- Email: [email protected]
When to Think of Surgery Plus or Minus Hipec for Peritoneal Carcinomatosis
Annals of Oncology 23 (Supplement 9): ix35–ix36, 2012 doi:10.1093/annonc/mds376
38IN
WHEN TO THINK OF SURGERY PLUS OR MINUS HIPEC FOR PERITONEAL CARCINOMATOSIS
D. Elias Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE
39IN
PRIORITIZING LIVER DIRECTED THERAPIES: SURGERY PLUS MINUS ABLATIVE TECHNIQUES
T.J.M. Ruers Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, NETHERLANDS Background: In patients with unresectable CRC LM there is an increasing tendency to combine systemic chemotherapy (CT) with local tumour destruction by RFA. Many retrospective studies indicate a possible benefit of this approach but definite proof was only obtained recently. Methods: In a randomised phase II intergroup study conducted by the EORTC the benefits of adding RFA to systemic CT was evaluated in patients with ≤9 unresectable CRC LM and no extrahepatic disease. Between 2002 and 2007, 119 pts were randomised between CT alone (59) or RFA plus CT (60) In both arms, CT consisted of 6 months FOLFOX (oxaliplatin 85mg/m2 and LV5FU2) plus, since October 2005, bevacizumab. The primary objective was to exclude a 30-months overall survival (OS) rate ≤38% with RFA + CT (Fleming Design). Safety and progression free survival (PFS) were secondary endpoints. Results: Baseline characteristics were similar between arms: 60% had ≥ 4 LM. 51 patients (85%) received CT in the RFA + CT arm and 59 (all) in the CT arm. The median number of CT cycles for patients who started CT was 10 in both arms. Toxicity profiles for CT were comparable between both arms. At a median follow up of 4.4 years, the 30-month OS rate was 61.7% (95% CI, 48.21-73.93) in the RFA +CT arm and 57.6% (44.07 – 70.39) in the CT arm. In eligible patients (RFA + CT; 57 pts, CT; 58 pts) these figures were 64.9% (95% CI, 51.13 – 77.09) and 56.9% (43.23 -69.84), respectively. The median PFS was 16.8 months in the RFA + CT arm (95% CI, 11.7-22.1) and 9.9 months (9.3-13.7) in the CT arm ( p = 0.025). The number of patients with first recurrence at the RFA site only was 5 (9%). 4 more patients (7%) had a first recurrence at a RFA site in combination with a recurrence elsewhere in the liver. In total 11 lesions (in 9 pt) out of 170 lesions treated by RFA recurred locally at first progression (6.5%). Conclusion: The EORTC CLOCC study is the first study that prospectively investigates the efficacy of RFA in combination with CT. The primary endpoint (30-months OS > 38%) was met, although also 30 months OS in the CT arm was much higher than 38%. RFA in combination with systemic therapy resulted in a significant prolongation of PFS of nearly 7 months. Local control of the lesions treated by RFA was high (93.5%). The study was not powered for OS.
40IN
INTEGRATING LIVER DIRECTED THERAPIES SUCH AS EMBOLIZATION AND IMRT INTO SYSTEMIC TREATMENT
D. Arnold, A. Stein Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center Hamburg (UCCH), Hamburg, GERMANY Metastatic colorectal cancer confined to the liver is a distinct entity characterized by different prognosis and a broad variety of available local treatment approaches. Beneath the classical, albeit continuously developed approaches like surgery, radio frequency ablation (RFA) and transarterial chemoembolization (TACE), local radiotherapy (delivered either by conventional, intensity modulated (IMRT) or stereotactic techniques (SBRT)) or selective intraarterial radiotherapy (SIRT) have been established in the last years. However, spread to the liver - even without extrahepatic manifestation - is the expression of systemic disease and thus urges for systemic control besides local ablation of existing metastases. For example, in liver metastases of mCRC, combination of systemic therapy and surgery or RFA has demonstrated beneficial impact. The sequence of systemic and local treatment is not well defined yet. Although individual patients tumour characteristics will strongly impact the choice of upfront treatment approach (e.g. single small metastases after a long disease free interval versus “upfront” large manifestations with high tumour