Abstract
Background:
Brain metastasis is the most common intracranial tumor in adults. Addition of boost dose to brain metastases with stereotactic radiosurgery following whole brain radiation therapy with concurrent temozolomide showed improved outcomes; hence, the current study aimed at evaluating toxicity, efficacy, and quality of life (QOL) of addition of intensity-modulated radiation therapy (IMRT) boost to whole brain radiation therapy (WBRT) and concurrent temozolomide (TMZ) in patients with newly diagnosed brain metastases.Methods:
Twenty patients with known primary histology, newly diagnosed brain metastases, underwent recursive partitioning analysis (RPA) class I/II, and fulfilling eligibility criteria were enrolled in the current study. Patients who initially received WBRT with concurrent TMZ were randomly assigned to receive IMRT boost to an additional 20 Gray (group A) or no further treatment (group B). Serial evaluations of toxicity (hematologic and non-hematologic), response (clinical, neurologic, and radiologic), and QOL were performed at 3 months and 6 months after the completion of Radiotherapy. The 2 groups were compared for toxicity, response, and QOL by appropriate statistical tests.Results:
At the median follow-up of 5 months, patients in group A demonstrated similar toxicity, superior response, and better QOL in 3 domains (physical functioning, role functioning, and global health status).Conclusions:
Addition of IMRT boost to WBRT and TMZ provided superior response and better QOL, without additional toxicity, compared with WBRT alone.Keywords
1. Background
Brain metastasis is the most common intracranial tumor in adults. In the Caucasian population, approximately 100,000 patients have symptomatic intracranial metastases annually; a number that is 6 times more than the 17,000 patients with malignant primary brain tumors (1).
About 20% to 40% of patients with cancer develop metastatic cancer to the brain during the course of their illness and even sometimes they present with brain secondaries (2). The clinical series of brain metastasis are reported 5% to 15% and on autopsy it is in the range of 14% to 63% (2).
The primary sites of the development of brain secondaries include carcinoma of lung, breast, kidney, prostate, melanoma, and in younger patients, osteosarcoma and rhabdomyosarcoma (3).
Many patients have no or minimal symptoms of tumor, and their metastases are found during a routine medical evaluation. If there are symptoms, they depend on the site involved. Brain metastases may cause headache, dizziness, blurred vision, nausea, or other symptoms related to the nervous system. Symptoms usually evolve over a few weeks. However, hemorrhage into the metastases can cause more dramatic presentation such as propensity to bleed, which is commonly observed with tumors such as malignant melanoma, thyroid carcinoma, renal cell carcinoma, and choriocarcinoma (4).
Management consists of symptomatic care and definitive treatment. Symptomatic management with corticosteroids can result in significant improvement in quality of life (QOL) for patients with brain metastasis, alongside proper management guideline for the primary site. Definitive treatment of brain metastases is external-beam radiation therapy delivered to the whole brain; 30 Gy administered in 10 fractions is the standard of care due to its tolerability, brief treatment course, cost-effectiveness, and trend of improved survival (5).
In the study by David W. Andrews et al., patients with brain metastasis were treated with whole brain radiation therapy (WBRT) with a boost for metastasis. Results showed that prescription of higher radiation doses was not associated with a greater incidence of toxicities; instead it showed statistically significant improvement in Karnofsky performance status (KPS) and decreased steroid use at 6 months in the stereotactic radiation boost treatment group.
Recent phase II trial data suggested that temozolomide (TMZ) was safe, and significantly improved the response rate when administered in combination with radiation therapy in patients with previously untreated brain metastases. The study by Antonadou D. suggested that concomitant treatment of solid tumors with WBRT and TMZ improves the QOL (6).
Hence, the current study aimed at evaluating the outcomes with respect to radiological response, QOL, and toxicities by giving the increased dose to metastases, using intensity-modulated radiation therapy (IMRT) technique along with WBRT and concurrent TMZ.
2. Methods
2.1. Inclusion Criteria
The study protocol and consent procedures were approved by the medical ethics review board. Inclusion criteria were patients aged 18 to 70 years with KPS ≥ 70, histological diagnosis of a systemic tumor and radiological evidence of brain metastases, no history of undergoing metastasectomy, radiosurgery, and chemotherapy 3 weeks prior to the study and prior to cranial radiotherapy.
After signing the informed consent, patients were randomly assigned to WBRT with IMRT boost to metastases (group A) and WBRT alone (group B) combined with chemotherapy in both of the groups.
