Chemotherapy + Radiation Therapy for Brain Cancer

Recruiting at 150 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Disqualifiers: Metastatic disease, Pregnant, Breastfeeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 16

160 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the best approach to combine chemotherapy and radiation therapy (RT) based on the patient's response to induction chemotherapy in patients with non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose chemotherapy followed by conventional RT in patients who did not respond to induction chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to chemotherapy before receiving radiation therapy, are more likely to be free of the disease for a longer time than are patients for whom the chemotherapy does not efficiently eliminate or reduce the size of the tumor. The purpose of this study is to see how well the tumors respond to induction chemotherapy to decide what treatment to give next. Some patients will be given RT to the spine and a portion of the brain. Others will be given high dose chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving treatment based on the response to induction chemotherapy may lower the side effects of radiation in some patients and adjust the therapy to a more efficient one for other patients with localized NGGCT.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor to get specific guidance based on your situation.

What data supports the effectiveness of the treatment involving chemotherapy and radiation therapy for brain cancer?

Research on similar treatments for lung cancer shows that combining chemotherapy drugs like carboplatin and etoposide with radiation therapy can improve local control and survival rates compared to using radiation alone. These findings suggest that a similar approach might be effective for brain cancer, although specific studies on brain cancer are needed to confirm this. ^{1 2 3 4 5}

Is the combination of chemotherapy and radiation therapy generally safe for humans?

Research shows that combining chemotherapy drugs like carboplatin, etoposide, and ifosfamide with radiation therapy has been studied in various cancers, including lung and brain cancers. While these treatments can be effective, they may cause side effects such as myelosuppression (a decrease in bone marrow activity), neutropenia (low white blood cell count), and mild to moderate esophagitis (inflammation of the esophagus). Overall, the safety profile is considered acceptable, but side effects can vary depending on the specific drugs and doses used. ^{2 3 6 7 8}

How is the chemotherapy and radiation therapy treatment for brain cancer different from other treatments?

This treatment combines chemotherapy drugs like carboplatin, etoposide, ifosfamide, and thiotepa with various forms of radiation therapy, offering a multimodal approach that targets brain cancer more aggressively than standard treatments. It is unique because it uses a combination of drugs and radiation techniques to potentially improve outcomes for patients with poor prognosis brain tumors, although it may come with severe side effects. ^{9 10 11 12 13}

Research Team

Shannon M MacDonald

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and young adults aged 3 to less than 30 with a localized brain tumor called NGGCT, without prior tumor-directed therapy other than surgery or steroids. Participants must have specific blood counts, organ function, no metastatic disease, not be pregnant or breastfeeding, and agree to use contraception if sexually active.

Inclusion Criteria

I have had a test for cancer markers in my spinal fluid.

My platelet count is at least 100,000 without needing a transfusion.

I have a specific brain tumor with certain marker levels.

Exclusion Criteria

My tumor is a mature teratoma with normal marker levels.

Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards Lactating females who plan to breastfeed their infants Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

My tumor is not in the brain's ventricles but in areas like the basal ganglia or thalamus.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive carboplatin, etoposide, and ifosfamide over multiple cycles to assess tumor response

18 weeks

6 cycles, each 21 days apart

Response Evaluation and Treatment Assignment

Patients are evaluated for response to induction chemotherapy and assigned to either WVSCI or HDCSCR based on response

1-2 weeks

Plan A: WVSCI Therapy

Patients undergo whole ventricular and spinal canal irradiation if they achieve a complete or partial response

6 weeks

5 days per week

Plan B: Consolidation Therapy (HDCSCR)

Patients receive high-dose chemotherapy with peripheral stem cell rescue followed by radiation therapy

6-8 weeks

5 days per week

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Treatment Details

Interventions

• Carboplatin
• Etoposide
• Ifosfamide
• Radiation Therapy
• Thiotepa

Trial Overview The study tests how well chemotherapy combined with radiation therapy works based on the patient's response to initial chemotherapy. It aims to optimize treatment by either adjusting radiation levels or using higher dose chemo followed by stem cell transplant before conventional radiation.

Participant Groups

Group I: Plan B (chemotherapy, HDCSCR, second-look surgery if needed) Experimental Treatment 13 Interventions

See Outline in Detailed Description.

