A prospective trial of proton radiotherapy for retreatment of recurrent tumors

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 13, 2011

Presenter: John P. Plastaras, MD PhD
Presenter's Affiliation: The University of Pennsylvania


  • Retreatment with radiation therapy presents a very challenging problem for both radiation oncologists and patients.
  • Certain types of cancers, such as sarcoma, are more prone to local recurrence than others, and therefore more likely to need retreatment.
  • Often, surgical options are not available without considerable morbidity, and systemic therapy may be ineffective.
  • Treatment planning for a repeat course of radiation is complex, and complications from retreatment are common and often severe. Specific concerns are related to the precise region being treated, and the normal organs and tissues in close proximity.
  • Prior studies have documented an incidence of severe complications as high as 50% with re-irradiation (Indelicato, IJROBP 2009), however local control and improvement in overall survival are achievable for some patients (Salama, IJROBP 2006).
  • The advent of intensity modulated radiation therapy has improved the safety of retreatment, however many radiation oncologists remain reluctant to offer reirradiation, particularly for malignancies other than head & neck or gynecologic cancers.
  • Proton radiotherapy is ideally suited to address the complexity of reirradiation because it can be highly conformal due to the characteristic spread out Bragg peak
  • The ultimate goal of investigation of proton irradiation is to determine how long-term gains in local control and overall survival can be achieved in spite of the high risks of adverse side effects.
  • The purpose of this study is to assess the feasibility and safety of reirradiation with proton therapy for locally recurrent tumors.


  • Eligibility
    • Adults > 18 yrs age with KPS > 60 and life expectancy > 3 months
    • Histologically confirmed non-CNS primary solid tumor
    • Recurrence in or near prior radiation fields
    • Patients were excluded if the initial radiation therapy was delivered less than 3 months prior to the start of reirradiation
    • Approval by the University of Pennsylvania Proton Triage Committee was required for participation in the study
  • Patients were deemed infeasible if they:
    • Had unacceptable dosimetry with > 10% deviations from dose constraints to organs at risk
    • Could not tolerate 15% of treatment with proton radiotherapy
    • Could not complete all treatment within 10 days of estimated date of treatment completion
    • Had a treatment break greater than 5 days
  • The cohort was stratified into 10 groups by treatment site and treatment volume.
  • Low treatment volume was defined as < 250 cc except for head and neck, which was < 50 cc. High volume was defined as > 250 cc, except for head and neck, which was > 50 cc.
  • Primary objective: To establish feasibility and acute toxicity of reirradiation with proton radiotherapy
  • Secondary objective: To assess late complications, compare dose distributions between photon and proton therapy, and monitor local control, overall survival, and disease-specific survival
  • The first 12 patients enrolled were examined for 90 days after the last proton radiation treatment for acute toxicity (feasibility phase). Subsequently, the remaining 11 patients were enrolled (registration phase).


  • Twenty-three patients were enrolled from March 2010 to February 2011
  • Mean follow-up is 67 days, with data available for 17 of 23 patients
  • The following table illustrates the distribution of patients in each of ten cohorts


Low Volume

High Volume

Head and Neck















  • Organ at-risk constraints were designed based on data supporting higher maximum and median tolerances in the retreatment setting, particularly if > 6 months had elapsed between courses and if each course delivered a modest dose.
  • The spinal cord maximum allowed dose was 75 RBE, cauda equina maximum allowed dose was 100 RBE, liver median allowed dose was 50 RBE, and kidney median allowed dose was 30 RBE.
  • IMRT back-up plans were created for all patients for purposes of dosimetric analysis and comparison. Advantages in dose to small bowel, bladder, and femoral heads were seen with proton treatment plans.
  • Ninety-day toxicity data was available on most patients. Nearly all pts had some grade 1 or grade 2 toxicity probably/definitely related to proton radiation therapy, however only 2 patients experienced grade 4 toxicity.
  • There were 15 patients with grade 3 dermatitis (due to overlapping fields on skin) who required a break from treatment
  • Most side effects were managed conservatively
  • Unfortunately, two deaths occurred while on study
  • Unusual complications, such as neuritis in patients with recurrent pelvic tumors, were seen in 2 patients. Both were treated with anti-inflammatories and/or steroids, and both cases resolved within a week.
  • The need for adaptive proton therapy planning was also recognized, particularly in a patient who developed a pleural effusion while on treatment. The IMRT back-up plan was used until a new proton plan was approved. The patient continued with weekly CT simulations to ensure no further adjustments in the treatment plan were necessary.

Author’s Conclusions

  • Proton radiotherapy may permit relatively safe reirradiation in a variety of malignancies and locations.
  • The study has been accruing well, with an enrollment goal of 12 patients per strata.
  • Future goals include further dosimetric comparison, evaluation of acute and late toxicity, determination of freedom from symptoms, time to progression, and survival analysis.


  • Locally recurrent malignancies are highly complex and challenging cases.
  • While the cohort in this study represents a heterogeneous group of patients, and therefore more patients are needed to show true differences in outcomes, the study addresses feasibility and acute toxicity of re-irradiation.
  • Re-irradiation may offer a unique treatment modality to patients with locally recurrent disease and limited surgical and/or systemic options.
  • Although patients must be counseled extensively on the risks of reirradiation, some patients may ultimately benefit.
  • As more patients enroll on study and longer follow-up becomes available, this prospective trial may also redefine normal tissue tolerance.