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Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy
lesions at 1 year after SRS was 86% in the lapatinib group and 69% in the non-lapatinib group (P < .001). This local control benefit within the brain is consistent with the results from a recent phase II study that revealed an objective CNS response rate of 65.9% in radiotherapy-naı¨ve patients with BC and BMs treated with lapatinib and capecitabine alone.2 The intriguing hypothesis that small-molecule tyrosine kinase inhibitors such as lapatinib may increase the efficacy of radiation in controlling BMs is an area of active
Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy Hennequin C, Bossard N, Servagi-Vernat S, et al (Hôpital Saint-Louis, France; Hospices Civils de Lyon, France; Centre hospitalier Universitaire de Besançon, France; et al) Int J Radiat Oncol Biol Phys 86:860-866, 2013
Purpose.dTo evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. Methods and Patients.dThis multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age < 75 and a Karnofsky index $70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no
158
investigation,3 and more studies are anticipated in the near future. S. L. McGovern, MD, PhD
References
2. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013; 14:64-71.
1. Taskar KS, Rudraraju V, Mittapalli RK, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012;29: 770-781.
3. Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31: 895-902.
chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. Results.dT total of 1334 patients were analyzed after a median followup of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P ¼ .8). According to stratification factors, we defined 6 subgroups (medial/ central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. Conclusions.dIn patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.
The question is whether elective radiation therapy (RT) of the nonremoved regional lymph nodes in patients with an involved axillary lymph node and/or a central or medially located breast tumor improves the outcome of breast cancer. The 10-year results of this French trial by Hennequin and colleagues seemingly do not support this hypothesis. However, in the meantime, 2 retrospective singleinstitution series1,2 demonstrated a benefit of IMN RT after long-term follow-up, and the results of both the National Cancer Institute of Canada (NCIC) and the European Organisation for Research and Treatment of Cancer (EORTC) trials have been presented at American Society of Clinical Oncology 20113 and European CanCer Organisation 2013,4 respectively, showing an improved disease-free and overall survival after IMN RT. At the 2014 European Breast Cancer Conference, the Danish national study comparing right-sided breast cancer treated with IMN RT with left-sided cancer treated without IMN RT was presented, confirming the benefit of IMN RT. Finally, the European Breast Cancer Trialists’ Collaborative
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
Group update5 on postmastectomy RT confirms the benefit of locoregional RT including the IMN irrespective of the number of axillary lymph nodes involved and of the administration of adjuvant systemic therapy. Taking all this together, the evidence is becoming overwhelming that subgroups of patientsdprobably the low-risk patients and the high-risk patients who received effective systemic therapyd might benefit from elective regional treatment without an increase in cardiovascular morbidity and toxicity, thanks to improved RT techniques. The question, then, is what explains the negative outcome of the French trial? To answer this, we have to recognize the possible drawbacks of this trial that might have influenced the results. First of all, patients who develop distant metastases can have protracted survival without a chance for cure, requiring a longer follow-up before the results on the level of overall survival become apparent. For this, it is a pity that the follow-up was not updated for this publication. Strikingly, the 5- and 10-year overall survival rates in the French trial were 10% and 20%, respectively, lower than those of the NCIC and EORTC trials despite an apparently similar patient population. Maybe the patient selection based on mastectomy indicates that it concerns a higher-risk group. The use of less effective systemic therapy in this trial, conducted in an era when systemic therapy was not yet routinely advised for patients with high-risk nodenegative disease and when chemotherapy and hormonal treatment were not yet routinely combined in patients with hormone-sensitive breast cancer with an indication for systemic
therapy, might explain these poorer results as well. All patients received chest wall and periclavicular RT. Therefore, the randomization was not between regional RT and no regional RT but concerned only a part of the regional lymph nodes that might, as recognized by the authors, not have been properly irradiated with the 2dimensional RT techniques that were used in this trial, which was conducted nearly 20 years agodand at the same time, patients randomized to receive no IMN RT might have unintentionally been (partially) treated on the IMNs as well, as shown by the quality assurance performed in the EORTC trial.6 The sample was too small for subgroup analyses as have been done. Also, the assumptions described in the discussion are quite difficult to follow, and it remains to be proven that the risk of IMN involvement could be estimated as stated. The published and presented results remain to be analyzed in further detail to determine which patient risk groups might benefit most from elective regional RT. Punglia and colleagues7 described the relationship between the anticipated benefit of local treatments and the effectiveness of systemic therapy. If we add the metastatic potential of the primary tumor to this model, we can anticipate that patients with either low-risk breast cancer or with higher-risk tumors who receive effective systemic therapy will benefit most from optimizing locoregional treatment.8 In the French trial, where overall survival was poor, we can thereby expect that the contribution of regional RT toward improving overall survival will be limited, whereas patients with a better