Group II: Plan A (chemotherapy, WVSCI, second-look surgery if needed) Experimental Treatment 11 Interventions

See Outline in Detailed Description.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Combined treatment of radiotherapy with cisplatin and etoposide has shown significant improvements in local control and survival rates for patients with locally advanced non-small cell lung cancer (NSCLC), with median survival rates reported between 15-18 months and 2-year survival rates around 35-40%.

Recent advancements in radiation technology and the use of third-generation chemotherapy drugs have led to promising results, including median survival exceeding 20 months, although careful management of treatment to minimize toxicity, particularly esophageal toxicity, remains crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and chemotherapy in locally advanced non-small cell lung cancer: preclinical and early clinical data. Reboul, FL.[2019]

In a phase II trial involving 67 patients with limited small-cell lung cancer, the combination of cisplatin, ifosfamide, and oral etoposide (PIEo) with accelerated hyperfractionated thoracic radiation resulted in a high overall response rate of 78%, with a median overall survival of 23.7 months.

While PIEo showed similar survival rates to conventional treatments, it was associated with significant acute toxicities, including severe granulocytopenia in 55% of patients and esophagitis in 43%, indicating a need for careful management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12. Glisson, B., Scott, C., Komaki, R., et al.[2018]

In a study of 43 patients with inoperable non-small cell lung cancer (NSCLC), the combination of carboplatin, ifosfamide, and etoposide resulted in a 40% objective response rate, indicating potential efficacy for this treatment regimen.

The treatment was generally well-tolerated, with myelosuppression being the main dose-limiting side effect, while serious issues like nephrotoxicity and neurotoxicity were not observed, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding studies with carboplatin, ifosfamide, etoposide, and mesna in non-small cell lung cancer. van Zandwijk, N., ten Bokkel Huinink, WW., Wanders, J., et al.[2018]

The modified triplet regimen of paclitaxel/ifosfamide/platinum (TIP) demonstrated a significantly higher response rate (52.7%) compared to the doublet regimen of paclitaxel/platinum (TP) (36.4%) in patients with recurrent or persistent cervical cancer, indicating its potential efficacy.

Despite the higher response rate, the median overall survival and progression-free survival were similar between the TIP and TP groups, suggesting that while TIP may be more effective in terms of response, it does not lead to longer survival times, and it does not increase the risk of severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to Combination Chemotherapy With Paclitaxel/Ifosfamide/Platinum Versus Paclitaxel/Platinum for Patients With Metastatic, Recurrent, or Persistent Carcinoma of the Uterine Cervix: A Retrospective Analysis. Choi, HJ., Paik, ES., Choi, CH., et al.[2019]

In a pilot trial involving 23 patients with inoperable Stage IIIa and IIIb non-small cell lung cancer (NSCLC), 78% of patients achieved objective responses to the concurrent chemoradiation therapy, indicating promising efficacy of the treatment regimen.

After a minimum follow-up of 5 years, 22% of patients were alive and disease-free, suggesting that intensive concurrent chemoradiation therapy can lead to long-term survival in some patients with advanced NSCLC, comparable to outcomes from multimodality treatments including surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot trial of hyperfractionated thoracic radiation therapy with concurrent cisplatin and oral etoposide for locally advanced inoperable non-small-cell lung cancer: a 5-year follow-up report. Lee, JS., Komaki, R., Fossella, FV., et al.[2019]

In a phase II study involving 79 patients with malignant glioma, accelerated hyperfractionated radiation therapy combined with carboplatin and etoposide showed median survival times of 14 months, with significant differences between glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) patients.

Despite being feasible and exhibiting low toxicity (only 6% experienced grade 3 leukopenia and 8% grade 3 thrombocytopenia), this treatment regimen did not improve survival or progression-free survival compared to existing therapies, indicating it is not suitable for further phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent accelerated hyperfractionated radiation therapy and carboplatin/etoposide in patients with malignant glioma: long-term results of a phase II study. Jeremic, B., Shibamoto, Y., Grujicic, D., et al.[2019]

In a study of 25 patients with newly diagnosed embryonal CNS tumors, preirradiation treatment with carboplatin and etoposide resulted in a 48% overall response rate, with 53% response in patients with high-risk medulloblastoma.

The treatment was associated with significant hematologic toxicity, particularly grade IV neutropenia, but had lower rates of ototoxicity compared to cisplatin, suggesting a potential benefit in terms of safety despite a higher progression rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. Heideman, RL., Kovnar, EH., Kellie, SJ., et al.[2017]

In a pilot study of 40 patients with limited-stage small-cell lung carcinoma, concurrent chemotherapy with cisplatin and etoposide alongside radiotherapy resulted in a high complete response rate, with 23 patients showing complete remission.

