PDT and Synergy The Effects of Combination Treatment in the Lung

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					    PDT and Synergy:
The Effects of Combination
  Treatment in the Lung
      Carter JH Childs, MD
   Pulmonary and Critical Care
 Brody School of Medicine at ECU
   PDT’s Role in Treating
Advanced Stage Lung Cancer-a
Team Player or the Lone Wolf?
• To review the basis for PDT and other
  interventional therapies in advanced stage
  lung cancer.
• To review the synergistic effects between
  PDT and:
  – Chemotherapy.
  – Radiation Therapy.
  – Other interventional therapies.
 PDT Clinical Capabilities-Lung
• Early Disease
  – Carcinoma-in-situ
• Advanced Disease
  – Local regional palliation
  – Maintaining organ function
• Pleural disease
   Rationale for airway interventions in
        non-operable lung cancer

• Schmassman et al. AJG 1996; 91(4):654-659

           » 165 patients with acute biliary obstruction
           » Treated with plastic or metal stents
           » Dramatic survival advantage in reversing
             acute obstruction
           » Take home message: Maintaining normal
             organ physiology has a positive influence on
             outcomes in patients with malignancy.
        Rationale continued

• Cavaliere S. et al. Chest 1996:110:1536-1542

            » 13 year experience with 2008 patients, all
              with malignant airway obstructions.
            » Interventional modalities including Nd:YAG
              laser, Brachytherapy and Stent placement,
              patency was achieved in 93%.
            » Most had improved quality : decreased
              dyspnea, improved ABG’s, resolution of
              post-obstructive pneumonia's.
            » Mean airway patency was 102 days.
            Rationale continued

• Marasso A., et al. 1998 Thorax;53:10-109

            » 98 patients with 3b or 4 NSCCA were
              studied retrospectively.
            » 50 pts. treated first with ChemoRx, XRT,
              then interventional techniques.
            » 48 pts. treated first with interventional
              techniques, then ChemoRX and XRT.
            » Second group demonstrated longer mean
              survival (14 months compared to 5months).
         Rationale continued

• Marasso and Cavaliere: Take home message

           » Interventional techniques are excellent
             methods to achieve airway patency.

           » Maintaining airway patency may have a
             positive effect on lung physiology and
             performance status.

           » Survival may be influenced in non-operable
             lung cancer
  Interventional Pulmonology Techniques

• Bronchoscopy
   – Rigid bronchoscopy
   – Flexible bronchoscopy
• Tumor ablation/airway restoration techniques
   – Thermal
      • Nd:YAG laser
      • Endobronchial Cryotherapy
      • Endobronchial Electrocautery/APC
   – Mechanical
      • Stents/Balloons
      • Core out
      • Rotoblator
  Tumor Ablation-continued
– Non-thermal, Non-mechanical
  • Brachytherapy.
  • Photodynamic Therapy.
       Which one to Choose?
• Choice of interventional technique is based
  – Lesion
     • Size, Site, Significance, Single/Multiple, Type.
  – Patient’s status
  – Physician
     • Training, Comfort, Costs, Availability.
Lung Cancer: Palliation of Advanced
Airway Carcinoma
• Moghissi et al 1999: 100 pts with
  inoperable NSCCa were Tx with PDT
    • 82 % had previous chemo/XRT
    • Stages 3a to 4, Tx with 2 mg/kg photofrin,
      interstitial placement of fibers at 200J/cm2
    • No Tx related morbidity or mortality
    • At 8 weeks: ^PFT’s. ^Performance status,
      Obstruction form 85% to 18%
    • Mean survival 9 months, with 53% > 2 years
Lung Cancer: Palliation of Advanced
Airway Carcinoma
• McCaughan et al 1997: 152 pts with
  inoperable stage 3a to 4 NSSCa were Tx
  with PDT over 14 years
     • Both superficial and interstitial TX used, variable
       laser light doses were employed
     • Advocates treatment ASAP to any size lesions
     • No stats difference between efficacy of PDT and
       other tumor ablation modalities (YAG laser)
        Why choose just one?
• Multimodality therapy has a long history in
  – Multiple antibiotics for infectious diseases(esp.
    TB and HIV).
  – Cardiac “cocktail” for CAD/CHF.
  – Multi-agent chemotherapy for lung cancer.
  – Multidisciplinary approach to regionally
    advanced lung cancer.
 Rationale behind Multimodality
• Maximize the treatment effect by hitting the
  disease from multiple angles, while
  minimizing side effects by reducing the
  amounts of any single therapy.
   PDT, can be Synergistic with
• Chemotherapy.
• Radiation Therapy.
  – External Beam.
  – Internal (Brachytherapy).
• Other Interventional Therapies.
       Potential Mechanisms for
•   Blood supply to tumor.
•   Oxygen content of tumor.
•   Treatment field augmentation/definition.
•   Immunologic destruction of tumor.
•   ????????
      PDT and Chemotherapy
• Baas et al in 1996 studied PDT using
  Photophrin and it’s synergy with mitomycin
  C in patients with skin recurrences from
  breast cancer.
• 4 patients were given Photophrin and light
  was applied to their lesions on days 1-2, and
  the amount of energy needed to achieve a
  response was determined.
                Baas, et al, Br. J Cancer, 1996
     PDT and Chemo-continued
• On day 3, MMC was injected and light was
  applied 20 and 40 minutes later on areas not
  previously treated, at ½ of the previously noted
  light dose.
• Found equivalent responses between the two
• No differences in wound healing.
• Theory: PDT causes tissue hypoxia, which is
  further treated by MMC.