2.2. Radiation Treatment
For the WBRT, entire brain parenchyma and meningeal reflections were treated. IMRT boost was given to the brain metastases and minimal normal brain tissue. Clinical target volume (CTV) consisted of all visualized tumor. A 2-mm margin is normally added to create a PTV, and it is reduced to 1 mm if close to any critical organs. Critical structures included bilateral eyes and optic nerves, optic chiasm, brainstem, as well as uninvolved brain. A dose of 40 Gy in 20 fractions for the WBRT and 20 Gy in 10 fractions for IMRT boost to metastatic sites were delivered 5 days a week.
2.3. Chemotherapy
Oral tablet of TMZ 75 mg/m2 was given to patients 5 days a week in both groups half an hour before radiation therapy under fasting condition. All patients received prophylactic antiemetic oral ondansetron tablet before TMZ.
2.4. Radiological Response Assessment
All patients underwent computed tomography (CT) scan /magnetic resonance imaging (MRI) of brain 3 months and 6 months after completion of chemoradiation therapy for the radiological response assessment. Disease evaluation was done and recorded by assessing objective regression in the form of dimension of the lesions, based on RECIST (response evaluation criteria in solid tumors).
2.5. Quality of Life
EORTC QLQ (the European organization for research and treatment of cancer quality of life questionnaire) C30, translated into Kannada (local language), was used with the permission of competitive authorities. This questionnaire was filled by the patients of both groups before starting and 3 months after completion of chemoradiation therapy to compare changes in their QOL.
2.6. Toxicity
Hematological (total leucocyte count, absolute neutrophil count, platelet count, serum bilirubin, and liver enzymes) and gastrointestinal (nausea and vomiting) toxicities were recorded in accordance with the CTCAE (common terminology criteria for adverse events) version 4.3 during the treatment.
2.7. Follow-Up
Patients were on follow-up till 6 months post-chemoradiation therapy.
3. Results
3.1. Statistical Methods
Data analysis was conducted by R software, version 3.0.2. A P value < 0.05 was considered as level of significance.
Characteristics of Patient and Tumors
| Variable | Group A | Group B | P value | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Total | 10 | 100 | 10 | 100 | |
| Age, y | 0.478 | ||||
| 18 - 30 | 1 | 10 | 1 | 10 | |
| 31 - 40 | 3 | 30 | 0 | 0 | |
| 41 - 50 | 4 | 40 | 5 | 50 | |
| 51 - 60 | 1 | 10 | 1 | 10 | |
| 61 - 70 | 1 | 10 | 3 | 30 | |
| Gender | |||||
| Male | 6 | 60 | 5 | 50 | |
| Female | 4 | 40 | 5 | 50 | |
| KPS | 0.154 | ||||
| 70 | 5 | 50 | 6 | 60 | |
| 80 | 4 | 40 | 4 | 40 | |
| 90 | 1 | 10 | 0 | 0 | |
| Neurological deficit | |||||
| Yes | 2 | 20 | 3 | 30 | |
| No | 8 | 80 | 7 | 70 | |
| Site of primary tumor | 1 | ||||
| Lung | 3 | 30 | 5 | 50 | |
| Breast | 6 | 60 | 5 | 50 | |
| Sigmoid colon | 1 | 10 | 0 | 0 | |
| BSA | |||||
| < 1.4 | 3 | 30 | 2 | 20 | 0.776 |
| 1.4 - 1.5 | 7 | 70 | 4 | 40 | |
| > 1.5 | 0 | 0 | 4 | 40 | |
| No. of brain metastases | |||||
| 1 | 5 | 50 | 1 | 10 | |
| 2 | 2 | 20 | 0 | 0 | |
| 3 | 3 | 30 | 3 | 30 | |
| 4 | 0 | 0 | 6 | 60 | |
| Mean ± SD | 1.8 ± 0.918 | 3.4 ± 0.966 | |||
Radiological Response Assessment
| Radiological Response | Group A | Group B | P Value | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Total | 10 | 100 | 10 | 100 | |
| After 3 months | |||||
| Progressive disease | 1 | 10 | 3 | 30 | 0.49 |
| Stable disease | 2 | 20 | 1 | 10 | |
| Partial Response | 7 | 70 | 6 | 60 | |
| After 6 months | |||||
| Partial response | 6 | 60 | 5 | 50 | 0.45 |
| Complete response | 1 | 10 | 0 | 0 | |
Survivala
| Survival at 6 Months | Group A | Group B | ||
|---|---|---|---|---|
| No. | % | No. | % | |
| Total | 10 | 100 | 10 | 100 |
