ACOSG ZO531: Report on a Multicenter, Phase II Trial for Adjuvant Therapy of Resected Pancreatic Cancer Using Cisplatin, 5-FU, and Alpha-Interferon

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 2 de junio del 2008

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Presenter: Picozzi R.A.
Presenter's Affiliation: Virginia Mason Medical Center, Seattle Washington
Type of Session: Scientific

Background

  • Pancreatic cancer is the fourth leading cause of cancer death in the United States and in 2007, over 37,000 cases were diagnosed, and over 33,000 deaths documented (Jemal, CA Cancer J Clin, 2007). 
  • Surgery is the only curative treatment; however, most patients are unresectable at the time of diagnosis (~80%), and even in those who undergo complete resection, there are high rates of local recurrence (50-80%). 
  • Adjuvant therapy for resected pancreatic cancer remains suboptimal. Patients treated with 5-FU- based adjuvant therapy for pancreatic cancer have a median survival of 16-23 months. Meanwhile, 5-year overall survival remains poor at 10-20%.
  • The role of radiation in the post-operative setting remains controversial, with data both supporting its use (GITSG 9173; Kalser M.H. et al., Arch Surg, 1985) and refuting it (ESPAC-1; Neoptolemos J.P. et al., Lancet, 2001).
  • Clearly, better systemic agents are needed to improve local control and decrease the risk of distant metastasis.
  • Prior pre-clinical trials have suggested that alpha interferon may augment cisplatin’s effect and may act as a radiosensitizer. This was the rationale for combining alpha interferon, cisplatin, 5-FU and radiation.
  • A prior phase II study (Picozzi V.J. et al., ACSO Annual Meeting 2003) demonstrated that the use of alpha-interferon resulted in promising rates of local control and overall survival (OS) in patients with resected pancreatic cancer treated postoperatively with radiation, alpha interferon, cisplatin, and 5-FU. However, there was significant toxicity associated with this treatment with 70% of patients requiring an interruption in chemoradiation and 43% of patients being hospitalized.

Materials and Methods

  • Patient inclusion and exclusion criteria included:
    • Patients had to have a pancreatic cancer of the head of the pancreas
    • The pancreas cancer had to be histologically confirmed and no peri-ampullary tumors were included
    • Patients had to have an R1 or R0 resection
    • Patients had to have an ECOG performance status of 0 or 1
    • Patients had to have radiologic re-evaluation prior to adjuvant therapy
    • Patients had to have chemoradiation initiated within 56 days of surgery
  • Radiation was given to a total dose of 5040 cGy on days 1-38. Clinical tumor volumes (CTV) and planning tumor volumes (PTV)’s were approximately 40% smaller than standard fields used in prior Radiation Therapy Oncology Group (RTOG) studies (in an attempt to limit toxicity).
  • Chemotherapy was given as follows:
    • Cisplatin: 30 mg/m2 on days 1, 8, 15, 22, 29, and 36
    • 5-FU: 175 mg/m2 IV, continuous infusion on days 1-38
    • Alpha-Interferon: 3 x106 U/ m2 on Monday, Wednesday, and Friday during radiation (days 1-38, total of 17 doses)
    • After completion of chemoradiation, 5-FU was given IV via continuous infusion at a dose of 200 mg/m2 for weeks 11-16 and 19-24
  • There was a 4-6 week break between chemoradiation and the initiation of adjuvant chemotherapy. 
  • The primary endpoint of this study was overall survival (OS) at 18 months from registration (equivalent to ~20 months from surgery).  A finding of greater than 65% OS at 18 months was considered a positive result.
  • Secondary endpoints were toxicity, disease-free survival (DFS), local recurrence rate (LRR) and distant recurrence rate (DRR).