prognosis or who undergo more effective systemic therapy are more likely to benefit from regional RT, as seen in the other studies. Although this model can be used for all tumor types, it should be interpreted with caution because of a number of confounding factors, including the chance for effective salvage treatment after a recurrence as well as patient-related factors such as age and comorbid conditions that influence life expectancy. This model and the more recent results supporting the value of regional RT are in agreement with the spectrum hypothesis, which bridges the Halstedian hypothesis (sequential spread of cancer from the primary to the nodes and further into the body) to the Fisher hypothesis (breast cancer as a systemic disease). Therefore, current paradigms in prescribing locoregional and systemic treatments should be revised to better advise an optimized combination of treatments based not only on patientand tumor-related factors but also on the availability of effective treatment modalities for the specific cancer. One of the arguments to diminish the intensity of especially regional treatments like axillary clearance and regional RT is the relatively low frequency of regional recurrences. This low frequency is, however, due to a combination of the primary event analysis, the unavailability of a simple clinical evaluation of the draining lymph node areas, and the lack of dedicated evaluation of the lymph nodes after distant metastases are diagnosed because of the absence of any clinical relevance. Therefore, regional recurrences should not be considered a valuable endpoint in evaluating the usefulness of regional treatments. Awaiting the publications of the NCIC and EORTC trials, we should be mindful not to jeopardize the progress in outcomes that we have obtained over the past decades by jumping to
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
159
conclusions based on the results of trials such as this French trial.
I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. Eur J Cancer. 2013;49 [abstract BA2].
P. M. P. Poortmans, MD, PhD
References 1. Chang JS, Park W, Kim YB, et al. Long-term survival outcomes following internal mammary node irradiation in stage II-III breast cancer: results of a large retrospective study with 12-year follow-up. Int J Radiat Oncol Biol Phys. 2013;86:867-872. 2. Courdi A, Chamorey E, Ferrero JM, Hannoun-Le´vi JM. Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in nodenegative breast cancer patients. Radiother Oncol. 2013;108:259-265. 3. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage
Five-Year Outcomes, Cosmesis, and Toxicity With 3Dimensional Conformal External Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation Rodríguez N, Sanz X, Dengra J, et al (Hospital de la Esperanza, Barcelona, Spain) Int J Radiat Oncol Biol Phys 87:1051-1057, 2013
Purpose.dTo report the interim results from a study comparing the efficacy, toxicity, and cosmesis of breastconserving treatment with accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) using 3-dimensional conformal external beam radiation therapy (3D-CRT).
160
4. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol. 2011;29 [abstract LBA1003]. http://meetinglibrary. asco.org/content/79126-102. Accessed March 21, 2014. 5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials [published online ahead of print March 19, 2014]. Lancet. 2014. http://www.thelancet. com/journals/lancet/article/PIIS01406736%2814%2960488-8/abstract. Accessed March 21, 2014.
Methods and Materials.d102 patients with early-stage breast cancer who underwent breast-conserving surgery were randomized to receive either WBI (n ¼ 51) or APBI (n ¼ 51). In the WBI arm, 48 Gy was delivered to the whole breast in daily fractions of 2 Gy, with or without additional 10 Gy to the tumor bed. In the APBI arm, patients received 37.5 Gy in 3.75 Gy per fraction delivered twice daily. Toxicity results were scored according to the Radiation Therapy Oncology Group Common Toxicity Criteria. Skin elasticity was measured using a dedicated device (Multi-Skin-Test-Center MC-750-B2, CKelectronic-GmbH). Cosmetic results were assessed by the physician and the patients as good/excellent, regular, or poor. Results.dThe median follow-up time was 5 years. No local recurrences
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
6. Poortmans PM, Venselaar JL, Struikmans H, et al. The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage IeIII breast cancer. Int J Radiat Oncol Biol Phys. 2001;49:1399-1408. 7. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med. 2007; 356:2399-2405. 8. Poortmans P. Postmastectomy radiation in breast cancer with one to three involved lymph nodes: ending the debate [published online ahead of print March 19, 2014]. Lancet. 2014. http://www.thelancet.com/journals/ lancet/article/PIIS0140-6736%2814% 2960192-6/fulltext. Accessed March 21, 2014.
were observed. No significant differences in survival rates were found. APBI reduced acute side effects and radiation doses to healthy tissues compared with WBI (P < .01). Late skin toxicity was no worse than grade 2 in either group, without significant differences between the 2 groups. In the ipsilateral breast, the areas that received the highest doses (ie, the boost or quadrant) showed the greatest loss of elasticity. WBI resulted in a greater loss of elasticity in the high-dose area compared with APBI (P < .05). Physician assessment showed that >75% of patients in the APBI arm had excellent or good cosmesis, and these outcomes appear to be stable over time. The percentage of patients with excellent/good cosmetic results was similar in both groups.
Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy Hennequin C, Bossard N, Servagi-Vernat S, et al (Hôpital Saint-Louis, France; Hospices Civils de Lyon, France; Centre hospitalier Universitaire de Besançon, France; et al) Int J Radiat Oncol Biol Phys 86:860-866, 2013
Purpose.dTo evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. Methods and Patients.dThis multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age < 75 and a Karnofsky index $70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no
158
investigation,3 and more studies are anticipated in the near future. S. L. McGovern, MD, PhD
References
2. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013; 14:64-71.
1. Taskar KS, Rudraraju V, Mittapalli RK, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012;29: 770-781.
3. Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31: 895-902.
chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. Results.dT total of 1334 patients were analyzed after a median followup of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P ¼ .8). According to stratification factors, we defined 6 subgroups (medial/ central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. Conclusions.dIn patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.
The question is whether elective radiation therapy (RT) of the nonremoved regional lymph nodes in patients with an involved axillary lymph node and/or a central or medially located breast tumor improves the outcome of breast cancer. The 10-year results of this French trial by Hennequin and colleagues seemingly do not support this hypothesis. However, in the meantime, 2 retrospective singleinstitution series1,2 demonstrated a benefit of IMN RT after long-term follow-up, and the results of both the National Cancer Institute of Canada (NCIC) and the European Organisation for Research and Treatment of Cancer (EORTC) trials have been presented at American Society of Clinical Oncology 20113 and European CanCer Organisation 2013,4 respectively, showing an improved disease-free and overall survival after IMN RT. At the 2014 European Breast Cancer Conference, the Danish national study comparing right-sided breast cancer treated with IMN RT with left-sided cancer treated without IMN RT was presented, confirming the benefit of IMN RT. Finally, the European Breast Cancer Trialists’ Collaborative
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
Group update5 on postmastectomy RT confirms the benefit of locoregional RT including the IMN irrespective of the number of axillary lymph nodes involved and of the administration of adjuvant systemic therapy. Taking all this together, the evidence is becoming overwhelming that subgroups of patientsdprobably the low-risk patients and the high-risk patients who received effective systemic therapyd might benefit from elective regional treatment without an increase in cardiovascular morbidity and toxicity, thanks to improved RT techniques. The question, then, is what explains the negative outcome of the French trial? To answer this, we have to recognize the possible drawbacks of this trial that might have influenced the results. First of all, patients who develop distant metastases can have protracted survival without a chance for cure, requiring a longer follow-up before the results on the level of overall survival become apparent. For this, it is a pity that the follow-up was not updated for this publication. Strikingly, the 5- and 10-year overall survival rates in the French trial were 10% and 20%, respectively, lower than those of the NCIC and EORTC trials despite an apparently similar patient population. Maybe the patient selection based on mastectomy indicates that it concerns a higher-risk group. The use of less effective systemic therapy in this trial, conducted in an era when systemic therapy was not yet routinely advised for patients with high-risk nodenegative disease and when chemotherapy and hormonal treatment were not yet routinely combined in patients with hormone-sensitive breast cancer with an indication for systemic
therapy, might explain these poorer results as well. All patients received chest wall and periclavicular RT. Therefore, the randomization was not between regional RT and no regional RT but concerned only a part of the regional lymph nodes that might, as recognized by the authors, not have been properly irradiated with the 2dimensional RT techniques that were used in this trial, which was conducted nearly 20 years agodand at the same time, patients randomized to receive no IMN RT might have unintentionally been (partially) treated on the IMNs as well, as shown by the quality assurance performed in the EORTC trial.6 The sample was too small for subgroup analyses as have been done. Also, the assumptions described in the discussion are quite difficult to follow, and it remains to be proven that the risk of IMN involvement could be estimated as stated. The published and presented results remain to be analyzed in further detail to determine which patient risk groups might benefit most from elective regional RT. Punglia and colleagues7 described the relationship between the anticipated benefit of local treatments and the effectiveness of systemic therapy. If we add the metastatic potential of the primary tumor to this model, we can anticipate that patients with either low-risk breast cancer or with higher-risk tumors who receive effective systemic therapy will benefit most from optimizing locoregional treatment.8 In the French trial, where overall survival was poor, we can thereby expect that the contribution of regional RT toward improving overall survival will be limited, whereas patients with a better
prognosis or who undergo more effective systemic therapy are more likely to benefit from regional RT, as seen in the other studies. Although this model can be used for all tumor types, it should be interpreted with caution because of a number of confounding factors, including the chance for effective salvage treatment after a recurrence as well as patient-related factors such as age and comorbid conditions that influence life expectancy. This model and the more recent results supporting the value of regional RT are in agreement with the spectrum hypothesis, which bridges the Halstedian hypothesis (sequential spread of cancer from the primary to the nodes and further into the body) to the Fisher hypothesis (breast cancer as a systemic disease). Therefore, current paradigms in prescribing locoregional and systemic treatments should be revised to better advise an optimized combination of treatments based not only on patientand tumor-related factors but also on the availability of effective treatment modalities for the specific cancer. One of the arguments to diminish the intensity of especially regional treatments like axillary clearance and regional RT is the relatively low frequency of regional recurrences. This low frequency is, however, due to a combination of the primary event analysis, the unavailability of a simple clinical evaluation of the draining lymph node areas, and the lack of dedicated evaluation of the lymph nodes after distant metastases are diagnosed because of the absence of any clinical relevance. Therefore, regional recurrences should not be considered a valuable endpoint in evaluating the usefulness of regional treatments. Awaiting the publications of the NCIC and EORTC trials, we should be mindful not to jeopardize the progress in outcomes that we have obtained over the past decades by jumping to
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
159
conclusions based on the results of trials such as this French trial.