| Alive | 5 | 50 | 2 | 20 |
| Dead | 5 | 50 | 8 | 80 |
Leucopeniaa
| Leucopenia | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 10 | 0 | 0 | 10 | 0 | 0 |
| Week 2 | 9 | 1 | 0 | 10 | 0 | 0 |
| Week 3 | 8 | 2 | 0 | 7 | 3 | 0 |
| Week 4 | 5 | 5 | 0 | 5 | 5 | 0 |
| Week 5 | 3 | 6 | 1 | 1 | 8 | 1 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 6 | 2 | 2 | |||
| Week 8 | 4 | 6 | 0 | |||
Neutropeniaa
| Neutropenia | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 10 | 0 | 0 | 9 | 1 | 0 |
| Week 2 | 9 | 1 | 0 | 9 | 1 | 0 |
| Week 3 | 8 | 2 | 0 | 9 | 1 | 0 |
| Week 4 | 5 | 5 | 0 | 4 | 6 | 0 |
| Week 5 | 2 | 8 | 0 | 1 | 7 | 2 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 6 | 4 | 0 | |||
| Week 8 | 4 | 6 | 0 | |||
Thrombocytopeniaa
| Thrombocytopenia | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 10 | 0 | 0 | 10 | 0 | 0 |
| Week 2 | 9 | 1 | 0 | 8 | 2 | 0 |
| Week 3 | 8 | 2 | 0 | 9 | 1 | 0 |
| Week 4 | 5 | 5 | 0 | 4 | 6 | 0 |
| Week 5 | 3 | 5 | 2 | 1 | 7 | 2 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 6 | 2 | 2 | |||
| Week 8 | 4 | 6 | 0 | |||
Elevated Bilirubin Levela
| Bilirubin | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 9 | 1 | 0 | 10 | 0 | 0 |
| Week 2 | 8 | 2 | 0 | 10 | 0 | 0 |
| Week 3 | 8 | 2 | 0 | 4 | 5 | 0 |
| Week 4 | 7 | 3 | 0 | 5 | 4 | 0 |
| Week 5 | 7 | 3 | 0 | 4 | 4 | 2 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 6 | 2 | 2 | |||
| Week 8 | 4 | 6 | 0 | |||
Elevated Aspartate Transaminasea
| AST | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 9 | 1 | 0 | 10 | 0 | 0 |
| Week 2 | 8 | 2 | 0 | 10 | 0 | 0 |
| Week 3 | 8 | 2 | 0 | 4 | 5 | 1 |
| Week 4 | 7 | 3 | 0 | 5 | 4 | 1 |
| Week 5 | 7 | 3 | 0 | 4 | 4 | 2 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 8 | 2 | 0 | |||
| Week 8 | 8 | 2 | 0 | |||
Nauseaa
| Nausea | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 7 | 3 | 0 | 10 | 0 | 0 |
| Week 2 | 10 | 0 | 0 | 10 | 0 | 0 |
| Week 3 | 9 | 1 | 0 | 7 | 2 | 1 |
| Week 4 | 5 | 4 | 1 | 8 | 2 | 0 |
| Week 5 | 7 | 2 | 1 | 5 | 5 | 0 |
| Week 6 | 9 | 1 | 0 | |||
| Week 7 | 3 | 5 | 2 | |||
| Week 8 | 2 | 6 | 2 | |||
Vomitinga
| Vomiting | Group A | Group B | ||||
|---|---|---|---|---|---|---|
| Grade 0 | Grade 1 | Grade 2 | Grade 0 | Grade 1 | Grade 2 | |
| Week 1 | 9 | 1 | 0 | 10 | 0 | 0 |
| Week 2 | 5 | 5 | 0 | 10 | 0 | 0 |
| Week 3 | 5 | 5 | 0 | 7 | 2 | 1 |
| Week 4 | 2 | 6 | 2 | 8 | 2 | 0 |
| Week 5 | 4 | 6 | 0 | 5 | 5 | 0 |
| Week 6 | 10 | 0 | 0 | |||
| Week 7 | 3 | 7 | 0 | |||
| Week 8 | 2 | 6 | 2 | |||
Analysis of EORTC QLQ-C30 in Group A (Pre-RT v/s Post-RT)
| Question No. | P Value | Comment |
|---|---|---|
| 1. | 0.006 | Patients could better perform strenuous activities after RT. |
| 2. | 0.006 | Patients could better walk long distances after RT. |
| 3. | 0.004 | Patients could better walk short distances after RT. |
| 4. | 0.003 | Patients could better stay awake after RT. |
| 5. | 0.004 | Patients could better eat, dress, and wash themselves after RT. |
| 6. | 0.004 | Patients could better perform daily activities after RT. |
| 7. | 0.003 | Patients could better perform hobbies after RT. |
| 8. | 0.23 | Shortness of breath among patients showed no statistical improvement, compared with pre-RT. |
| 9. | 0.007 | Patients’ pain improved after RT. |
| 10. | 0.004 | Patients needed less rest after RT. |
| 11. | 0.004 | Patients could better sleep better RT. |
| 12. | 0.004 | Patients felt less weak after RT. |
| 13. | 0.016 | Patients appetite improved after RT. |
| 14. | 0.030 | Patient felt less nauseated after RT. |
| 15. | 0.026 | Patients had no complaint about vomiting after RT. |
| 16. | 0.007 | Patients had no complaint about constipation after RT. |
| 17. | 0.059 | No statistical significant difference was observed in diarrhea episodes of the patients before and after RT. |