burden), upfront systemic treatment followed by local treatment and postprocedural systemic treatment if feasible may generally bear several benefits: beside prompt control of systemic disease and potential extrahepatic spread, an interval with systemic chemotherapy will provide information about biology of metastatic cancer (e.g. rapid progression during chemotherapy) and will furthermore enable a more tailored approach for remaining lesions after treatment induced tumour shrinkage. Therefore, current treatment approaches for localized liver metastases are using sequential either neoadjuvant or periprocedural systemic and local treatment (e.g. RFA or surgery) or a concomitant approach with systemic treatment and local ablation in given intervals (e.g. TACE). Some local treatment approaches (e.g. SIRT or TACE) have demonstrated efficacy in malignant disease refractory to chemotherapy, but the possibly greater impact in earlier disease settings combined with or after systemic treatment have not been elucidated yet. Further research will need to determine the optimal combination and timing of local and systemic treatment approaches. Disclosure: D. Arnold: has received honoraria from Roche, sanofi-aventis, Merck Serono and Amgen, and research support from Roche and sanofi-aventis. A. Stein: received honoraria from Roche and Merck Serono
41IN
PURSUING THE NED CONDITION IN ADVANCED COLORECTAL CANCER: IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL DESIGN
A. Sobrero1, A.A. Cogoni2 1 Oncologia Medica, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY, 2Medical Oncology, “SS. Annunziata” Hospital, Sassari, ITALY Cure is the most relevant endpoint in cancer treatment. Next comes OS followed by DFS. Cure actually transits through DFS of sufficiently long duration to assure no relapse. Hence the value of DFS and its link to cure. The appeal of getting a NED state is so strong just because of this link. However its clinical value is dependent upon two factors: the toxicity of the multimodal intervention and the duration of the NED state. If the absence of disease lasts 12 months, giving the patient the hope for cure during this period, anybody may consider this a meaningful result; but if RFS lasts only 4 months and the “toll” paid by the patient has been substantial, this is clearly an irrelevant benefit. The heart of the issue is that whenever a treatment has the potential of rendering the patient NED, we should consider it, but at the same time we should not be deceived by this perspective if the chances of benefit are too remote, as it is in the great majority of cases. Therefore our strategic choice towards aggressive programs should not be guided by eradicating all visible tumor deposits (technical
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at University of Michigan on July 13, 2015
The occurrence of PC considerably worsens the prognosis of cancers. The classic treatment yields an overall survival of below 5% at 5years. However, in 20% of the cases, the disease is exclusively peritoneal, and a treatment combining complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has made it possible to achieve a major increase in 5-year overall survival. HIPEC is only proposed for treating residual infra-millimetric,PC and therefore, is logical and useful exclusively after CCRS. The current appropriate indications are as follows: For peritoneal pseudomyxomas (5-year OSR is above 80%). For colorectal PC (5-year OSR exceed 40%, with 18% of patients definitively cured). For mesotheliomas (the 5-year OSR is close to 58%) Current doubtful indications are as follows: For gastric tumours (the 5-year OSR is close to 15%). For ovarian cancers (OSR are very low when CCRS + HIPEC is used as a salvage treatment). For few rare PC (not detailed). Conclusion: CCRS + HIPEC are the current gold standard therapy for peritoneal extension of pseudomyxoma, mesotheliomas and colorectal PC, for selected patients. Disclosure: The author has declared no conflicts of interest.
Longer follow-will have to be awaited to eventually assess the effect of RFA on OS. Disclosure: All authors have declared no conflicts of interest.