                   Baas, et al, Br. J Cancer, 1996
   PDT and Radiation Therapy
• Schaffer, et al studied Photophrin and other
  porphyrins in mice implanted with human
  bladder carcinoma cells treated with XRT.
• Only Photophrin had any significant effect,
  it reduced the doubling time of the cancer
  cells from 6.2 days to 10.9 days.
• Higher doses of RT (5 vs 15 Gy) did not
  improve this effect.
               Schaffer et al, J of Photochemistry
                    and Photobiology 2002
             PDT and XRT
• Madsen, et al studied PDT’s and XRT’s
  effects on Human Glioma Spheroids.
• Found that Photophrin was not a
  radiosensitizer by itself.
• Spheroids treated with both PDT and XRT
  had a larger fraction of apotototic cells.

               Madsen, et al, Photochemistry and
                     Photobiology, 2002
Fraction of cells in apoptosis as a function of treatment type

      Apoptotic Fraction





                                                                                                                      8 Gy + 150/50
                                                                                        PDT (150/50)

                                                                                                       8 Gy + 25/25
                                                                          PDT (25/25)
                                   + Control

                                               - Control

                                                                  16 Gy
                                                           8 Gy

                                   Madsen, et al, Photochemistry and
                                         Photobiology, 2002
       PDT and Brachytheapy
• Freitag, et al studied sequential PDT,
  followed by brachytherapy in patients with
  non-small cell carcinoma.
• 32 patients were treated initially with PDT,
  2 mg/kg photophrin, and 630nm light.
• 200J/cm for interstitial treatment, 100J/cm2
  for surface treatment.

                 Freitag, et al, Thorax 2004
      PDT and Brachytherapy-
• Brachytherapy was then performed, 5 treatments
  at 4 Gy = total dose of 20 Gy at a distance of 10
  mm from the source.
• Complete histological response rate of 97% was
  seen after the combination. (75% after PDT
• 1 patient (3%) had continued disease, and was
  treated with additional brachytherapy.
• No significant side effects requiring additional
                   Freitag, et al, Thorax 2004
             PDT and Stenting
• Stents can:
  –   Define treatment field.
  –   Make treatment field more uniform.
  –   Cause tumor death from radial traction.
  –   Control Bleeding
    PDT Combined with other Modalities
    PLACEMENT IN LUNG CANCER Imtiaz Khurshid, MB,BS, Ron R.
    Allison, MD, Rosa E. Cuenca, MD, Gordon H. Downie MD, Ph.D.
• Material and methods: five consecutive patients … 8
  self-expandable metal stents… One to twelve months
  post-placement, refractory tumor required direct ablation.
  PDT at a median dose of 100 joules/cm2
• Results: Serial bronchoscopies demonstrated uniform
  tumor ablation in all five patients. Random biopsies
  showed no viable tumor in any field, including tissue from
  behind metal. Examination of all eight stents revealed no
  displacement, fracture, deformity or occlusion of any
Too Much Synergy?
Multidisciplinary Approach

• Advantages
      • Clinical debate
      • Dosimetry, patient prognosis, oncologic options, light delivery
        options, wound care issues
      • Coverage
      • Patient support; financial, psychological, nutritional
      • United front
      • Opportunities for clinical research
• Disadvantages
      • Initial planning, up front energy, money and patience
              The Future
• Develop multidisciplinary approach at
• Develop a body of prospective randomized
  trials supporting PDT.
• Bring Dosimetry up to XRT standards.
• Continue to develop new drugs and devices.
• Continue to study PDT’s synergistic effects
  with other modalities.

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