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The German Multinational GPOH-HD 95 Trial: Treatment Results and Analysis of Failures in Pediatric Hodgkins Disease Using Combination Chemotherapy With and Without Radiation

Reviewer: John Wilson, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 11 de octubre del 2004

Presenter: Ruhl, Ursula
Presenter's Affiliation: Radiation Oncology, Moabit Hospital, Berlin, Germany
Type of Session: Plenary

Background

• Treatment results of pediatric Hodgkin's disease are excellent now and are difficult to improve with respect to tumor control and overall survival
• However, there have been concerns in the past about intensive treatments using chemotherapy and radiation causing late effects like impairment of vital organ function, male infertility, infections, and especially the induction of second malignancies
• Therefore, attempts have been made to reduce the intensity of treatment, including reducing and replacing chemotherapy, and decreasing radiation dose and volume
• Despite these restrictions, the results of the past five German trials have been very favorable, with overall survivals of 95% or higher
• It is still too early to tell if the incidence of second malignancies will go down as well
• The German GPOH HD 95 trial continued on this approach and reduced the radiation volume from standard involved fields to modified involved fields
• The standard radiation dose was decreased to 20 Gy, and in some cases, radiation was omitted completely

Materials and Methods

• Patients below 18 years of age were treated in 3 different treatment groups according to stage, B symptoms, and extranodal extension
• The low risk group (TG1) was defined as patients with clinical stage (CS) I and IIA
• The intermediate risk group (TG2) included CS IIAE, IIB, and IIIA patients
• The high risk group (TG3) included CS IIBE, IIIAE, IIIB, and IV patients
• The low risk group received two intensive cycles of chemotherapy, with girls receiving OPPA (Oncovin (vincristine), Procarbazine, Prednisone, and Adriamycin), and boys receiving OEPA (E stands for Etoposide which is replacing the Procarbazine, which is gonadotoxic)
• The intermediate risk group received the same 2 cycles of chemotherapy as the low risk group, but then received two cycles of COPP (Cyclophosphamide, Oncovin (vincristine), Procarbazine, and Prednisone)
• The highest risk group was treated with the same 2 cycles as the low risk group and then received 4 cycles of COPP
• Patients who had a complete remission, or more than 95% tumor volume reduction, and residual disease <=2ml, received no radiotherapy
• Those with a partial remission, defined as more than 75% tumor volume reduction, were treated with 20 Gy
• Areas that responded with less than 75% reduction were locally treated to 30 Gy
• Treatment fields were "modified involved fields" which included areas of nodal involvement determined by serial sectioning of CT and ultrasounds, and were meant to be smaller than standard "involved fields" which include an entire nodal region
• Residual disease of more than 50 ml received a 35 Gy local boost
• Central planning as well as all results of staging and restaging were reviewed at the trial coordination center in Berlin

Results

• Between 1995 and 2001, 1018 patients enrolled in the protocol, mostly from Germany, but also from Austria, Switzerland, the Netherlands, Sweden, Norway, and Denmark
• Chemotherapy induced a complete remission in 211 (21%) patients, all of whom received no radiotherapy
• 66% had a partial remission and 12% had a poor response
• 28% of the low risk group received no radiotherapy because of complete remission and only a few had a boost to 35 Gy, whereas in the intermediate and high risk groups CR was below 20% and they needed a local boost to 35 Gy in nearly 30%
• Median follow-up was 50 months
• At six years (almost 2 years longer than the median follow-up time), 915 pts (90%) were in complete continuous first remission and without other events
• there were 95 treatment failures: 38 patients with progressive disease and 57 with relapses after complete remission
• in the 57 relapses, 20 belonged to the group receiving no radiotherapy after complete remission (about 10%), and 38 to the group with partial remission and radiotherapy (less than 5%), so radiation decreased the recurrences in half in a more unfavorable group
• 31 patients had died, and overall survival for all patients is 97% at 6 years, with no difference in survival for patients receiving or not receiving RT (radiotherapy), and not a big difference whether the patients belonged to the low risk group or the high risk group, 99 vs 93%
• Disease free survival for the low risk group was similar if the patients received radiation or not, 97 vs 95%, p=non significant
• However, there was a remarkable difference in the advanced stages, TG2 and TG3, such that patients with a partial remission and radiotherapy did much better than those with a complete remission and no radiotherapy, with a highly significant difference in DFS of 92 vs 77%, p=0.006
• The significant risk factors of the trial were found to be: stage IV, B symptoms, extranodal extension, male gender, and nodular sclerosis type 2

Author's Conclusions

• The overall survival for patients with and without RT is identical because there are very potent salvage treatments
• The trial turned out to have favorable results, high cure rates, few treatment failures, and about 20% of the children were "spared radiotherapy and potential late effects from radiotherapy"
• Response adjusted low dose radiotherapy and reduced involved field treatment seems to be safe
• However the omission of radiotherapy is only safe for the low risk treatment group
• Further reduction of treatment intensity might be possible for some cases and intensified treatment might be necessary for others
• The effect on late sequelae and second cancers remains to be seen

Clinical/Scientific Implications

The appropriate dose of radiation still must be addressed.  Data from other studies suggest that a dose of 15-25 Gy provides excellent local control, and 30-35 Gy are no longer needed for involved field radiotherapy.  The German data confirm a published CCG trial, 9542, of risk adapted COPP-ABV (Cyclophosphamice, Oncovin, Procarbazine, Prednisone, Adriamycin, Bleomycin, and Vinblastine) chemotherapy.  In this CCG trial, those achieving a CR to chemotherapy were then randomized to receive or not receive 21 Gy involved field radiotherapy.  The CCG study actually showed the value of radiotherapy for the group as a whole, and in each individual risk group: low, intermediate, and high risk.  However, there were different definitions of low risk between the German and CCG studies.  The CCG included stage I and IIA patients like the German study, but excluded those with other adverse features such as hilar LAD, involvement of more than four nodal regions, mediastinal tumor greater than 1/3 the intrathoracic diameter, and nodal aggregate greater than 10cm, so therefore, the low risk criteria was more, not less stringent in the CCG compared to the GPOH study.  The CCG study also used slightly different chemotherapy, with COPP/ABV for the low and intermediate risk groups, and cytarabine and etoposide added on in the high risk group, so the GPOH study did not use vinblastine or cytarabine as the CCG study did.  Finally, the GPOH study assigned therapy, while CCG study was randomized, which gives the CCG study more credibility.  It may be that the CCG data reanalyzed using a different definition of low risk could show less of a difference with and without radiation.

The data for low risk patients are controversial regarding the need for radiation.  People at Stanford, Harvard, and St Jude have treated children with low risk Hodgkin's disease with four cycles of VAMP (Vinblastine, Adria, Methtrexate, and Prednisone) and response based involved field radiotherapy (15 Gy to CR and 25.5 Gy to PR after VAMP x 2), with a 5 yr EFS of 93% (J Clin Oncol. 2002 Jul 15;20(14):3051-3.)  In a new study at Stanford, they use PET + CT to assess response, and omit radiation in those who achieve a rapid, early complete response after 2 cycles of VAMP and give those with a PR 25.5 Gy involved field radiotherapy.  This study may answer the question regarding the need for radiotherapy in low risk pediatric Hodgkin's disease.  In conclusion, the value of RT for those with low risk disease still remains unclear, but children with intermediate and high risk disease should routinely be irradiated.