| 18. | 0.007 | Patients felt less tired after RT. |
| 19. | 0.004 | There was no interference of pain in work after RT. |
| 20. | 0.006 | Patients’ concentration improved after RT. |
| 21. | 0.008 | Patients’ tension was less after RT. |
| 22. | 0.025 | Patient was less worried after RT. |
| 23. | 0.009 | Patient was less irritable after RT. |
| 24. | 0.020 | Patient had no depression after RT. |
| 25. | 0.149 | There was no statistical significant difference in remembering things, compared with before RT. |
| 26. | 0.301 | There was no statistical significance in family life. |
| 27. | 0.059 | Patient felt better about social activities after RT. |
| 28. | 0.007 | Financial status was exacerbated after RT. |
| 29. | 0.004 | General health status was improved after RT. |
| 30. | 0.004 | Quality of life was improved after RT. |
Analysis of EORTC QLQ-C30 of Group B (Pre-RT v/s Post- RT)
| Question No. | P Value | Comment |
|---|---|---|
| 1. | 0.014 | Patients could better perform strenuous activities after RT. |
| 2. | 0.008 | Patients could better walk long distances after RT. |
| 3. | 0.034 | Patients could better walk short distances after RT. |
| 4. | 0.008 | Patients could better stay awake after RT. |
| 5. | 0.010 | Patients could better eat, dress, and wash themselves after RT. |
| 6. | 0.038 | Patients could better perform daily activities after RT. |
| 7. | 0.020 | Patients could better perform hobbies after RT. |
| 8. | 0.038 | Shortness of breath improved after RT. |
| 9. | 0.026 | Patients’ pain improved after RT. |
| 10. | 0.004 | Patients needed less rest after RT. |
| 11. | 0.010 | Patients could better sleep after RT. |
| 12. | 0.023 | Patients felt less weak after RT. |
| 13. | 0.008 | Patients appetite improved after RT. |
| 14. | 0.011 | Patient felt less nauseated after RT. |
| 15. | 0.010 | Patients had no complaint about vomiting after RT. |
| 16 | 0.023 | Patients had no complaint about constipation after RT. |
| 17. | 0.157 | No statistical significant difference was observed regarding diarrhea episodes in patients before and after RT. |
| 18. | 0.010 | Patients felt less tired after RT. |
| 19. | 0.004 | There was no interference of pain in work after RT. |
| 20. | 0.008 | Patients’ concentration improved after RT. |
| 21. | 0.026 | Patients’ tension was less after RT. |
| 22. | 0.004 | Patient less worried after RT. |
| 23. | 0.011 | Patient were less irritable after RT. |
| 24. | 0.004 | Patient had no depression after RT. |
| 25. | 0.030 | There was no statistical significant difference in remembering things, compared with before RT. |
| 26. | 0.026 | There was no statistical significance in family life. |
| 27. | 0.023 | Patient had better feelings in social activities after RT. |
| 28. | 0.492 | Financial status did not change after RT. |
| 29. | 0.058 | General health did not change and no statistical significant difference was noted. |
| 30. | 0.006 | Quality of life was slightly exacerbated, compared with before RT. |
Analysis of EORTC QLQ-C30 of Group A v/s Group B
| Question No. | P Value | Result |
|---|---|---|
| 1. | 0.080 | No statistical difference between the groups. |
| 2. | 0.051 | No statistical difference between the groups. |
| 3. | 0.004 | Group A > group B |
| 4. | 0.005 | Group A > group B |
| 5. | 0.077 | No statistical difference between the groups. |
| 6. | 0.004 | Group A > group B |
| 7. | 0.000 | Group A > group B |
| 8. | 0.785 | No statistical difference between the groups. |
| 9. | 0.258 | No statistical difference between the groups. |
| 10. | 0.749 | No statistical difference between the groups. |
| 11. | 0.132 | No statistical difference between the groups. |
| 12. | 0.094 | No statistical difference between the groups. |
| 13. | 0.487 | No statistical difference between the groups. |
| 14. | 0.295 | No statistical difference between the groups. |