abstracts
pursuing the ned condition in stage iv colorectal cancer
Annals of Oncology
feasibility), but by how high the chances are of obtaining a DFS of at least 6-12 months. There are a series of concepts and data guiding us between what is technically feasible and what is oncologically sound. First, curability of stage IV may be as high as 50% in very selected case series, but in unselected cases curability is extremely low, 1 to 4% in non-dedicated randomized trials. Second, whenever we “push” for very extensive surgery, the median RFS is < 12 and sometimes < 6 months. Third the disease might accelerate its course under the “shower” of wounds–related growth factors. Fourth, toxicity and costs of these approaches are very high. The contrast between the appeal (and sometimes
strong benefit) of the NED state and the questionable clinical value of this condition, when short lived, has implications on both clinical practice and the design of clinical trials. Wrong deviations from the classical palliative systemic treatment, pursuing miraculous results, but actually promoting clinical deterioration, are the most common consequences of these approaches in practice. Very high originality and relevance, but low intrinsic and external validity of the results are the classical features and limits of the trials designed and conducted in this field. Disclosure: All authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at University of Michigan on July 13, 2015
ix | Abstracts
Volume 23 | Supplement 9 | September 2012
38IN
WHEN TO THINK OF SURGERY PLUS OR MINUS HIPEC FOR PERITONEAL CARCINOMATOSIS
D. Elias Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE
39IN
PRIORITIZING LIVER DIRECTED THERAPIES: SURGERY PLUS MINUS ABLATIVE TECHNIQUES
T.J.M. Ruers Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, NETHERLANDS Background: In patients with unresectable CRC LM there is an increasing tendency to combine systemic chemotherapy (CT) with local tumour destruction by RFA. Many retrospective studies indicate a possible benefit of this approach but definite proof was only obtained recently. Methods: In a randomised phase II intergroup study conducted by the EORTC the benefits of adding RFA to systemic CT was evaluated in patients with ≤9 unresectable CRC LM and no extrahepatic disease. Between 2002 and 2007, 119 pts were randomised between CT alone (59) or RFA plus CT (60) In both arms, CT consisted of 6 months FOLFOX (oxaliplatin 85mg/m2 and LV5FU2) plus, since October 2005, bevacizumab. The primary objective was to exclude a 30-months overall survival (OS) rate ≤38% with RFA + CT (Fleming Design). Safety and progression free survival (PFS) were secondary endpoints. Results: Baseline characteristics were similar between arms: 60% had ≥ 4 LM. 51 patients (85%) received CT in the RFA + CT arm and 59 (all) in the CT arm. The median number of CT cycles for patients who started CT was 10 in both arms. Toxicity profiles for CT were comparable between both arms. At a median follow up of 4.4 years, the 30-month OS rate was 61.7% (95% CI, 48.21-73.93) in the RFA +CT arm and 57.6% (44.07 – 70.39) in the CT arm. In eligible patients (RFA + CT; 57 pts, CT; 58 pts) these figures were 64.9% (95% CI, 51.13 – 77.09) and 56.9% (43.23 -69.84), respectively. The median PFS was 16.8 months in the RFA + CT arm (95% CI, 11.7-22.1) and 9.9 months (9.3-13.7) in the CT arm ( p = 0.025). The number of patients with first recurrence at the RFA site only was 5 (9%). 4 more patients (7%) had a first recurrence at a RFA site in combination with a recurrence elsewhere in the liver. In total 11 lesions (in 9 pt) out of 170 lesions treated by RFA recurred locally at first progression (6.5%). Conclusion: The EORTC CLOCC study is the first study that prospectively investigates the efficacy of RFA in combination with CT. The primary endpoint (30-months OS > 38%) was met, although also 30 months OS in the CT arm was much higher than 38%. RFA in combination with systemic therapy resulted in a significant prolongation of PFS of nearly 7 months. Local control of the lesions treated by RFA was high (93.5%). The study was not powered for OS.
40IN
INTEGRATING LIVER DIRECTED THERAPIES SUCH AS EMBOLIZATION AND IMRT INTO SYSTEMIC TREATMENT
D. Arnold, A. Stein Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center Hamburg (UCCH), Hamburg, GERMANY Metastatic colorectal cancer confined to the liver is a distinct entity characterized by different prognosis and a broad variety of available local treatment approaches. Beneath the classical, albeit continuously developed approaches like surgery, radio frequency ablation (RFA) and transarterial chemoembolization (TACE), local radiotherapy (delivered either by conventional, intensity modulated (IMRT) or stereotactic techniques (SBRT)) or selective intraarterial radiotherapy (SIRT) have been established in the last years. However, spread to the liver - even without extrahepatic manifestation - is the expression of systemic disease and thus urges for systemic control besides local ablation of existing metastases. For example, in liver metastases of mCRC, combination of systemic therapy and surgery or RFA has demonstrated beneficial impact. The sequence of systemic and local treatment is not well defined yet. Although individual patients tumour characteristics will strongly impact the choice of upfront treatment approach (e.g. single small metastases after a long disease free interval versus “upfront” large manifestations with high tumour burden), upfront systemic treatment followed by local treatment and postprocedural systemic