Results

  • Target accrual for this study was 93 patients; however, accrual was halted early at 89 patients due to high toxicity rates. Patients were accrued from 15 cancer centers
  • Median follow up was 27.1 months
  • Patient demographics and tumor characteristics:
    • The median age of all patients was 59 yo
    • ECOG 0 patients: 55%/ ECOG 1 patients: 45%
    • T3: 83%
    • Tumors greater than 3 cm: 51%
    • Poorly differentiated tumors: 46%
    • Node-positive patients: 73%
    • Positive margins: 25%
  • Survival data:
    • At last follow up, 49% of patients were alive
    • 20 month OS was 69%
    • 2-year OS was 58%
    • Median OS was 27.1 months
    • DFS was 14.1 months (95% CI= 12.2-21.4 months)
    • Local recurrence rate was 46%
    • Distant recurrence rate was 35%
  • Toxicity:
    • 96% of patients had grade 3 or 4 toxicity, the majority of which was grade 3.
    • Most common grade 3 and 4 toxicities were: anorexia 30%, dehydration 27%, diarrhea 25%, and nausea 36% 
    • There were no deaths related to toxicity
  • 80% of patients received at least 4,500 cGy of radiation. 56% of patients were able to begin the third cycle of chemotherapy.
  • Margin status (negative margins 31.8 months versus positive margins 18.8 months; (p=0.021)) and tumor grade (grade 1 or 2 31.7 months versus grade 3 22.3 months; (p=0.045)) were both significantly associated with median OS.
  • T-stage, nodal status, and size of the tumor were not found to be of prognostic value, which is similar to results from other studies.
  • Patients who began all treatment cycles had a median OS of 31.8 months (as compared to 27.1 months for the entire cohort of patients).

Author's Conclusions

  • This multi-center study achieved its primary endpoint of greater than 65% OS at 18 months. These results are consistent with prior single institution reports (Picozzi V.J. et al., ACSO Annual Meeting 2003).
  • Marginal status and grade were significantly associated with median OS.
  • OS for margin-positive patients was higher in the present study compared with prior reports.
  • Toxicity was significant, but potentially manageable with appropriate intervensions.
  • The inability of patients to receive the intended therapy had a negative impact on outcome.
  • Ways to increase successful delivery of therapy are needed to further develop this promising therapy.

Clinical/Scientific Implications

  • There are now three studies evaluating the efficacy of cisplatin, 5-FU, alpha interferon and radiation. These studies include the Virginia Mason study (Picozzi V.J. et al., ACSO Annual Meeting 2003), the CapRI study (Knaebel H.P. et al., BMC Cancer, 2005; presently under analysis) and the present study. Data is available for over 174 patients from these studies, and they have consistently demonstrated a 2-year OS of greater than 50%. The CapRI study is the only randomized trial, and results are pending. It is important to note that the patients in this study were highly selected, and there is the potential for bias regarding patient enrollment. 
  • The greatest problem with this regimen is the toxicity related to treatment, as seen now in multiple studies. Even with the use of smaller radiation fields in the present study there was still a high rate of toxicity. 96% of patients in the present study had grade 3 or 4 toxicity. The majority of these toxicities were related to anorexia and dehydration. It is unclear what supportive care patients received, such as whether feeding tubes were placed and used, the use of IV fluids, monitoring of patient weight during treatment, and use of pre-albumin levels. Without this information, it is difficult to know if there was adequate supportive care to get patients safely through treatment.  The inability to complete treatment was associated with worse outcome and this was likely affected by the high toxicity associated with treatment. However, despite this toxicity and the significant number of patients who could not complete therapy, the outcomes were quite good compared with historical controls. Hence, if the tolerability of this treatment could be improved, such as through better supportive care, outcomes might improve as well.   
  • Another way to manage toxicity is to determine which aspects of this combined treatment are improving outcomes. It is unclear which components of this regimen are causing the improvement in outcomes, and studies to determine if a certain component could be eliminated would greatly reduce toxicity (i.e. is the 5-FU really necessary? is cisplatin with abdominal radiation the best choice?).  Radiation therapy using protons, which have greater sparing of normal tissues, may also decrease toxicities. 
  • This trial is a phase II study with a highly selected group of patients, so it is hard to compare its outcomes from prior studies with more traditional adjuvant therapies. We await the results of the CapRI study, and so at present the addition of alpha interferon therapy remains promising but still investigational. 

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