation: M.D. Anderson Cancer Center
Type of Session: Scientific

Background

The concurrent use of chemoradiation is the standard of care for patients with stage III non-small cell lung cancer (NSCLC). Because of the toxicities associated with chemoradiation these patients are at increased risk for bone marrow suppression. The bone marrow of the thorax comprises approximately 25% of the total bone marrow. The largest proportion of the bone marrow in the thorax is comprised of the sternum and thoracic vertebral bodies.

Due to the size and location of NSCLCs it is often difficult to deliver adequate dose to the tumor while sparing osseus structures. Protons may allow for greater conformality around the tumor compared with IMRT plans which would spare more normal tissues, such as the bone marrow. This could limit hematologic toxicity and allow escalation of both radiation and chemotherapy doses.;

The present retrospective single institution study compared patients treated with concurrent chemotherapy and photon based therapy with those treated with concurrent chemotherapy and protons.

Materials and Methods

From January 2003 to September 2007 106 patients met the eligibility criteria for the present study. There were a total of 31 patients in the proton beam radiation group and 75 patients in the IMRT group.

Eligibility Criteria:

All patients had to have histologically confirmed, locally advanced, non-small cell lung cancer. All patients had to be treated with concurrent chemotherapy, have had no prior thoracic radiation therapy, and have had received a total dose of greater than or equal to 60 cobalt gray equivalents (CGE). Patients who were treated with a combination of protons and photons, such as IMRT or 3D conformal radiation with protons, were excluded form this study. Additionally, patients treated with both 3D conformal radiation and IMRT were excluded from this study. After 2004 all patients had radiation planning performed using 4D CT.

Toxicity:

The Common Terminology Criteria (CTC) for adverse events (version 3.0) was used to grade toxicity in patients. All patients had hemoglobin, platelet, lymphocyte, and white blood cell counts draw prior to and after treatment. The grade of fatigue was also assessed in both groups of patients before and after treatment.

Chemotherapy: There were various regimens used in this study but the majority of patients received carboplatin and taxol with approximately 60% of patients in both arms receiving this regimen.

Results

The demographics and chemotherapy for the two treatment arms were similar. There was no significant difference between the two arms in the pretreatment hemoglobin, platelet, lymphocyte, and white blood cell counts. The majority of patients had stage III disease, however, some patients with stage IIB and well controlled Stage IV disease were included in this study.

Median Follow up: For the proton group the median follow up was 9.5 months as compared to 9.8 months for the IMRT group

Functional Status: The median KPS for both groups was 80.

Median gross tumor volume (GTV): The median GTV for the IMRT group was 247.7 cc as compared to the proton group where the median GTV was 93.6.

Median Dose: The median dose delivered was 74 cobalt Gray equivalents (CGE) for the proton group (range 63-74) and 63 Gy for the IMRT group (range 60-76).

Toxicity (Not controlled for volume of tumor):

Hemoglobin: There was a significant decrease in hemoglobin toxicity between the proton and IMRT groups when all grades of toxicity were compared (p=0.003). However, when the comparison was limited to grade 2 or greater hemoglobin toxicity between the two groups, there was not a significant difference (p=0.25).

Platelets: There was no significant difference between the two groups with regard to platelet toxicity when they compared all grades of toxicity (p=0.31) as well as when they limited the analysis to grade 2 toxicity or greater (p=0.45).

Neutrophils: There was no difference in neutrophil toxicity when all grades of toxicity were compared between the two groups (p=0.14). However, when this analysis was limited to Grade 2 or higher toxicity there was a significantly lower rate of toxicity in the proton group (p=0.009).

Fatigue: There was significantly less fatigue in patients treated with protons when all grade of fatigued were compared (p=0.04) as well as when the analysis was limited to grade 2 or greater fatigue (p<0.001).

Toxicity (volume based): Comparison of toxicities between patients treated with concurrent chemotherapy with protons versus those treated with concurrent chemotherapy and IMRT based on GTV:

Tumor Volume (cc)	Lymphocytes	Neutrophils	Hemoglobin	Platelets
≤100	0.24	NS	NS	0.06
≤200	0.03	NS	NS	0.007
≤300	0.002	NS	NS	0.006
≤400	0.001	NS	NS	0.002
≤500	0.002	NS	NS	0.004

Author's Conclusions

1) Limitations: This is a retrospective study and detailed information regarding the use of transfusions and growth factor was not available. Additionally, detailed information regarding chemotherapy treatment breaks and dose reduction data was not available.

2) Patients treated with chemotherapy and concurrent proton beam therapy had decreased toxicity when compared with IMRT:

a. Decreased all grades of fatigue as well as grade 2 or higher fatigue
b. Decreased all grades of hemoglobin toxicity
c. Decreased grade 2 or higher neutrophil toxicity
d. Breaking down toxicity by tumor volume demonstrated decreased lymphocyte and platelet toxicity with proton therapy

3) The results of this study have served as the basis for a prospective trial which is currently accruing at MD Anderson comparing the use of concurrent proton/chemotherapy with IMRT/chemotherapy in patients with stage III lung cancer. The target goal for accrual in 168 patients.

Clinical/Scientific Implications

Due to the toxicities associated with concurrent chemoradiation there are limitations regarding both the dose of chemotherapy and radiation that can be used concurrently. Sequential use of chemotherapy and radiation allows for higher dosing but appears to be less effective than the concurrent use of these modalities. Myelosupression is a toxicity that is associated with both radiation and chemotherapy. The present study suggests that the greater conformality that is possible with proton therapy compared with IMRT may decrease myelotoxicity. However, the target volumes treated with protons in this study are somewhat smaller than the volumes treated with IMRT, which could impact the results. Distant disease is a major problem in advanced lung cancers and by limiting the myelosupression associated with radiation it may be possible to decrease the number of patients who require a break from chemotherapy or a dose reduction. It may be possible to escalate the concurrent dose of chemotherapy or allow other agents (such as biologicals) to be added to the chemoradiation, which could potentially improve outcomes.

However, it is important to note that this study was retrospective and examined a small number of patients. There are a number of potential biases which could have been associated with the selection of the radiation modality used in these patients as demonstrated by the large disparity in the size of the GTV’s in the proton versus the IMRT groups. While they did stratify patients by GTV, the number of patients in each of these categories was fairly small. However, this study does suggest that there is a reduction in hematologic toxicities in patients treated with proton therapy compared with photon therapy and this has served as the basis for a prospective study which is ongoing at MD Anderson. Pneumonitis is another important toxicity that could potentially be decreased with the use of protons and this is discussed in another session.