Type II & III

To collect a large group of Types I, II and III PPB patients for event-free and overall survival analysis, the PPB/DICER1 Registry is enrolling participants on the new Treatment and Biology Registry protocol

PPB/DICER1 Registry Treatment Recommendations

PPB therapy choices are the decision of each institution. The Treatment and Biology Registry presents surgery and chemotherapy guidelines. Through the Treatment and Biology Registry protocol study it is anticipated that analysis of a group of similarly treated children with PPB will advance the knowledge of effective ways to treat PPB. The secured PPB Registry Treatment and Biology Registry Information Portal provides physicians further details for treating Types I, II and III PPB, including a copy of the Registry’s treatment protocol and consent forms.

The International PPB/DICER1 Registry is not a part of, nor funded by, any cooperative oncology group, although Children’s Oncology Group Rare Tumor Sub-Committee recognizes the Registry as a major collection of PPB cases.

Type II and III PPB are aggressive sarcomas with an overall prognosis of about 45-50% (see Registry Publications: Priest et al. 1997). A prognosis difference between Types II and III PPB has not been demonstrated. The Registry recommends the same, aggressive multimodal treatment for Types II and III PPB.

The secured PPB Registry Treatment and Biology Registry Information Portal provides physicians further details for treating Types I, II, and III PPB, including a copy of the Registry’s treatment protocol and consent forms.

Surgery - Types II and III PPB

This study recommends attempted initial tumor resection, if it can be accomplished. When this is not deemed possible, open biopsy is recommended. Multiple core needle biopsies may replace open biopsy. Fine-needle aspiration for cytology is not adequate.

When predominantly solid PPB is of moderate size, thoracotomy resections are recommended. Lobectomy or bilobectomy is recommended. Pre- or intra-operative rupture/spillage may occur, requiring piecemeal resection. Usually one lobe is unaffected and re-expands. Surgical margins should be sampled and marked for the pathologist. Sites of unresectable residual disease should be titanium clipped for radiographic and possible radiotherapy. Fresh tissue should be submitted to the laboratory for frozen section and for biology studies.

For very large lesions, pneumonectomy occasionally has been performed.

Neo-adjuvant and Adjuvant Chemotherapy - Types II and III PPB

Cures have been achieved with surgery and chemotherapy, with and without radiation therapy. There has never been a large prospective study of PPB therapy. It is estimated that 30-50 cases of Type I PPB and 40-60 cases of Types II and III PPB are diagnosed annually worldwide. Consultations among international pediatric sarcoma experts concluded that because of (1) the rarity of PPB, (2) regulatory complexity and (3) regulatory differences between countries, a prospective treatment study could not be organized.

Therefore, to collect a large group of Types I, II and III PPB patients for event-free and overall survival analysis, this project is organized as a “Treatment and Biology Registry” protocol for the collection of treatment data on patients for whom therapy decisions are made by each institution.

Historically, Types II and III PPB have been treated as sarcomas similar to rhabdomyosarcoma. For many years, attempted surgical extirpation was followed by various adjuvant therapies. More recently, because many PPBs are very large and because neo-adjuvant chemotherapy can reduce the volume of other tumors, PPB has been approached with biopsy, neo-adjuvant chemotherapy, extirpative surgery and further adjuvant therapies. In “biopsy-first” cases, chemotherapy may result in >90% volume reduction. Responses are seen after the first 2-4 courses of neo-adjuvant therapy and can be lost; anaplastic cells are the least responsive to chemotherapy. Surgery should be performed after 2-4 courses of neo-adjuvant therapy (unpublished IPPBR observations). No data is available to compare cure or metastasis outcomes for initial biopsy versus initial resection strategies.

In an unpublished 2006 analysis by the IPPBR, the chemotherapy of 137 Types II and III PPB patients was evaluated. This case population was comprised of 102 pathology-reviewed IPPBR cases, 16 cases reported by Kirsch, which were not differentiated as to Type II vs. III, (see "Pub Med" or Google Scholar: Kirsch et al. 2005) and 19 cases reported by Indolfi (see "Pub Med" or Google Scholar: Indolfi et al. 2007). There were 64 Type II cases, 52 Type III cases and 21 Type II/III NOS cases. This analysis suggests that vincristine, actinomycin D, ifosfamide and doxorubicin are more active in PPB than other agents.

Because the number of PPB patients worldwide is small and because there is insufficient data for stratification by prognostic group, the Registry staff and representatives from France, Germany, Italy, United Kingdom, and the United States met in 2006 to discuss treatment options. The majority of those present approved treating PPB Types II and III with a single-arm chemotherapy regimen. The IVADo (ifosfamide, doxorubicin, vincristine, and actinomycin D) regimen for 36 weeks was chosen because of the four chemotherapy agents involved and because the up-front dose intensity of IVADo may be especially useful in neo-adjuvant setting.

Since February 2007, when contacted by physicians treating PPB, the IPPBR has recommended IVADo therapy for Types II and III PPB patients. Forty-one patients have been treated through February 2011. The results are preliminary but responses and outcome so far suggest that IVADo is at least as useful as one could expect compared to heterogeneously-treated historical controls.

PPB Registry Recommendations for Chemotherapy for
Types II and III PPB

The secured PPB Registry Treatment and Biology Registry Information Portal provides physicians further details for treating Types I, II, and III PPB, including a copy of the Registry’s treatment protocol and consent forms.

Chemotherapy Response and Definitive or 2nd Look Surgery

Experience suggests that response to chemotherapy is prompt, and maximum response occurs after 2 - 4 courses of therapy. If the patient had a partial resection as initial surgery, we recommend repeat (2nd look) surgery and an attempt at complete resection (with sampling of resection margins) after 2 - 4 courses (approximately 10 - 12 weeks) of IVADo therapy. Also, in the neo-adjuvant setting, we recommend surgery and an attempt at complete resection (with sampling of resection margins) after 2 - 4 courses (approximately 10 - 12 weeks) of the therapy.