| 15. | 0.512 | No statistical difference between the groups. |
| 16. | 0.749 | No statistical difference between the groups. |
| 17. | 0.268 | No statistical difference between the groups. |
| 18. | 0.216 | No statistical difference between the groups. |
| 19. | 1 | No statistical difference between the groups. |
| 20. | 0.207 | No statistical difference between the groups. |
| 21. | 0.251 | No statistical difference between the groups. |
| 22. | 0.512 | No statistical difference between the groups. |
| 23. | 0.346 | No statistical difference between the groups. |
| 24. | 0.160 | No statistical difference between the groups. |
| 25. | 0.719 | No statistical difference between the groups. |
| 26. | 0.386 | No statistical difference between the groups. |
| 27. | 0.673 | No statistical difference between the groups. |
| 28. | 0.001 | Group A > group B |
| 29. | 0.009 | Group A > group B |
| 30. | 0.001 | Group A > group B |
Results of group A were significantly better than those of group B in 3 different domains of EORTC QOL C-30 as physical functioning, role functioning, and global health status. Hence, QOL was better in group A than group B.
4. Discussion
The WBRT is given to the patients with brain metastasis to ensure that the radiation takes care of micro metastasis, which is otherwise unaddressed, and to control presenting neurological symptoms, which can be achieved in 70% to 90% of cases without causing acute neurological side effects. The current study observed neurological improvement of 70% in both groups. There was no difference in clinical neurological responses among patients in the 2 groups.
The intention of giving boost to the visible brain metastasis was to decrease the gross tumor burden, unaddressed with 40 Gy. Hence, boost of 20 Gy was given to brain metastasis with IMRT technique. Edwards et al. (7), gave IMRT boost to brain metastasis and their results indicated no acute toxicity or morbidity associated with the boost treatment, and it was an alternate modality of treatment where single-fraction stereotactic radiosurgery (SRS) boost was not available. In the current study, toxicities were within acceptable limits.
Radiological response between the 2 groups were analyzed. The current study observed that at the end of 3 months, 70% of patients had partial response, 20% had stable disease, and 1 patient had progressive disease in group A, as evaluated by CT/MRI brain examinations.
At 6 months, 60% of the patients had partial response and 10% had complete response in both the groups. It can be concluded that the response of metastatic tumor was in both groups, but favoring group A statistically.
References
-
1.
Posner JB. Neurologic Complications of Cancer. Philadelphia: Davis Company; 1995.
-
2.
Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst. 2003;95(17):1276-99. [PubMed ID: 12953083]. https://doi.org/10.1093/jnci/djg040.
-
3.
Cloughesy T, Selch MT, Liau L. Brain. Haskell CM: Cancer Treatment. 5th ed. Philadelphia: WB Saunders Co; 2001. p. 1106-42.
-
4.
Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer. 1983;52(12):2349-54. [PubMed ID: 6640506]. https://doi.org/10.1002/1097-0142(19831215)52:12<2349::AID-CNCR2820521231>3.0.CO;2-B.
-
5.
Murray KJ, Scott C, Greenberg HM, Emami B, Seider M, Vora NL, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys. 1997;39(3):571-4. [PubMed ID: 9336134]. https://doi.org/10.1016/S0360-3016(97)00341-6.
-
6.
Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20(17):3644-50. [PubMed ID: 12202665]. https://doi.org/10.1200/JCO.2002.04.140.
-
7.
Edwards AA, Keggin E, Plowman PN. The developing role for intensity-modulated radiation therapy (IMRT) in the non-surgical treatment of brain metastases. Br J Radiol. 2010;83(986):133-6. [PubMed ID: 20019176]. https://doi.org/10.1259/bjr/28596848.