treatment if feasible may generally bear several benefits: beside prompt control of systemic disease and potential extrahepatic spread, an interval with systemic chemotherapy will provide information about biology of metastatic cancer (e.g. rapid progression during chemotherapy) and will furthermore enable a more tailored approach for remaining lesions after treatment induced tumour shrinkage. Therefore, current treatment approaches for localized liver metastases are using sequential either neoadjuvant or periprocedural systemic and local treatment (e.g. RFA or surgery) or a concomitant approach with systemic treatment and local ablation in given intervals (e.g. TACE). Some local treatment approaches (e.g. SIRT or TACE) have demonstrated efficacy in malignant disease refractory to chemotherapy, but the possibly greater impact in earlier disease settings combined with or after systemic treatment have not been elucidated yet. Further research will need to determine the optimal combination and timing of local and systemic treatment approaches. Disclosure: D. Arnold: has received honoraria from Roche, sanofi-aventis, Merck Serono and Amgen, and research support from Roche and sanofi-aventis. A. Stein: received honoraria from Roche and Merck Serono
41IN
PURSUING THE NED CONDITION IN ADVANCED COLORECTAL CANCER: IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL DESIGN
A. Sobrero1, A.A. Cogoni2 1 Oncologia Medica, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY, 2Medical Oncology, “SS. Annunziata” Hospital, Sassari, ITALY Cure is the most relevant endpoint in cancer treatment. Next comes OS followed by DFS. Cure actually transits through DFS of sufficiently long duration to assure no relapse. Hence the value of DFS and its link to cure. The appeal of getting a NED state is so strong just because of this link. However its clinical value is dependent upon two factors: the toxicity of the multimodal intervention and the duration of the NED state. If the absence of disease lasts 12 months, giving the patient the hope for cure during this period, anybody may consider this a meaningful result; but if RFS lasts only 4 months and the “toll” paid by the patient has been substantial, this is clearly an irrelevant benefit. The heart of the issue is that whenever a treatment has the potential of rendering the patient NED, we should consider it, but at the same time we should not be deceived by this perspective if the chances of benefit are too remote, as it is in the great majority of cases. Therefore our strategic choice towards aggressive programs should not be guided by eradicating all visible tumor deposits (technical
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at University of Michigan on July 13, 2015
The occurrence of PC considerably worsens the prognosis of cancers. The classic treatment yields an overall survival of below 5% at 5years. However, in 20% of the cases, the disease is exclusively peritoneal, and a treatment combining complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has made it possible to achieve a major increase in 5-year overall survival. HIPEC is only proposed for treating residual infra-millimetric,PC and therefore, is logical and useful exclusively after CCRS. The current appropriate indications are as follows: For peritoneal pseudomyxomas (5-year OSR is above 80%). For colorectal PC (5-year OSR exceed 40%, with 18% of patients definitively cured). For mesotheliomas (the 5-year OSR is close to 58%) Current doubtful indications are as follows: For gastric tumours (the 5-year OSR is close to 15%). For ovarian cancers (OSR are very low when CCRS + HIPEC is used as a salvage treatment). For few rare PC (not detailed). Conclusion: CCRS + HIPEC are the current gold standard therapy for peritoneal extension of pseudomyxoma, mesotheliomas and colorectal PC, for selected patients. Disclosure: The author has declared no conflicts of interest.
Longer follow-will have to be awaited to eventually assess the effect of RFA on OS. Disclosure: All authors have declared no conflicts of interest.
abstracts
pursuing the ned condition in stage iv colorectal cancer
Annals of Oncology
feasibility), but by how high the chances are of obtaining a DFS of at least 6-12 months. There are a series of concepts and data guiding us between what is technically feasible and what is oncologically sound. First, curability of stage IV may be as high as 50% in very selected case series, but in unselected cases curability is extremely low, 1 to 4% in non-dedicated randomized trials. Second, whenever we “push” for very extensive surgery, the median RFS is < 12 and sometimes < 6 months. Third the disease might accelerate its course under the “shower” of wounds–related growth factors. Fourth, toxicity and costs of these approaches are very high. The contrast between the appeal (and sometimes
strong benefit) of the NED state and the questionable clinical value of this condition, when short lived, has implications on both clinical practice and the design of clinical trials. Wrong deviations from the classical palliative systemic treatment, pursuing miraculous results, but actually promoting clinical deterioration, are the most common consequences of these approaches in practice. Very high originality and relevance, but low intrinsic and external validity of the results are the classical features and limits of the trials designed and conducted in this field. Disclosure: All authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at University of Michigan on July 13, 2015
ix | Abstracts
Volume 23 | Supplement 9 | September 2012