 

Chest radiographs and CT scans should be done after each course to assess response and/or continuing response.

If disease remains after week 10, consideration should be given to repeat thoracotomy (“3rd look”) and attempted complete resection after 2-3 further courses of chemotherapy. This study recommends up to three thoracotomies to attempt complete resection. Attempted resection times would be approximately Week 0, Week 10, and Week 19. If there is a complete radiographic response to chemotherapy, as has been rarely reported, we recommend surgery to resect any observable remainder of the primary site.

After definitive surgery and assuming no evidence of recurrence, chemotherapy should continue for the planned IVADo courses. Use of radiation is discussed below.

Intracavitary Chemotherapy or Radiotherapy

Types II and III PPB are often found at surgery to be extremely friable, hemorrhagic, and/or “necrotic”. Resection may be morselized or piecemeal and “spillage” is common. Whether this phenomenon contributes to recurrence is not known, but in Wilms’ tumor treatment, spillage leads to more intensive therapy and to the use of abdominal radiation.

Clinicians facing gross PPB spillage may want to consider intracavitary chemotherapy. Intracavitary therapy, especially cis-platinum, has been used quite extensively in medical oncology for pleural and peritoneal metastatic disease, and the doses and toxicities are well described. (See "Pub Med" or Google Scholar: Boyer et al. 1995, Brenner 1986, and Markman 2001.) Intracavitary (“topical”) therapy is useful only for small-volume surface disease: nodules less than 0.5 to 1.0 cm diameter. (See "Pub Med" or Google Scholar: Markman 2001.)

Intracavitary cis-platinum has been reported in three cases of PPB. (See "Pub Med" or Google Scholar: Boyer et al. 1995; Yang et al. 1997.) In one case (Type II), a recurrent nodule in the pleura was excised, and the patient then received 200 mg/M2 cis-platinum intrathoracically, 4200 cGy radiation, and systemic platinum and doxorubicin. The child is well 15 years later. In the second case (Type II), the child received intracavitary platinum at diagnosis for spillage, aggressive additional chemotherapy and is NED 9 years later [Boyer + unpublished data]. In the third case (Type II), a 29-month old had extensive disease in the right upper lobe and a pleural nodule. After lobectomy and nodulectomy, the child was given 10 mg cis-platinum intrathoracically in the operating room before closure. Post-operative systemic chemotherapy (VAC) was given for 3 months. The child was disease free at 3 years [Yang].

Intracavitary 32P, along with other therapies, has also been given for pleural disease in two Registry cases. One child received 32P at diagnosis for gross tumor spillage. He also received aggressive additional chemotherapy and thoracic radiation; at last follow up he was NED 48 months from diagnosis. The other child received 32P five months after diagnosis for recurrent pleural disease; he died 8 months later of CNS disease. Intraoperative brachytherapy has also been reported for control of residual intrathoracic disease (see "Pub Med" or Google Scholar: Nag et al. 2001) and for one case of intracerebral disease.

Chemotherapy for Recurrent PPB

Therapy for PPB that recurs after chemotherapy must be highly individualized. HDCT + ASCR has been attempted in several children and is summarized in the HDCT + ASCR Table. This table abstracts several cases treated by high-dose chemotherapy and ASCR. Some of these children have survived longer than 36 months, suggesting that ASCR appears to offer some promise from these small numbers.

Several children appear to have been successfully treated for CNS recurrence. Clinicians are encouraged to contact the Registry for data on treatment and outcome in CNS recurrence. A child in the literature was treated with high-dose cyclophosphamide and whole brain radiation (3000 cGy in 12 doses). (See "Pub Med" or Google Scholar; focus: survival of CNS metastasis.)

Radiation Therapy

Although there are no specific studies or case reports specifically supporting a curative role for radiation therapy in PPB radiation therapy should be considered for known, unresectable residual primary disease, after chemotherapy and aggressive attempts at surgical resection. In the published Registry series of 50 cases, statistical benefit to the use of radiation was not shown. Of the 16 children with Type III disease who received radiation therapy, 8 developed recurrences and 5 of those recurrences were in the radiation field.

Patients with Types II and III disease have been cured after surgery and chemotherapy, with and without radiation. The amount of radiation to the entire (or hemi) thorax is limited to 1200 - 1400 cGy due to lung toxicity. Use of anthracycline also poses limits.

The treating institution must individualize the use of radiation in PPB. The Registry recommends that radiation be strongly considered for sites of known residual disease after surgery, whether primary ablative surgery or surgery following neo-adjuvant chemotherapy. Doses given to PPB patients have been in the range of 1200 - 1400 cGy to a hemithorax with focal fields receiving 3000 - 5000 cGy. (See Registry Publications: Priest et al 1997.) If radiation is to be used, it is not known when it should be given. If radiation therapy is to be used during chemotherapy, doxorubicin and actinomycin D should be omitted during the radiation. If radiation to the mediastinum is to be used, doxorubicin cumulative total doses are adjusted as discussed above.

Intracavitary 32P has also been given for pleural disease in two Registry cases along with other therapies two Registry cases along with other therapies. One child received 32P at diagnosis for gross tumor spillage. He also received aggressive additional chemotherapy and thoracic radiation; he was NED 48 months from diagnosis. The other child received 32P five months after diagnosis for recurrent pleural disease; he died 8 months later of CNS disease.

Radiation therapy has commonly been used after surgery for CNS (cerebral parenchyma) metastasis.