I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. Eur J Cancer. 2013;49 [abstract BA2].
P. M. P. Poortmans, MD, PhD
References 1. Chang JS, Park W, Kim YB, et al. Long-term survival outcomes following internal mammary node irradiation in stage II-III breast cancer: results of a large retrospective study with 12-year follow-up. Int J Radiat Oncol Biol Phys. 2013;86:867-872. 2. Courdi A, Chamorey E, Ferrero JM, Hannoun-Le´vi JM. Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in nodenegative breast cancer patients. Radiother Oncol. 2013;108:259-265. 3. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage
Five-Year Outcomes, Cosmesis, and Toxicity With 3Dimensional Conformal External Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation Rodríguez N, Sanz X, Dengra J, et al (Hospital de la Esperanza, Barcelona, Spain) Int J Radiat Oncol Biol Phys 87:1051-1057, 2013
Purpose.dTo report the interim results from a study comparing the efficacy, toxicity, and cosmesis of breastconserving treatment with accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) using 3-dimensional conformal external beam radiation therapy (3D-CRT).
160
4. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol. 2011;29 [abstract LBA1003]. http://meetinglibrary. asco.org/content/79126-102. Accessed March 21, 2014. 5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials [published online ahead of print March 19, 2014]. Lancet. 2014. http://www.thelancet. com/journals/lancet/article/PIIS01406736%2814%2960488-8/abstract. Accessed March 21, 2014.
Methods and Materials.d102 patients with early-stage breast cancer who underwent breast-conserving surgery were randomized to receive either WBI (n ¼ 51) or APBI (n ¼ 51). In the WBI arm, 48 Gy was delivered to the whole breast in daily fractions of 2 Gy, with or without additional 10 Gy to the tumor bed. In the APBI arm, patients received 37.5 Gy in 3.75 Gy per fraction delivered twice daily. Toxicity results were scored according to the Radiation Therapy Oncology Group Common Toxicity Criteria. Skin elasticity was measured using a dedicated device (Multi-Skin-Test-Center MC-750-B2, CKelectronic-GmbH). Cosmetic results were assessed by the physician and the patients as good/excellent, regular, or poor. Results.dThe median follow-up time was 5 years. No local recurrences
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 2 2014
6. Poortmans PM, Venselaar JL, Struikmans H, et al. The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage IeIII breast cancer. Int J Radiat Oncol Biol Phys. 2001;49:1399-1408. 7. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med. 2007; 356:2399-2405. 8. Poortmans P. Postmastectomy radiation in breast cancer with one to three involved lymph nodes: ending the debate [published online ahead of print March 19, 2014]. Lancet. 2014. http://www.thelancet.com/journals/ lancet/article/PIIS0140-6736%2814% 2960192-6/fulltext. Accessed March 21, 2014.
were observed. No significant differences in survival rates were found. APBI reduced acute side effects and radiation doses to healthy tissues compared with WBI (P < .01). Late skin toxicity was no worse than grade 2 in either group, without significant differences between the 2 groups. In the ipsilateral breast, the areas that received the highest doses (ie, the boost or quadrant) showed the greatest loss of elasticity. WBI resulted in a greater loss of elasticity in the high-dose area compared with APBI (P < .05). Physician assessment showed that >75% of patients in the APBI arm had excellent or good cosmesis, and these outcomes appear to be stable over time. The percentage of patients with excellent/good cosmetic results was similar in both groups.