The median survival for all patients was 18 months, and five patients survived over 2 years without therapy, indicating promising long-term outcomes and acceptable toxicity levels, primarily neutropenia and mild to moderate radiation-related effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent chemotherapy and radiotherapy for limited small-cell carcinoma of the lung: a Southwest Oncology Group Study. McCracken, JD., Janaki, LM., Taylor, SB., et al.[2018]

In a study of 17 patients aged 2 to 25 years with unfavorable brain tumors, a combined treatment of chemotherapy and radiotherapy led to a median overall survival of 36 months, with 9 patients still alive at a median follow-up of 25 months.

While the treatment showed promise with 4 complete remissions and 2 partial remissions, it also resulted in severe toxicity, including one therapy-related death, highlighting the need for careful management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults. Urban, C., Benesch, M., Pakisch, B., et al.[2019]

The review discusses various treatment options for newly diagnosed and recurrent brain metastases, including whole-brain radiotherapy, radiosurgery, and chemotherapy, highlighting the importance of tailoring treatments to specific patient prognostic subgroups.

Emerging therapies, such as new radiosensitizers and cytotoxic agents, are being explored to improve local control and survival rates while managing the risk of late neurotoxicity associated with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and chemotherapy of brain metastases. Soffietti, R., Costanza, A., Laguzzi, E., et al.[2018]

In a study of 20 patients with brain metastases from non-small cell lung cancer (NSCLC), the combination of whole brain irradiation and chemotherapy (carboplatin and teniposide) resulted in significant neurological improvements, with 45% of patients achieving complete remission of symptoms.

The treatment was associated with mild toxicity and a median survival of 7 months, suggesting that aggressive treatment strategies may be beneficial even for patients with poor prognostic features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy plus carboplatin and teniposide in patients with brain metastases from non small cell lung cancer. Pronzato, P., Bruna, F., Neri, E., et al.[2013]

A treatment regimen combining thiotepa, topotecan, and carboplatin was administered to ten pediatric patients with recurrent central nervous system tumors, showing potential to consolidate remission in this challenging group.

Out of the ten patients, four are long-term survivors, particularly those with no evidence of disease at the time of stem cell rescue, suggesting that the extent of disease prior to treatment significantly influences outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system. Gilheeney, SW., Khakoo, Y., Souweidane, M., et al.[2013]

In a study of 107 patients with brain metastases from breast carcinoma (BC) and nonsmall cell lung carcinoma (NSCLC), the combination of cisplatin and etoposide showed significant efficacy, with a complete response rate of 13% for BC and 7% for NSCLC, and a combined response rate of 38% and 30% respectively.

The median survival for patients treated with this chemotherapy was 31 weeks for BC and 32 weeks for NSCLC, which is comparable to survival rates seen in patients with disseminated disease without brain involvement, suggesting this treatment could be a viable option for patients not suitable for surgery or radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Franciosi, V., Cocconi, G., Michiara, M., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Radiotherapy and chemotherapy in locally advanced non-small cell lung cancer: preclinical and early clinical data. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Dose-finding studies with carboplatin, ifosfamide, etoposide, and mesna in non-small cell lung cancer. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Response to Combination Chemotherapy With Paclitaxel/Ifosfamide/Platinum Versus Paclitaxel/Platinum for Patients With Metastatic, Recurrent, or Persistent Carcinoma of the Uterine Cervix: A Retrospective Analysis. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

A pilot trial of hyperfractionated thoracic radiation therapy with concurrent cisplatin and oral etoposide for locally advanced inoperable non-small-cell lung cancer: a 5-year follow-up report. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Concurrent accelerated hyperfractionated radiation therapy and carboplatin/etoposide in patients with malignant glioma: long-term results of a phase II study. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Concurrent chemotherapy and radiotherapy for limited small-cell carcinoma of the lung: a Southwest Oncology Group Study. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Radiotherapy and chemotherapy of brain metastases. [2018]

11. Greece pubmed.ncbi.nlm.nih.gov

Radiotherapy plus carboplatin and teniposide in patients with brain metastases from non small cell lung cancer. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system. [2013]

13. United States pubmed.ncbi.nlm.nih.gov

Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. [2013]